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Impaired senses, especially smell, linked to dementia
new research suggests. The study, which included almost 1,800 participants, adds to emerging evidence that even mild levels of multisensory impairment are associated with accelerated cognitive aging, the researchers noted.
Clinicians should be aware of this link between sensory impairment and dementia risk, said lead author Willa Brenowitz, PhD, assistant professor, department of psychiatry and behavioral sciences, University of California, San Francisco. “Many of these impairments are treatable, or at least physicians can monitor them; and this can improve quality of life, even if it doesn’t improve dementia risk.”
The findings were published online July 12 in Alzheimer’s and Dementia.
Additive effects
Previous research has focused on the link between dementia and individual senses, but this new work is unique in that it focuses on the additive effects of multiple impairments in sensory function, said Dr. Brenowitz. The study included 1,794 dementia-free participants in their 70s from the Health, Aging and Body Composition study, a prospective cohort study of healthy Black and White men and women.
Researchers tested participants’ hearing using a pure tone average without hearing aids and vision using contrast sensitivity with glasses permitted. They also measured vibrations in the big toe to assess touch and had participants identify distinctive odors such as paint thinner, roses, lemons, and onions to assess smell.
A score of 0-3 was assigned based on sample quartiles for each of the four sensory functions. Individuals with the best quartile were assigned a score of 0 and those with the worst were assigned a score of 3.
The investigators added scores across all senses to create a summary score of multisensory function (0-12) and classified the participants into tertiles of good, medium, and poor. Individuals with a score of 0 would have good function in all senses, whereas those with 12 would have poor function in all senses. Those with medium scores could have a mix of impairments.
Participants with good multisensory function were more likely to be healthier than those with poor function. They were also significantly more likely to have completed high school (85.0% vs. 72.1%), were significantly less likely to have diabetes (16.9% vs. 27.9%), and were marginally less likely to have cardiovascular disease, high blood pressure, and history of stroke.
Investigators measured cognition using the Modified Mini-Mental State (3MS) examination, a test of global cognitive function, and the Digit Symbol Substitution Test (DSST), a measure of cognitive processing speed. Cognitive testing was carried out at the beginning of the study and repeated every other year.
Dementia was defined as the use of dementia medication, being hospitalized with dementia as a primary or secondary diagnosis, or having a 3MS score 1.5 standard deviations lower than the race-stratified Health ABC study baseline mean.
Over an average follow-up of 6.3 years, 18% of participants developed dementia.
Dose-response increase
Results showed that, with worsening multisensory function score, the risk for dementia increased in a dose-response manner. In models adjusted for demographics and health conditions, participants with a poor multisensory function score were more than twice as likely to develop dementia than those with a good score (hazard ratio, 2.05; 95% confidence interval, 1.50-2.81; P < .001). Those with a middle multisensory function score were 1.45 times more likely to develop dementia (HR, 1.45; 95% CI, 1.09-1.91; P < .001).
Even a 1-point worse multisensory function score was associated with a 14% higher risk for dementia (95% CI, 8%-21%), while a 4-point worse score was associated with 71% higher risk for dementia (95% CI, 38%-211%).
Smell was the sensory function most strongly associated with dementia risk. Participants whose sense of smell declined by 10% had a 19% higher risk for dementia versus a 1%-3% higher risk for declines in vision, hearing, and touch.
It is not clear why smell was a stronger determinant of dementia risk. However, loss of this sense is often considered to be a marker for Alzheimer’s disease “because it is closely linked with brain regions that are affected” in that disease, said Dr. Brenowitz.
However, that does not necessarily mean smell is more important than vision or hearing, she added. “Even if hearing and vision have a smaller contribution to dementia, they have a stronger potential for intervention.” The findings suggest “some additive or cumulative” effects for loss of the different senses. “There’s an association above and beyond those which can be attributed to individual sensory domains,” she said.
Frailty link
After including mobility, which is a potential mediator, estimates for the multisensory function score were slightly lower. “Walking speed is pretty strongly associated with dementia risk,” Dr. Brenowitz noted. Physical frailty might help explain the link between sensory impairment and dementia risk. “It’s not clear if that’s because people with dementia are declining or because people with frailty are especially vulnerable to dementia,” she said.
The researchers also assessed the role of social support, another potential mechanism by which sensory decline, especially in hearing and vision, could influence dementia risk. Although the study did not find substantial differences in social support measures, the investigators noted that questions assessing social support were limited in scope.
Interactions between multisensory function score and race, APOE e4 allele status, and sex were not significant.
Worsening multisensory function was also linked to faster annual rates of cognitive decline as measured by both the 3MS and DSST. Each 1-point worse score was associated with faster decline (P < .05), even after adjustment for demographics and health conditions.
Possible mechanisms
A number of possible mechanisms may explain the link between poor sensory function and dementia. It could be that neurodegeneration underlying dementia affects the senses, or vision and/or hearing loss leads to social isolation and poor mental health, which in turn could affect dementia risk, the researchers wrote. It also is possible that cardiovascular disease or diabetes affect both dementia risk and sensory impairment.
Dr. Brenowitz noted that, because cognitive tests rely on a certain degree of vision and hearing, impairment of these senses may complicate such tests. Still to be determined is whether correcting sensory impairments, such as wearing corrective lenses or hearing aids, affects dementia risk.
Meanwhile, it might be a good idea to more regularly check sensory function, especially vision and hearing, the researchers suggested. These functions affect various aspects of health and can be assessed rather easily. However, because smell is so strongly associated with dementia risk, Dr. Brenowitz said she would like to see it also become “part of a screening tool.”
A possible study limitation cited was that the researchers checked sensory function only once. “Most likely, some of these would change over time, but at least it captured sensory function at one point,” Dr. Brenowitz said.
“Sheds further light”
Commenting on the study, Jo V. Rushworth, PhD, associate professor and national teaching fellow, De Montfort University Leicester (England), said it “sheds further light on the emerging links” between multisensory impairment and cognitive decline leading to dementia. “The authors show that people with even mild loss of function in various senses are more likely to develop cognitive impairment.”
Dr. Rushworth was not involved with the study but has done research in the area.
The current results suggest that measuring patients’ hearing, vision, sense of smell, and touch might “flag at-risk groups” who could be targeted for dementia prevention strategies, Dr. Rushworth noted. Such tests are noninvasive and potentially less distressing than other methods of diagnosing dementia. “Importantly, the relatively low cost and simplicity of sensory tests offer the potential for more frequent testing and the use of these methods in areas of the world where medical facilities and resources are limited.”
This new study raises the question of whether the observed sensory impairments are a cause or an effect of dementia, Dr. Rushworth noted. “As the authors suggest, decreased sensory function can lead to a decrease in social engagement, mobility, and other factors which would usually contribute to counteracting cognitive decline.”
The study raises other questions, too, said Dr. Rushworth. She noted that the participants who experienced more severe sensory impairments were, on average, 2 years older than those with the least impairments. “To what degree were the observed sensory deficits linked to normal aging rather than dementia?”
As well, Dr. Rushworth pointed out that the molecular mechanisms that “kick-start” dementia are believed to occur in midlife – so possibly at an age younger than the study participants. “Do younger people of a ‘predementia’ age range display multisensory impairments?”
Because study participants could wear glasses during vision tests but were not allowed to wear hearing aids for the hearing tests, further standardization of sensory impairment is required, Dr. Rushworth said.
“Future studies will be essential in determining the value of clinical measurement of multisensory impairment as a possible dementia indicator and prevention strategy,” she concluded.
The study was funded by the National Institute on Aging, the National Institute of Nursing Research, and the Alzheimer’s Association. Dr. Brenowitz and Dr. Rushworth have reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
new research suggests. The study, which included almost 1,800 participants, adds to emerging evidence that even mild levels of multisensory impairment are associated with accelerated cognitive aging, the researchers noted.
Clinicians should be aware of this link between sensory impairment and dementia risk, said lead author Willa Brenowitz, PhD, assistant professor, department of psychiatry and behavioral sciences, University of California, San Francisco. “Many of these impairments are treatable, or at least physicians can monitor them; and this can improve quality of life, even if it doesn’t improve dementia risk.”
The findings were published online July 12 in Alzheimer’s and Dementia.
Additive effects
Previous research has focused on the link between dementia and individual senses, but this new work is unique in that it focuses on the additive effects of multiple impairments in sensory function, said Dr. Brenowitz. The study included 1,794 dementia-free participants in their 70s from the Health, Aging and Body Composition study, a prospective cohort study of healthy Black and White men and women.
Researchers tested participants’ hearing using a pure tone average without hearing aids and vision using contrast sensitivity with glasses permitted. They also measured vibrations in the big toe to assess touch and had participants identify distinctive odors such as paint thinner, roses, lemons, and onions to assess smell.
A score of 0-3 was assigned based on sample quartiles for each of the four sensory functions. Individuals with the best quartile were assigned a score of 0 and those with the worst were assigned a score of 3.
The investigators added scores across all senses to create a summary score of multisensory function (0-12) and classified the participants into tertiles of good, medium, and poor. Individuals with a score of 0 would have good function in all senses, whereas those with 12 would have poor function in all senses. Those with medium scores could have a mix of impairments.
Participants with good multisensory function were more likely to be healthier than those with poor function. They were also significantly more likely to have completed high school (85.0% vs. 72.1%), were significantly less likely to have diabetes (16.9% vs. 27.9%), and were marginally less likely to have cardiovascular disease, high blood pressure, and history of stroke.
Investigators measured cognition using the Modified Mini-Mental State (3MS) examination, a test of global cognitive function, and the Digit Symbol Substitution Test (DSST), a measure of cognitive processing speed. Cognitive testing was carried out at the beginning of the study and repeated every other year.
Dementia was defined as the use of dementia medication, being hospitalized with dementia as a primary or secondary diagnosis, or having a 3MS score 1.5 standard deviations lower than the race-stratified Health ABC study baseline mean.
Over an average follow-up of 6.3 years, 18% of participants developed dementia.
Dose-response increase
Results showed that, with worsening multisensory function score, the risk for dementia increased in a dose-response manner. In models adjusted for demographics and health conditions, participants with a poor multisensory function score were more than twice as likely to develop dementia than those with a good score (hazard ratio, 2.05; 95% confidence interval, 1.50-2.81; P < .001). Those with a middle multisensory function score were 1.45 times more likely to develop dementia (HR, 1.45; 95% CI, 1.09-1.91; P < .001).
Even a 1-point worse multisensory function score was associated with a 14% higher risk for dementia (95% CI, 8%-21%), while a 4-point worse score was associated with 71% higher risk for dementia (95% CI, 38%-211%).
Smell was the sensory function most strongly associated with dementia risk. Participants whose sense of smell declined by 10% had a 19% higher risk for dementia versus a 1%-3% higher risk for declines in vision, hearing, and touch.
It is not clear why smell was a stronger determinant of dementia risk. However, loss of this sense is often considered to be a marker for Alzheimer’s disease “because it is closely linked with brain regions that are affected” in that disease, said Dr. Brenowitz.
However, that does not necessarily mean smell is more important than vision or hearing, she added. “Even if hearing and vision have a smaller contribution to dementia, they have a stronger potential for intervention.” The findings suggest “some additive or cumulative” effects for loss of the different senses. “There’s an association above and beyond those which can be attributed to individual sensory domains,” she said.
Frailty link
After including mobility, which is a potential mediator, estimates for the multisensory function score were slightly lower. “Walking speed is pretty strongly associated with dementia risk,” Dr. Brenowitz noted. Physical frailty might help explain the link between sensory impairment and dementia risk. “It’s not clear if that’s because people with dementia are declining or because people with frailty are especially vulnerable to dementia,” she said.
The researchers also assessed the role of social support, another potential mechanism by which sensory decline, especially in hearing and vision, could influence dementia risk. Although the study did not find substantial differences in social support measures, the investigators noted that questions assessing social support were limited in scope.
Interactions between multisensory function score and race, APOE e4 allele status, and sex were not significant.
Worsening multisensory function was also linked to faster annual rates of cognitive decline as measured by both the 3MS and DSST. Each 1-point worse score was associated with faster decline (P < .05), even after adjustment for demographics and health conditions.
Possible mechanisms
A number of possible mechanisms may explain the link between poor sensory function and dementia. It could be that neurodegeneration underlying dementia affects the senses, or vision and/or hearing loss leads to social isolation and poor mental health, which in turn could affect dementia risk, the researchers wrote. It also is possible that cardiovascular disease or diabetes affect both dementia risk and sensory impairment.
Dr. Brenowitz noted that, because cognitive tests rely on a certain degree of vision and hearing, impairment of these senses may complicate such tests. Still to be determined is whether correcting sensory impairments, such as wearing corrective lenses or hearing aids, affects dementia risk.
Meanwhile, it might be a good idea to more regularly check sensory function, especially vision and hearing, the researchers suggested. These functions affect various aspects of health and can be assessed rather easily. However, because smell is so strongly associated with dementia risk, Dr. Brenowitz said she would like to see it also become “part of a screening tool.”
A possible study limitation cited was that the researchers checked sensory function only once. “Most likely, some of these would change over time, but at least it captured sensory function at one point,” Dr. Brenowitz said.
“Sheds further light”
Commenting on the study, Jo V. Rushworth, PhD, associate professor and national teaching fellow, De Montfort University Leicester (England), said it “sheds further light on the emerging links” between multisensory impairment and cognitive decline leading to dementia. “The authors show that people with even mild loss of function in various senses are more likely to develop cognitive impairment.”
Dr. Rushworth was not involved with the study but has done research in the area.
The current results suggest that measuring patients’ hearing, vision, sense of smell, and touch might “flag at-risk groups” who could be targeted for dementia prevention strategies, Dr. Rushworth noted. Such tests are noninvasive and potentially less distressing than other methods of diagnosing dementia. “Importantly, the relatively low cost and simplicity of sensory tests offer the potential for more frequent testing and the use of these methods in areas of the world where medical facilities and resources are limited.”
This new study raises the question of whether the observed sensory impairments are a cause or an effect of dementia, Dr. Rushworth noted. “As the authors suggest, decreased sensory function can lead to a decrease in social engagement, mobility, and other factors which would usually contribute to counteracting cognitive decline.”
The study raises other questions, too, said Dr. Rushworth. She noted that the participants who experienced more severe sensory impairments were, on average, 2 years older than those with the least impairments. “To what degree were the observed sensory deficits linked to normal aging rather than dementia?”
As well, Dr. Rushworth pointed out that the molecular mechanisms that “kick-start” dementia are believed to occur in midlife – so possibly at an age younger than the study participants. “Do younger people of a ‘predementia’ age range display multisensory impairments?”
Because study participants could wear glasses during vision tests but were not allowed to wear hearing aids for the hearing tests, further standardization of sensory impairment is required, Dr. Rushworth said.
“Future studies will be essential in determining the value of clinical measurement of multisensory impairment as a possible dementia indicator and prevention strategy,” she concluded.
The study was funded by the National Institute on Aging, the National Institute of Nursing Research, and the Alzheimer’s Association. Dr. Brenowitz and Dr. Rushworth have reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
new research suggests. The study, which included almost 1,800 participants, adds to emerging evidence that even mild levels of multisensory impairment are associated with accelerated cognitive aging, the researchers noted.
Clinicians should be aware of this link between sensory impairment and dementia risk, said lead author Willa Brenowitz, PhD, assistant professor, department of psychiatry and behavioral sciences, University of California, San Francisco. “Many of these impairments are treatable, or at least physicians can monitor them; and this can improve quality of life, even if it doesn’t improve dementia risk.”
The findings were published online July 12 in Alzheimer’s and Dementia.
Additive effects
Previous research has focused on the link between dementia and individual senses, but this new work is unique in that it focuses on the additive effects of multiple impairments in sensory function, said Dr. Brenowitz. The study included 1,794 dementia-free participants in their 70s from the Health, Aging and Body Composition study, a prospective cohort study of healthy Black and White men and women.
Researchers tested participants’ hearing using a pure tone average without hearing aids and vision using contrast sensitivity with glasses permitted. They also measured vibrations in the big toe to assess touch and had participants identify distinctive odors such as paint thinner, roses, lemons, and onions to assess smell.
A score of 0-3 was assigned based on sample quartiles for each of the four sensory functions. Individuals with the best quartile were assigned a score of 0 and those with the worst were assigned a score of 3.
The investigators added scores across all senses to create a summary score of multisensory function (0-12) and classified the participants into tertiles of good, medium, and poor. Individuals with a score of 0 would have good function in all senses, whereas those with 12 would have poor function in all senses. Those with medium scores could have a mix of impairments.
Participants with good multisensory function were more likely to be healthier than those with poor function. They were also significantly more likely to have completed high school (85.0% vs. 72.1%), were significantly less likely to have diabetes (16.9% vs. 27.9%), and were marginally less likely to have cardiovascular disease, high blood pressure, and history of stroke.
Investigators measured cognition using the Modified Mini-Mental State (3MS) examination, a test of global cognitive function, and the Digit Symbol Substitution Test (DSST), a measure of cognitive processing speed. Cognitive testing was carried out at the beginning of the study and repeated every other year.
Dementia was defined as the use of dementia medication, being hospitalized with dementia as a primary or secondary diagnosis, or having a 3MS score 1.5 standard deviations lower than the race-stratified Health ABC study baseline mean.
Over an average follow-up of 6.3 years, 18% of participants developed dementia.
Dose-response increase
Results showed that, with worsening multisensory function score, the risk for dementia increased in a dose-response manner. In models adjusted for demographics and health conditions, participants with a poor multisensory function score were more than twice as likely to develop dementia than those with a good score (hazard ratio, 2.05; 95% confidence interval, 1.50-2.81; P < .001). Those with a middle multisensory function score were 1.45 times more likely to develop dementia (HR, 1.45; 95% CI, 1.09-1.91; P < .001).
Even a 1-point worse multisensory function score was associated with a 14% higher risk for dementia (95% CI, 8%-21%), while a 4-point worse score was associated with 71% higher risk for dementia (95% CI, 38%-211%).
Smell was the sensory function most strongly associated with dementia risk. Participants whose sense of smell declined by 10% had a 19% higher risk for dementia versus a 1%-3% higher risk for declines in vision, hearing, and touch.
It is not clear why smell was a stronger determinant of dementia risk. However, loss of this sense is often considered to be a marker for Alzheimer’s disease “because it is closely linked with brain regions that are affected” in that disease, said Dr. Brenowitz.
However, that does not necessarily mean smell is more important than vision or hearing, she added. “Even if hearing and vision have a smaller contribution to dementia, they have a stronger potential for intervention.” The findings suggest “some additive or cumulative” effects for loss of the different senses. “There’s an association above and beyond those which can be attributed to individual sensory domains,” she said.
Frailty link
After including mobility, which is a potential mediator, estimates for the multisensory function score were slightly lower. “Walking speed is pretty strongly associated with dementia risk,” Dr. Brenowitz noted. Physical frailty might help explain the link between sensory impairment and dementia risk. “It’s not clear if that’s because people with dementia are declining or because people with frailty are especially vulnerable to dementia,” she said.
The researchers also assessed the role of social support, another potential mechanism by which sensory decline, especially in hearing and vision, could influence dementia risk. Although the study did not find substantial differences in social support measures, the investigators noted that questions assessing social support were limited in scope.
Interactions between multisensory function score and race, APOE e4 allele status, and sex were not significant.
Worsening multisensory function was also linked to faster annual rates of cognitive decline as measured by both the 3MS and DSST. Each 1-point worse score was associated with faster decline (P < .05), even after adjustment for demographics and health conditions.
Possible mechanisms
A number of possible mechanisms may explain the link between poor sensory function and dementia. It could be that neurodegeneration underlying dementia affects the senses, or vision and/or hearing loss leads to social isolation and poor mental health, which in turn could affect dementia risk, the researchers wrote. It also is possible that cardiovascular disease or diabetes affect both dementia risk and sensory impairment.
Dr. Brenowitz noted that, because cognitive tests rely on a certain degree of vision and hearing, impairment of these senses may complicate such tests. Still to be determined is whether correcting sensory impairments, such as wearing corrective lenses or hearing aids, affects dementia risk.
Meanwhile, it might be a good idea to more regularly check sensory function, especially vision and hearing, the researchers suggested. These functions affect various aspects of health and can be assessed rather easily. However, because smell is so strongly associated with dementia risk, Dr. Brenowitz said she would like to see it also become “part of a screening tool.”
A possible study limitation cited was that the researchers checked sensory function only once. “Most likely, some of these would change over time, but at least it captured sensory function at one point,” Dr. Brenowitz said.
“Sheds further light”
Commenting on the study, Jo V. Rushworth, PhD, associate professor and national teaching fellow, De Montfort University Leicester (England), said it “sheds further light on the emerging links” between multisensory impairment and cognitive decline leading to dementia. “The authors show that people with even mild loss of function in various senses are more likely to develop cognitive impairment.”
Dr. Rushworth was not involved with the study but has done research in the area.
The current results suggest that measuring patients’ hearing, vision, sense of smell, and touch might “flag at-risk groups” who could be targeted for dementia prevention strategies, Dr. Rushworth noted. Such tests are noninvasive and potentially less distressing than other methods of diagnosing dementia. “Importantly, the relatively low cost and simplicity of sensory tests offer the potential for more frequent testing and the use of these methods in areas of the world where medical facilities and resources are limited.”
This new study raises the question of whether the observed sensory impairments are a cause or an effect of dementia, Dr. Rushworth noted. “As the authors suggest, decreased sensory function can lead to a decrease in social engagement, mobility, and other factors which would usually contribute to counteracting cognitive decline.”
The study raises other questions, too, said Dr. Rushworth. She noted that the participants who experienced more severe sensory impairments were, on average, 2 years older than those with the least impairments. “To what degree were the observed sensory deficits linked to normal aging rather than dementia?”
As well, Dr. Rushworth pointed out that the molecular mechanisms that “kick-start” dementia are believed to occur in midlife – so possibly at an age younger than the study participants. “Do younger people of a ‘predementia’ age range display multisensory impairments?”
Because study participants could wear glasses during vision tests but were not allowed to wear hearing aids for the hearing tests, further standardization of sensory impairment is required, Dr. Rushworth said.
“Future studies will be essential in determining the value of clinical measurement of multisensory impairment as a possible dementia indicator and prevention strategy,” she concluded.
The study was funded by the National Institute on Aging, the National Institute of Nursing Research, and the Alzheimer’s Association. Dr. Brenowitz and Dr. Rushworth have reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Plasma exchange is ‘encouraging’ as a novel Alzheimer’s disease treatment
Results from the phase 2b/3 AMBAR study showed that the treatment, which aims to remove amyloid-beta (Abeta) from plasma, was associated with a 60% decrease in functional and cognitive decline in patients with moderate Alzheimer’s disease.
The reduction in cognitive decline uncovered by the study is more striking than that reported for other investigational treatments targeting Abeta, such as monoclonal antibodies, said coinvestigator Antonio Páez, MD, medical director of the AMBAR program, Alzheimer’s Research Group, Grifols, Barcelona.
The results “open a new path for the development of plasma protein replacement therapies not only in Alzheimer’s disease but also in other degenerative diseases that we are planning to investigate,” Dr. Páez said.
The findings were presented at the virtual annual meeting of the Alzheimer’s Association International Conference and were simultaneously published in Alzheimer’s and Dementia.
Removing amyloid
Plasma exchange treatments, which have been available for several decades, are used to treat a range of neurologic, immunologic, and metabolic disorders. The treatment involves plasmapheresis, whereby plasma is separated from blood cells (red blood cells, white blood cells, platelets, etc) and toxic substances are removed. The albumin in plasma, to which plasma Abeta is bound, is replaced with a fresh commercial albumin product made from plasma from healthy donors.
“Our initial hypothesis was that, by removing albumin together with Abeta and substituting it with newer albumin periodically, we may be removing Abeta from the cerebrospinal fluid and eventually from the brain,” Dr. Páez said.
The AMBAR study included 347 men and women aged 55-85 years with probable Alzheimer’s disease dementia who were enrolled at 41 sites in Spain and the United States. All were diagnosed with mild Alzheimer’s disease, as shown by a baseline Mini-Mental State Examination score of 22-26, or moderate Alzheimer’s disease, having a baseline MMSE score of 18-21.
Investigators randomly assigned the participants to four groups; one group received placebo, and each of the other three treatment arms received different doses of albumin and intravenous immunoglobulin (IVIg) replacement.
During the first 6-week study phase, patients received weekly sham or conventional plasma exchange treatments of 2.5-3 liters of plasma, which Dr. Páez referred to as the “intensive-treatment phase to remove as much Abeta as possible.”
This was followed by a 12-month maintenance phase, which involved monthly low-volume (700-800 mL) plasma exchange or sham treatments.
Although the volume of plasma removed was the same in all three active-treatment groups, the amount of albumin and IVIg that was subsequently replaced varied. In one group, the same amount of albumin and IVIg that was removed was replaced; in another, half the amount removed was replaced; and in the third, only albumin was replaced.
The researchers collected cerebrospinal fluid (CSF) samples at baseline and after each treatment period. They assessed Abeta40, Abeta42, total tau, and phosphorylated-tau biomarkers.
The two primary outcomes were change from baseline to 14 months in scores on the Alzheimer’s Disease Cooperative Study–Activities of Daily Living (ADCS-ADL) scale and the Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog).
Symptom reduction
Results showed a reduction in the progression of symptoms in the plasma exchange–treated patients for both primary endpoints.
The ADCS-ADL showed 52% less decline in the plasma exchange–treated group, compared with the placebo group (P = .03); the ADAS-Cog showed 66% less decline (P = 0.06). In the moderate group, both endpoints showed 61% less decline (P = .002 and .05, respectively).
There were no clear differences between the three active-treatment groups, “suggesting that any of them could be considered for further investigation,” said Dr. Páez.
Differences in baseline demographic characteristics did not appear to have an influence on the outcomes. ADAS-Cog was more than twice as effective as some candidate monoclonal antibodies targeting Abeta that are being investigated for Alzheimer’s disease, Dr. Páez noted.
Although the plasma exchange approach is relatively invasive, so too are monoclonal antibody therapies that are infused intravenously through a pump, he said. In addition, a low-volume plasma exchange maintenance treatment takes less than 2 hours, which is on a par with some monoclonal antibody treatments.
Key secondary outcomes
For both primary outcomes, changes were found in those with moderate but not mild Alzheimer’s disease, possibly because the ADAS-Cog was designed for patients with more severe symptoms and may not be sensitive enough for patients with better cognitive performance, said Dr. Páez.
However, the difference between mild and moderate Alzheimer’s disease did not hold up in post hoc analyses that included additional baseline characteristics, including amyloid and APOE e4 status.
“We observed that both mild and moderate subjects performed better than placebo even in the two coprimary endpoints,” Dr. Páez said. “It suggested that the differences between mild and moderate patients was not so apparent.”
The study’s key secondary outcomes included scores on the Clinical Dementia Rating Sum of Boxes (CDR-sb) and the Alzheimer’s Disease Cooperative Study–Clinical Global Impression of Change (ADCS-CGIC) scales. Treated patients scored better than the placebo group on both the CDR-sb (71% less decline, P = .002) and the ADCS-CGIC (100% less decline, P < .0001) scales.
For disease biomarkers in the moderate Alzheimer’s disease study population, levels of CSF Abeta42 and tau protein remained stable in the treated patients. In the placebo group, Abeta42 was decreased and tau protein increased. Dr. Páez explained that, if amyloid in the brain comes from the CSF, this process may take some time.
The findings suggest that more than one mechanism may be involved in the plasma exchange approach, such as changes in oxidation status and inflammatory mediators, the investigators noted.
Safety profile
About 28% of the participants dropped out of the study, which the researchers note is a rate similar to that reported in studies of solanezumab and other treatments in patients with Alzheimer’s disease. “The high percentage (72%) of patients who completed the study further supports that this procedure is feasible in mild to moderate Alzheimer’s disease,” the investigators wrote.
Overall, adverse events were similar to the known safety profile of plasma exchange procedures for other indications. The two most common adverse events were catheter local reactions and hypotension.
Almost 90% of the apheresis procedures were “uneventful,” the researchers reported. Two patients (0.6%) died during the study, which is similar to the low mortality rates reported elsewhere.
However, the investigators stressed that, because many patients with Alzheimer’s disease are in fragile health, plasma exchange treatments should be undertaken with caution, because of its invasive nature.
Dr. Páez noted that a possible limitation of this treatment approach is the availability of plasma for manufacturing plasma products. In the future, this plasma exchange approach might be combined with current and future Alzheimer’s disease therapies.
They are currently in discussions with the American Society for Apheresis, which develops guidelines for plasma exchange. After additional research, the investigators hope to eventually receive Food and Drug Administration approval of plasma exchange with albumin replacement as a treatment for Alzheimer’s disease.
Speculative, yet reasonable approach
Commenting on the research findings, Pierre N. Tariot, MD, director of Banner Alzheimer’s Institute and research professor of psychiatry at the University of Arizona, both in Phoenix, said the study is “meaningful and large enough” to “come close” to determining whether the therapy is safe and effective. “The fundamental rationale for this experimental approach, while speculative, is reasonable and certainly seems to be worth testing,” said Dr. Tariot, who was not involved with the research.
However, “there’s a decent chance” that not all trial participants had Alzheimer’s disease. Although some CSF amyloid measures suggest levels consistent with AD, “this is not conclusive,” he said.
In addition, “there’s a slightly low rate of apolipoprotein E4 allele carriage [in the current study], compared with most Alzheimer’s disease trials,” Dr. Tariot said.
He also pointed out that the trial failed to show statistical significance on both coprimary outcomes. “It’s unclear what health authorities, if presented with these data, would decide to do with the file.”
Although it was “encouraging” that secondary endpoints were supportive, the fact that they had greater statistical significance than some of the other objective measures “raises at least the potential for partial unblinding as a result of side effects,” said Dr. Tariot. It is also unclear why changes would be more evident in the moderate subpopulation.
The study was funded by Grifols. Dr. Páez is an employee of Grifols. Dr. Tariot reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Results from the phase 2b/3 AMBAR study showed that the treatment, which aims to remove amyloid-beta (Abeta) from plasma, was associated with a 60% decrease in functional and cognitive decline in patients with moderate Alzheimer’s disease.
The reduction in cognitive decline uncovered by the study is more striking than that reported for other investigational treatments targeting Abeta, such as monoclonal antibodies, said coinvestigator Antonio Páez, MD, medical director of the AMBAR program, Alzheimer’s Research Group, Grifols, Barcelona.
The results “open a new path for the development of plasma protein replacement therapies not only in Alzheimer’s disease but also in other degenerative diseases that we are planning to investigate,” Dr. Páez said.
The findings were presented at the virtual annual meeting of the Alzheimer’s Association International Conference and were simultaneously published in Alzheimer’s and Dementia.
Removing amyloid
Plasma exchange treatments, which have been available for several decades, are used to treat a range of neurologic, immunologic, and metabolic disorders. The treatment involves plasmapheresis, whereby plasma is separated from blood cells (red blood cells, white blood cells, platelets, etc) and toxic substances are removed. The albumin in plasma, to which plasma Abeta is bound, is replaced with a fresh commercial albumin product made from plasma from healthy donors.
“Our initial hypothesis was that, by removing albumin together with Abeta and substituting it with newer albumin periodically, we may be removing Abeta from the cerebrospinal fluid and eventually from the brain,” Dr. Páez said.
The AMBAR study included 347 men and women aged 55-85 years with probable Alzheimer’s disease dementia who were enrolled at 41 sites in Spain and the United States. All were diagnosed with mild Alzheimer’s disease, as shown by a baseline Mini-Mental State Examination score of 22-26, or moderate Alzheimer’s disease, having a baseline MMSE score of 18-21.
Investigators randomly assigned the participants to four groups; one group received placebo, and each of the other three treatment arms received different doses of albumin and intravenous immunoglobulin (IVIg) replacement.
During the first 6-week study phase, patients received weekly sham or conventional plasma exchange treatments of 2.5-3 liters of plasma, which Dr. Páez referred to as the “intensive-treatment phase to remove as much Abeta as possible.”
This was followed by a 12-month maintenance phase, which involved monthly low-volume (700-800 mL) plasma exchange or sham treatments.
Although the volume of plasma removed was the same in all three active-treatment groups, the amount of albumin and IVIg that was subsequently replaced varied. In one group, the same amount of albumin and IVIg that was removed was replaced; in another, half the amount removed was replaced; and in the third, only albumin was replaced.
The researchers collected cerebrospinal fluid (CSF) samples at baseline and after each treatment period. They assessed Abeta40, Abeta42, total tau, and phosphorylated-tau biomarkers.
The two primary outcomes were change from baseline to 14 months in scores on the Alzheimer’s Disease Cooperative Study–Activities of Daily Living (ADCS-ADL) scale and the Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog).
Symptom reduction
Results showed a reduction in the progression of symptoms in the plasma exchange–treated patients for both primary endpoints.
The ADCS-ADL showed 52% less decline in the plasma exchange–treated group, compared with the placebo group (P = .03); the ADAS-Cog showed 66% less decline (P = 0.06). In the moderate group, both endpoints showed 61% less decline (P = .002 and .05, respectively).
There were no clear differences between the three active-treatment groups, “suggesting that any of them could be considered for further investigation,” said Dr. Páez.
Differences in baseline demographic characteristics did not appear to have an influence on the outcomes. ADAS-Cog was more than twice as effective as some candidate monoclonal antibodies targeting Abeta that are being investigated for Alzheimer’s disease, Dr. Páez noted.
Although the plasma exchange approach is relatively invasive, so too are monoclonal antibody therapies that are infused intravenously through a pump, he said. In addition, a low-volume plasma exchange maintenance treatment takes less than 2 hours, which is on a par with some monoclonal antibody treatments.
Key secondary outcomes
For both primary outcomes, changes were found in those with moderate but not mild Alzheimer’s disease, possibly because the ADAS-Cog was designed for patients with more severe symptoms and may not be sensitive enough for patients with better cognitive performance, said Dr. Páez.
However, the difference between mild and moderate Alzheimer’s disease did not hold up in post hoc analyses that included additional baseline characteristics, including amyloid and APOE e4 status.
“We observed that both mild and moderate subjects performed better than placebo even in the two coprimary endpoints,” Dr. Páez said. “It suggested that the differences between mild and moderate patients was not so apparent.”
The study’s key secondary outcomes included scores on the Clinical Dementia Rating Sum of Boxes (CDR-sb) and the Alzheimer’s Disease Cooperative Study–Clinical Global Impression of Change (ADCS-CGIC) scales. Treated patients scored better than the placebo group on both the CDR-sb (71% less decline, P = .002) and the ADCS-CGIC (100% less decline, P < .0001) scales.
For disease biomarkers in the moderate Alzheimer’s disease study population, levels of CSF Abeta42 and tau protein remained stable in the treated patients. In the placebo group, Abeta42 was decreased and tau protein increased. Dr. Páez explained that, if amyloid in the brain comes from the CSF, this process may take some time.
The findings suggest that more than one mechanism may be involved in the plasma exchange approach, such as changes in oxidation status and inflammatory mediators, the investigators noted.
Safety profile
About 28% of the participants dropped out of the study, which the researchers note is a rate similar to that reported in studies of solanezumab and other treatments in patients with Alzheimer’s disease. “The high percentage (72%) of patients who completed the study further supports that this procedure is feasible in mild to moderate Alzheimer’s disease,” the investigators wrote.
Overall, adverse events were similar to the known safety profile of plasma exchange procedures for other indications. The two most common adverse events were catheter local reactions and hypotension.
Almost 90% of the apheresis procedures were “uneventful,” the researchers reported. Two patients (0.6%) died during the study, which is similar to the low mortality rates reported elsewhere.
However, the investigators stressed that, because many patients with Alzheimer’s disease are in fragile health, plasma exchange treatments should be undertaken with caution, because of its invasive nature.
Dr. Páez noted that a possible limitation of this treatment approach is the availability of plasma for manufacturing plasma products. In the future, this plasma exchange approach might be combined with current and future Alzheimer’s disease therapies.
They are currently in discussions with the American Society for Apheresis, which develops guidelines for plasma exchange. After additional research, the investigators hope to eventually receive Food and Drug Administration approval of plasma exchange with albumin replacement as a treatment for Alzheimer’s disease.
Speculative, yet reasonable approach
Commenting on the research findings, Pierre N. Tariot, MD, director of Banner Alzheimer’s Institute and research professor of psychiatry at the University of Arizona, both in Phoenix, said the study is “meaningful and large enough” to “come close” to determining whether the therapy is safe and effective. “The fundamental rationale for this experimental approach, while speculative, is reasonable and certainly seems to be worth testing,” said Dr. Tariot, who was not involved with the research.
However, “there’s a decent chance” that not all trial participants had Alzheimer’s disease. Although some CSF amyloid measures suggest levels consistent with AD, “this is not conclusive,” he said.
In addition, “there’s a slightly low rate of apolipoprotein E4 allele carriage [in the current study], compared with most Alzheimer’s disease trials,” Dr. Tariot said.
He also pointed out that the trial failed to show statistical significance on both coprimary outcomes. “It’s unclear what health authorities, if presented with these data, would decide to do with the file.”
Although it was “encouraging” that secondary endpoints were supportive, the fact that they had greater statistical significance than some of the other objective measures “raises at least the potential for partial unblinding as a result of side effects,” said Dr. Tariot. It is also unclear why changes would be more evident in the moderate subpopulation.
The study was funded by Grifols. Dr. Páez is an employee of Grifols. Dr. Tariot reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Results from the phase 2b/3 AMBAR study showed that the treatment, which aims to remove amyloid-beta (Abeta) from plasma, was associated with a 60% decrease in functional and cognitive decline in patients with moderate Alzheimer’s disease.
The reduction in cognitive decline uncovered by the study is more striking than that reported for other investigational treatments targeting Abeta, such as monoclonal antibodies, said coinvestigator Antonio Páez, MD, medical director of the AMBAR program, Alzheimer’s Research Group, Grifols, Barcelona.
The results “open a new path for the development of plasma protein replacement therapies not only in Alzheimer’s disease but also in other degenerative diseases that we are planning to investigate,” Dr. Páez said.
The findings were presented at the virtual annual meeting of the Alzheimer’s Association International Conference and were simultaneously published in Alzheimer’s and Dementia.
Removing amyloid
Plasma exchange treatments, which have been available for several decades, are used to treat a range of neurologic, immunologic, and metabolic disorders. The treatment involves plasmapheresis, whereby plasma is separated from blood cells (red blood cells, white blood cells, platelets, etc) and toxic substances are removed. The albumin in plasma, to which plasma Abeta is bound, is replaced with a fresh commercial albumin product made from plasma from healthy donors.
“Our initial hypothesis was that, by removing albumin together with Abeta and substituting it with newer albumin periodically, we may be removing Abeta from the cerebrospinal fluid and eventually from the brain,” Dr. Páez said.
The AMBAR study included 347 men and women aged 55-85 years with probable Alzheimer’s disease dementia who were enrolled at 41 sites in Spain and the United States. All were diagnosed with mild Alzheimer’s disease, as shown by a baseline Mini-Mental State Examination score of 22-26, or moderate Alzheimer’s disease, having a baseline MMSE score of 18-21.
Investigators randomly assigned the participants to four groups; one group received placebo, and each of the other three treatment arms received different doses of albumin and intravenous immunoglobulin (IVIg) replacement.
During the first 6-week study phase, patients received weekly sham or conventional plasma exchange treatments of 2.5-3 liters of plasma, which Dr. Páez referred to as the “intensive-treatment phase to remove as much Abeta as possible.”
This was followed by a 12-month maintenance phase, which involved monthly low-volume (700-800 mL) plasma exchange or sham treatments.
Although the volume of plasma removed was the same in all three active-treatment groups, the amount of albumin and IVIg that was subsequently replaced varied. In one group, the same amount of albumin and IVIg that was removed was replaced; in another, half the amount removed was replaced; and in the third, only albumin was replaced.
The researchers collected cerebrospinal fluid (CSF) samples at baseline and after each treatment period. They assessed Abeta40, Abeta42, total tau, and phosphorylated-tau biomarkers.
The two primary outcomes were change from baseline to 14 months in scores on the Alzheimer’s Disease Cooperative Study–Activities of Daily Living (ADCS-ADL) scale and the Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog).
Symptom reduction
Results showed a reduction in the progression of symptoms in the plasma exchange–treated patients for both primary endpoints.
The ADCS-ADL showed 52% less decline in the plasma exchange–treated group, compared with the placebo group (P = .03); the ADAS-Cog showed 66% less decline (P = 0.06). In the moderate group, both endpoints showed 61% less decline (P = .002 and .05, respectively).
There were no clear differences between the three active-treatment groups, “suggesting that any of them could be considered for further investigation,” said Dr. Páez.
Differences in baseline demographic characteristics did not appear to have an influence on the outcomes. ADAS-Cog was more than twice as effective as some candidate monoclonal antibodies targeting Abeta that are being investigated for Alzheimer’s disease, Dr. Páez noted.
Although the plasma exchange approach is relatively invasive, so too are monoclonal antibody therapies that are infused intravenously through a pump, he said. In addition, a low-volume plasma exchange maintenance treatment takes less than 2 hours, which is on a par with some monoclonal antibody treatments.
Key secondary outcomes
For both primary outcomes, changes were found in those with moderate but not mild Alzheimer’s disease, possibly because the ADAS-Cog was designed for patients with more severe symptoms and may not be sensitive enough for patients with better cognitive performance, said Dr. Páez.
However, the difference between mild and moderate Alzheimer’s disease did not hold up in post hoc analyses that included additional baseline characteristics, including amyloid and APOE e4 status.
“We observed that both mild and moderate subjects performed better than placebo even in the two coprimary endpoints,” Dr. Páez said. “It suggested that the differences between mild and moderate patients was not so apparent.”
The study’s key secondary outcomes included scores on the Clinical Dementia Rating Sum of Boxes (CDR-sb) and the Alzheimer’s Disease Cooperative Study–Clinical Global Impression of Change (ADCS-CGIC) scales. Treated patients scored better than the placebo group on both the CDR-sb (71% less decline, P = .002) and the ADCS-CGIC (100% less decline, P < .0001) scales.
For disease biomarkers in the moderate Alzheimer’s disease study population, levels of CSF Abeta42 and tau protein remained stable in the treated patients. In the placebo group, Abeta42 was decreased and tau protein increased. Dr. Páez explained that, if amyloid in the brain comes from the CSF, this process may take some time.
The findings suggest that more than one mechanism may be involved in the plasma exchange approach, such as changes in oxidation status and inflammatory mediators, the investigators noted.
Safety profile
About 28% of the participants dropped out of the study, which the researchers note is a rate similar to that reported in studies of solanezumab and other treatments in patients with Alzheimer’s disease. “The high percentage (72%) of patients who completed the study further supports that this procedure is feasible in mild to moderate Alzheimer’s disease,” the investigators wrote.
Overall, adverse events were similar to the known safety profile of plasma exchange procedures for other indications. The two most common adverse events were catheter local reactions and hypotension.
Almost 90% of the apheresis procedures were “uneventful,” the researchers reported. Two patients (0.6%) died during the study, which is similar to the low mortality rates reported elsewhere.
However, the investigators stressed that, because many patients with Alzheimer’s disease are in fragile health, plasma exchange treatments should be undertaken with caution, because of its invasive nature.
Dr. Páez noted that a possible limitation of this treatment approach is the availability of plasma for manufacturing plasma products. In the future, this plasma exchange approach might be combined with current and future Alzheimer’s disease therapies.
They are currently in discussions with the American Society for Apheresis, which develops guidelines for plasma exchange. After additional research, the investigators hope to eventually receive Food and Drug Administration approval of plasma exchange with albumin replacement as a treatment for Alzheimer’s disease.
Speculative, yet reasonable approach
Commenting on the research findings, Pierre N. Tariot, MD, director of Banner Alzheimer’s Institute and research professor of psychiatry at the University of Arizona, both in Phoenix, said the study is “meaningful and large enough” to “come close” to determining whether the therapy is safe and effective. “The fundamental rationale for this experimental approach, while speculative, is reasonable and certainly seems to be worth testing,” said Dr. Tariot, who was not involved with the research.
However, “there’s a decent chance” that not all trial participants had Alzheimer’s disease. Although some CSF amyloid measures suggest levels consistent with AD, “this is not conclusive,” he said.
In addition, “there’s a slightly low rate of apolipoprotein E4 allele carriage [in the current study], compared with most Alzheimer’s disease trials,” Dr. Tariot said.
He also pointed out that the trial failed to show statistical significance on both coprimary outcomes. “It’s unclear what health authorities, if presented with these data, would decide to do with the file.”
Although it was “encouraging” that secondary endpoints were supportive, the fact that they had greater statistical significance than some of the other objective measures “raises at least the potential for partial unblinding as a result of side effects,” said Dr. Tariot. It is also unclear why changes would be more evident in the moderate subpopulation.
The study was funded by Grifols. Dr. Páez is an employee of Grifols. Dr. Tariot reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
FROM AAIC 2020
‘Long sleep’ or apnea in middle age double risk for Alzheimer’s disease
new research suggests. A U.K. Biobank study of more than 500,000 individuals also showed that excessive daytime sleepiness was associated with increased risk for Alzheimer’s disease.
“Addressing sleep problems in middle-age may play a role in improving brain health,” said lead author Lei Gao, MD, assistant professor of anesthesia at Harvard Medical School and associate scientist in the division of sleep and circadian disorders at Brigham and Women’s Hospital, both in Boston.
The findings were presented at the virtual annual meeting of the Alzheimer’s Association International Conference 2020.
Intricately linked
Sleep disturbances are common and on the rise around the world. In recent years, researchers have become increasingly aware of the intricate link between sleep health and brain health, Dr. Gao noted.
The current study included 502,538 individuals from the U.K. Biobank (mean age, 57 years) who were free from Alzheimer’s disease at baseline. They were followed for up to 12 years. The participants self-reported sleep traits, including hours of nighttime sleep, daytime sleepiness, sleep apnea diagnosis, snoring, and napping. Researchers determined Alzheimer’s disease diagnoses from hospital admissions and from death registries.
In addition to adjusting for age, sex, education, and ethnicity, the full model adjusted for socioeconomic status, body mass index, physical activity, smoking and alcohol use, cardiovascular diseases and risk factors, neurological diseases, respiratory diseases, depression/anxiety, and medication use. Over the course of a mean follow-up of 6.4 years, 932 participants developed Alzheimer’s disease.
Complex disorder
Compared with those who got an average of 6-9 hours of sleep per night, those getting more than 9 hours had a higher risk for Alzheimer’s disease (hazard ratio, 2.04; 95% confidence interval, 1.56-2.67; P < .001). Having sleep apnea also raised the risk significantly (HR, 2.05; 95% CI, 1.23-3.42; P = .006), as did daytime sleepiness (HR, 1.56; 95% CI, 1.18-2.03; P = .001).
Dr. Gao noted that daytime sleepiness and sleep apnea remained predictive after controlling for sleep duration. “In fact, all three sleep traits remained associated with Alzheimer’s disease within the same model, suggesting some degree of independence.”
Interestingly, snoring, which is a common symptom of sleep apnea, was not linked to Alzheimer’s disease risk. The “vast majority” of people who snore don’t meet criteria for a diagnosis of sleep apnea, which was particularly true for this large cohort of relatively healthy study participants, Dr. Gao noted.
“Sleep apnea is a complex, multisystemic sleep disorder associated with obesity, high blood pressure, and often other heart problems,” he said.
He added that, as an anesthesiologist, he is particularly wary if patients have this condition, “given their increased risk for airway difficulties, adverse cardiac events, postoperative respiratory complications, and confusion or delirium, which is also associated with higher risk for eventual Alzheimer’s disease and death.”
These multisystemic factors may be driving the link to Alzheimer’s disease. “We certainly need to address this better as the population ages and obesity rates rise,” Dr. Gao said.
No association with napping
Unlike another of Dr. Gao’s studies that was conducted in a much older population, napping was not a risk factor for Alzheimer’s disease in the current study’s younger participants. It could be that the impacts of different sleep traits on health outcome change with age, Dr. Gao said, or this could represent a limitation of using self-reported sleep measures as opposed to objective and/or quantitative measures, such as actigraphy. The reasons for napping, which differ around the world with the habit being common in certain parts, may also help explain differences in observed associations.
Although the investigators tried to control for comorbidities and medication use, there “most certainly” could be a reverse causation at work. For example, sleeping too much could be both a cause and a symptom of dementia. Dr. Gao noted that sleep disturbances often become more prevalent with dementia, and sleeping too much or complaining of daytime sleepiness may be a result of preclinical Alzheimer’s disease. Even if there is a reverse causation, however, the average time to Alzheimer’s disease diagnosis was over 6 years in this study. “This may be a significant window of time to intervene,” he said.
To improve sleep health, he recommends going to bed and waking at similar times every day, avoiding caffeine or alcohol close to bedtime, limiting screen time before bed, dimming lights, and reducing noise.
It’s also important to have sleep apnea treated. “While more studies are needed, it’s generally believed that addressing the pauses in breathing, the apnea episodes, will help reduce cardiovascular health risks such as obesity, high blood pressure and heart failure. All are known to be strongly linked to dementia risk,” Dr. Gao said.
Results from an assessment of 100,000 actigraphy records from a subset of the same population are expected soon and will add objective confirmation of these self-reported results, he added.
Unique, powerful
Commenting on the findings, Alberto Ramos, MD, associate professor of clinical neurology and research director of the sleep medicine program at the University of Miami, called the study “unique” and “powerful” because of its prospective design and large sample size.
“Another strength of the study was that it included a population-based sample as opposed to one from a memory or sleep clinic where people already have symptoms or are already sick,” said Dr. Ramos, who was not involved with the research.
In addition, while most studies that have linked sleep disturbances with dementia risk have been in older adults, this study’s population was middle-aged to start out, he noted.
Dr. Gao and Dr. Ramos reported no relevant financial relationships. Although Dr. Gao’s lab receives funding from the National Institutes of Health, the BrightFocus Foundation, the University of Manchester, the Medical Biodynamics Program, Brigham and Women’s Hospital, and the Broad Institute, the study itself does not have its own specific funding.
A version of this article originally appeared on Medscape.com.
new research suggests. A U.K. Biobank study of more than 500,000 individuals also showed that excessive daytime sleepiness was associated with increased risk for Alzheimer’s disease.
“Addressing sleep problems in middle-age may play a role in improving brain health,” said lead author Lei Gao, MD, assistant professor of anesthesia at Harvard Medical School and associate scientist in the division of sleep and circadian disorders at Brigham and Women’s Hospital, both in Boston.
The findings were presented at the virtual annual meeting of the Alzheimer’s Association International Conference 2020.
Intricately linked
Sleep disturbances are common and on the rise around the world. In recent years, researchers have become increasingly aware of the intricate link between sleep health and brain health, Dr. Gao noted.
The current study included 502,538 individuals from the U.K. Biobank (mean age, 57 years) who were free from Alzheimer’s disease at baseline. They were followed for up to 12 years. The participants self-reported sleep traits, including hours of nighttime sleep, daytime sleepiness, sleep apnea diagnosis, snoring, and napping. Researchers determined Alzheimer’s disease diagnoses from hospital admissions and from death registries.
In addition to adjusting for age, sex, education, and ethnicity, the full model adjusted for socioeconomic status, body mass index, physical activity, smoking and alcohol use, cardiovascular diseases and risk factors, neurological diseases, respiratory diseases, depression/anxiety, and medication use. Over the course of a mean follow-up of 6.4 years, 932 participants developed Alzheimer’s disease.
Complex disorder
Compared with those who got an average of 6-9 hours of sleep per night, those getting more than 9 hours had a higher risk for Alzheimer’s disease (hazard ratio, 2.04; 95% confidence interval, 1.56-2.67; P < .001). Having sleep apnea also raised the risk significantly (HR, 2.05; 95% CI, 1.23-3.42; P = .006), as did daytime sleepiness (HR, 1.56; 95% CI, 1.18-2.03; P = .001).
Dr. Gao noted that daytime sleepiness and sleep apnea remained predictive after controlling for sleep duration. “In fact, all three sleep traits remained associated with Alzheimer’s disease within the same model, suggesting some degree of independence.”
Interestingly, snoring, which is a common symptom of sleep apnea, was not linked to Alzheimer’s disease risk. The “vast majority” of people who snore don’t meet criteria for a diagnosis of sleep apnea, which was particularly true for this large cohort of relatively healthy study participants, Dr. Gao noted.
“Sleep apnea is a complex, multisystemic sleep disorder associated with obesity, high blood pressure, and often other heart problems,” he said.
He added that, as an anesthesiologist, he is particularly wary if patients have this condition, “given their increased risk for airway difficulties, adverse cardiac events, postoperative respiratory complications, and confusion or delirium, which is also associated with higher risk for eventual Alzheimer’s disease and death.”
These multisystemic factors may be driving the link to Alzheimer’s disease. “We certainly need to address this better as the population ages and obesity rates rise,” Dr. Gao said.
No association with napping
Unlike another of Dr. Gao’s studies that was conducted in a much older population, napping was not a risk factor for Alzheimer’s disease in the current study’s younger participants. It could be that the impacts of different sleep traits on health outcome change with age, Dr. Gao said, or this could represent a limitation of using self-reported sleep measures as opposed to objective and/or quantitative measures, such as actigraphy. The reasons for napping, which differ around the world with the habit being common in certain parts, may also help explain differences in observed associations.
Although the investigators tried to control for comorbidities and medication use, there “most certainly” could be a reverse causation at work. For example, sleeping too much could be both a cause and a symptom of dementia. Dr. Gao noted that sleep disturbances often become more prevalent with dementia, and sleeping too much or complaining of daytime sleepiness may be a result of preclinical Alzheimer’s disease. Even if there is a reverse causation, however, the average time to Alzheimer’s disease diagnosis was over 6 years in this study. “This may be a significant window of time to intervene,” he said.
To improve sleep health, he recommends going to bed and waking at similar times every day, avoiding caffeine or alcohol close to bedtime, limiting screen time before bed, dimming lights, and reducing noise.
It’s also important to have sleep apnea treated. “While more studies are needed, it’s generally believed that addressing the pauses in breathing, the apnea episodes, will help reduce cardiovascular health risks such as obesity, high blood pressure and heart failure. All are known to be strongly linked to dementia risk,” Dr. Gao said.
Results from an assessment of 100,000 actigraphy records from a subset of the same population are expected soon and will add objective confirmation of these self-reported results, he added.
Unique, powerful
Commenting on the findings, Alberto Ramos, MD, associate professor of clinical neurology and research director of the sleep medicine program at the University of Miami, called the study “unique” and “powerful” because of its prospective design and large sample size.
“Another strength of the study was that it included a population-based sample as opposed to one from a memory or sleep clinic where people already have symptoms or are already sick,” said Dr. Ramos, who was not involved with the research.
In addition, while most studies that have linked sleep disturbances with dementia risk have been in older adults, this study’s population was middle-aged to start out, he noted.
Dr. Gao and Dr. Ramos reported no relevant financial relationships. Although Dr. Gao’s lab receives funding from the National Institutes of Health, the BrightFocus Foundation, the University of Manchester, the Medical Biodynamics Program, Brigham and Women’s Hospital, and the Broad Institute, the study itself does not have its own specific funding.
A version of this article originally appeared on Medscape.com.
new research suggests. A U.K. Biobank study of more than 500,000 individuals also showed that excessive daytime sleepiness was associated with increased risk for Alzheimer’s disease.
“Addressing sleep problems in middle-age may play a role in improving brain health,” said lead author Lei Gao, MD, assistant professor of anesthesia at Harvard Medical School and associate scientist in the division of sleep and circadian disorders at Brigham and Women’s Hospital, both in Boston.
The findings were presented at the virtual annual meeting of the Alzheimer’s Association International Conference 2020.
Intricately linked
Sleep disturbances are common and on the rise around the world. In recent years, researchers have become increasingly aware of the intricate link between sleep health and brain health, Dr. Gao noted.
The current study included 502,538 individuals from the U.K. Biobank (mean age, 57 years) who were free from Alzheimer’s disease at baseline. They were followed for up to 12 years. The participants self-reported sleep traits, including hours of nighttime sleep, daytime sleepiness, sleep apnea diagnosis, snoring, and napping. Researchers determined Alzheimer’s disease diagnoses from hospital admissions and from death registries.
In addition to adjusting for age, sex, education, and ethnicity, the full model adjusted for socioeconomic status, body mass index, physical activity, smoking and alcohol use, cardiovascular diseases and risk factors, neurological diseases, respiratory diseases, depression/anxiety, and medication use. Over the course of a mean follow-up of 6.4 years, 932 participants developed Alzheimer’s disease.
Complex disorder
Compared with those who got an average of 6-9 hours of sleep per night, those getting more than 9 hours had a higher risk for Alzheimer’s disease (hazard ratio, 2.04; 95% confidence interval, 1.56-2.67; P < .001). Having sleep apnea also raised the risk significantly (HR, 2.05; 95% CI, 1.23-3.42; P = .006), as did daytime sleepiness (HR, 1.56; 95% CI, 1.18-2.03; P = .001).
Dr. Gao noted that daytime sleepiness and sleep apnea remained predictive after controlling for sleep duration. “In fact, all three sleep traits remained associated with Alzheimer’s disease within the same model, suggesting some degree of independence.”
Interestingly, snoring, which is a common symptom of sleep apnea, was not linked to Alzheimer’s disease risk. The “vast majority” of people who snore don’t meet criteria for a diagnosis of sleep apnea, which was particularly true for this large cohort of relatively healthy study participants, Dr. Gao noted.
“Sleep apnea is a complex, multisystemic sleep disorder associated with obesity, high blood pressure, and often other heart problems,” he said.
He added that, as an anesthesiologist, he is particularly wary if patients have this condition, “given their increased risk for airway difficulties, adverse cardiac events, postoperative respiratory complications, and confusion or delirium, which is also associated with higher risk for eventual Alzheimer’s disease and death.”
These multisystemic factors may be driving the link to Alzheimer’s disease. “We certainly need to address this better as the population ages and obesity rates rise,” Dr. Gao said.
No association with napping
Unlike another of Dr. Gao’s studies that was conducted in a much older population, napping was not a risk factor for Alzheimer’s disease in the current study’s younger participants. It could be that the impacts of different sleep traits on health outcome change with age, Dr. Gao said, or this could represent a limitation of using self-reported sleep measures as opposed to objective and/or quantitative measures, such as actigraphy. The reasons for napping, which differ around the world with the habit being common in certain parts, may also help explain differences in observed associations.
Although the investigators tried to control for comorbidities and medication use, there “most certainly” could be a reverse causation at work. For example, sleeping too much could be both a cause and a symptom of dementia. Dr. Gao noted that sleep disturbances often become more prevalent with dementia, and sleeping too much or complaining of daytime sleepiness may be a result of preclinical Alzheimer’s disease. Even if there is a reverse causation, however, the average time to Alzheimer’s disease diagnosis was over 6 years in this study. “This may be a significant window of time to intervene,” he said.
To improve sleep health, he recommends going to bed and waking at similar times every day, avoiding caffeine or alcohol close to bedtime, limiting screen time before bed, dimming lights, and reducing noise.
It’s also important to have sleep apnea treated. “While more studies are needed, it’s generally believed that addressing the pauses in breathing, the apnea episodes, will help reduce cardiovascular health risks such as obesity, high blood pressure and heart failure. All are known to be strongly linked to dementia risk,” Dr. Gao said.
Results from an assessment of 100,000 actigraphy records from a subset of the same population are expected soon and will add objective confirmation of these self-reported results, he added.
Unique, powerful
Commenting on the findings, Alberto Ramos, MD, associate professor of clinical neurology and research director of the sleep medicine program at the University of Miami, called the study “unique” and “powerful” because of its prospective design and large sample size.
“Another strength of the study was that it included a population-based sample as opposed to one from a memory or sleep clinic where people already have symptoms or are already sick,” said Dr. Ramos, who was not involved with the research.
In addition, while most studies that have linked sleep disturbances with dementia risk have been in older adults, this study’s population was middle-aged to start out, he noted.
Dr. Gao and Dr. Ramos reported no relevant financial relationships. Although Dr. Gao’s lab receives funding from the National Institutes of Health, the BrightFocus Foundation, the University of Manchester, the Medical Biodynamics Program, Brigham and Women’s Hospital, and the Broad Institute, the study itself does not have its own specific funding.
A version of this article originally appeared on Medscape.com.
FROM AAIC 2020
A better tau blood test for diagnosing Alzheimer’s disease?
.
In one new development, experts at the University of California, San Francisco (UCSF) compared phosphorylated-tau181 (P-tau181) to a related form of tau called P-tau217 to determine which can best identify individuals with Alzheimer’s disease.
Results showed that the two biomarkers were similar overall, but P-tau 217 had a slight edge in terms of accuracy. Importantly, both tau isoforms distinguished frontotemporal lobar degeneration (FTLD).
“These new blood tests for P-tau are going to be really exciting because they will improve our ability to simply and inexpensively assess whether someone is at high risk for having Alzheimer’s disease,” said study author Adam L. Boxer, MD, PhD, professor in UCSF’s department of neurology.
With the approval of the first disease-modifying therapy for Alzheimer’s disease possibly around the corner, developing an accurate diagnostic blood test for this condition is even more urgent, added Dr. Boxer, who is also director of UCSF’s Neurosciences Clinical Research Unit and AD and FTD Clinical Trials Program.
The findings were presented at the virtual annual meeting of the Alzheimer’s Association International Conference.
Important implications
Currently, the only approved Alzheimer’s disease biomarkers are expensive positron emission tomography (PET) scans using agents that detect tau or amyloid, another hallmark Alzheimer’s disease protein, and cerebrospinal fluid levels of amyloid and tau, the measurement of which entails invasive lumbar puncture procedures. This limits the ability to easily confirm the underlying cause of dementia or cognitive impairment, which “obviously has important prognostic and therapeutic implications,” said Dr. Boxer.
Having a plasma biomarker, especially for tau, would be extremely useful. Patients with increased tau in the brain tend to exhibit Alzheimer’s disease symptoms while those with amyloid plaques do not always have clear signs, at least not immediately. “We think that P-tau is probably a better measure because it is much more closely related to symptoms of disease,” said Dr. Boxer.
Earlier this year, he and colleagues published a study in Nature Medicine showing that P-tau181 is more than three times as high in individuals with Alzheimer’s disease compared with healthy elderly people. It also differentiated Alzheimer’s disease from frontotemporal dementia (FTD). “We found that P-tau 181 was almost as good as a PET scan or lumbar puncture at identifying individuals with Alzheimer’s disease pathology in the brain,” said Dr. Boxer.
They next wanted to assess how well P-tau 217 held up as a possible biomarker.
The new retrospective study was composed of 210 participants: 37 who acted as healthy controls, 99 who had FTLD, 39 who had Alzheimer’s disease, and 35 who had mild cognitive impairment.
More accurate test
Results showed that plasma P-tau217 was increased 5.7-fold in the participants with Alzheimer’s disease compared with the healthy controls group, and increased fivefold compared with those who had FTLD (both comparisons, P < .001).
The increase in plasma P-tau181 was lower. It was increased only 4.5-times in participants with Alzheimer’s disease compared with the healthy controls and 3.8-times relative to those with FTLD (both, P < .001). In addition, P-tau217 was potentially superior in predicting whether a person had a tau positive FTP-PET brain scan.
“This newer P-tau 217 test produces very similar results to the previous test we published [on P-tau181], but might be incrementally better or slightly more accurate, and even more closely related to the signal you get with a tau PET scan,” Dr. Boxer said.
The researchers are now examining these issues in a larger group of participants (N = 617). Results for those analyses are expected to be published soon. In addition to tau and amyloid markers, the researchers are examining another potential biomarker of neurodegeneration: the triple protein neurofilament light chain.
It’s too early to say which biomarker or biomarkers will prove to be the most useful in diagnosing Alzheimer’s disease, Dr. Boxer noted. “It’s an open question whether it will be necessary to measure multiple P-taus plus beta amyloid plus neurofilament, or maybe just measuring one P-tau level will be sufficient,” he said.
Upcoming therapy?
Having a test that verifies Alzheimer’s disease is becoming all the more important now that a therapy might soon be available. Massachusetts-based biotech company Biogen has submitted aducanumab, a monoclonal antibody that targets amyloid-beta (Abeta), to the Food and Drug Administration for approval. Should that move forward, aducanumab would be the first disease-modifying therapy for Alzheimer’s disease.
“If that’s the case, it will be even more important to have simple ways to screen people, to see if they might eventually be eligible for treatment,” said Dr. Boxer. Even if the drug isn’t approved, many patients simply want to know what is causing their cognitive problems, he added. Knowing they have Alzheimer’s disease might impact their life planning. If they have mild symptoms, interventions such as exercise and reducing cardiovascular risk could improve their overall health and quality of life, he said.
If individuals have another type of dementia, such as FTLD, that, too, might determine a different approach. Some forms of FTLD are caused by “completely different biological processes,” which are now being studied, Dr. Boxer said. So knowing that patients have this condition would allow them to participate in relevant clinical trials.
Exciting aspect
Having a tau blood test will also help those in underserviced and minority communities who can’t easily access memory specialists, Dr. Boxer noted. “It might allow them to access care, and get help much more easily, and that is a really exciting aspect of this new technology,” he said. It’s not clear when such blood tests will be on the market, although many companies are “scrambling” to make them available, said Dr. Boxer.
P-tau217 also holds promise as a marker for early Alzheimer’s disease pathology, according to another study presented at AAIC 2020. A Swedish research team measured P-tau217 in more than 1,000 participants, including those who were unimpaired and those with mild cognitive impairment, Alzheimer’s disease dementia, or non-Alzheimer’s disease neurodegenerative diseases.
Results showed that plasma P-tau217 levels increase in early stages of Alzheimer’s disease when insoluble tau aggregates are not yet detectable with PET. They also predict subsequent increases in tau-PET, as well as conversion to Alzheimer’s disease dementia.
‘Incredible breakthrough’
Commenting on the research, Howard Fillit, MD, founding executive director and chief science officer of the Alzheimer’s Drug Discovery Foundation, called the study amazing and “an incredible breakthrough.
“Researchers are able to detect disease up to 20 years before symptoms. The blood test has very good characteristics in terms of sensitivity and specificity. It correlates with the spinal fluid, it’s better than the PET imaging, it correlates with the amyloid test, and the results are being confirmed in many different cohorts,” said Dr. Fillit, who was not involved with the research.
A tau blood test, especially for P-tau 217, has the potential to be as important to determining dementia risk as cholesterol is to gauging heart disease risk, he added.
Having a tau blood test will “make our clinical trials much more precise and more efficient and reduce costs tremendously,” Dr. Fillit said, adding that he thinks tau blood tests might come to market as early as within a year.
Also commenting on the research, Rebecca M. Edelmayer, PhD, director of scientific engagement for the Alzheimer’s Association, said the new studies illustrate the rapid progress being made “in the blood biomarker space.”
Even 5 years ago, researchers would “never have thought” that blood biomarkers could be used as a tool to detect brain changes related to Alzheimer’s disease, said Dr. Edelmayer.
These new studies are “filling a gap in our understanding around tau” in Alzheimer’s disease and other neurodegenerative diseases, she said. “Being able to distinguish between diseases is going to be very, very crucial for clinicians in the future,” she added.
Dr. Edelmayer foresees that in the future there will be a panel of blood biomarkers in addition to imaging tests to help clinicians make an accurate diagnosis.
The study was supported by the National Institutes of Health and the Tau Research Consortium. Dr. Boxer disclosed that the blood p-tau test was done as part of a research collaboration between UCSF and Eli Lilly. Dr. Fillit and Dr. Edelmayer have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
.
In one new development, experts at the University of California, San Francisco (UCSF) compared phosphorylated-tau181 (P-tau181) to a related form of tau called P-tau217 to determine which can best identify individuals with Alzheimer’s disease.
Results showed that the two biomarkers were similar overall, but P-tau 217 had a slight edge in terms of accuracy. Importantly, both tau isoforms distinguished frontotemporal lobar degeneration (FTLD).
“These new blood tests for P-tau are going to be really exciting because they will improve our ability to simply and inexpensively assess whether someone is at high risk for having Alzheimer’s disease,” said study author Adam L. Boxer, MD, PhD, professor in UCSF’s department of neurology.
With the approval of the first disease-modifying therapy for Alzheimer’s disease possibly around the corner, developing an accurate diagnostic blood test for this condition is even more urgent, added Dr. Boxer, who is also director of UCSF’s Neurosciences Clinical Research Unit and AD and FTD Clinical Trials Program.
The findings were presented at the virtual annual meeting of the Alzheimer’s Association International Conference.
Important implications
Currently, the only approved Alzheimer’s disease biomarkers are expensive positron emission tomography (PET) scans using agents that detect tau or amyloid, another hallmark Alzheimer’s disease protein, and cerebrospinal fluid levels of amyloid and tau, the measurement of which entails invasive lumbar puncture procedures. This limits the ability to easily confirm the underlying cause of dementia or cognitive impairment, which “obviously has important prognostic and therapeutic implications,” said Dr. Boxer.
Having a plasma biomarker, especially for tau, would be extremely useful. Patients with increased tau in the brain tend to exhibit Alzheimer’s disease symptoms while those with amyloid plaques do not always have clear signs, at least not immediately. “We think that P-tau is probably a better measure because it is much more closely related to symptoms of disease,” said Dr. Boxer.
Earlier this year, he and colleagues published a study in Nature Medicine showing that P-tau181 is more than three times as high in individuals with Alzheimer’s disease compared with healthy elderly people. It also differentiated Alzheimer’s disease from frontotemporal dementia (FTD). “We found that P-tau 181 was almost as good as a PET scan or lumbar puncture at identifying individuals with Alzheimer’s disease pathology in the brain,” said Dr. Boxer.
They next wanted to assess how well P-tau 217 held up as a possible biomarker.
The new retrospective study was composed of 210 participants: 37 who acted as healthy controls, 99 who had FTLD, 39 who had Alzheimer’s disease, and 35 who had mild cognitive impairment.
More accurate test
Results showed that plasma P-tau217 was increased 5.7-fold in the participants with Alzheimer’s disease compared with the healthy controls group, and increased fivefold compared with those who had FTLD (both comparisons, P < .001).
The increase in plasma P-tau181 was lower. It was increased only 4.5-times in participants with Alzheimer’s disease compared with the healthy controls and 3.8-times relative to those with FTLD (both, P < .001). In addition, P-tau217 was potentially superior in predicting whether a person had a tau positive FTP-PET brain scan.
“This newer P-tau 217 test produces very similar results to the previous test we published [on P-tau181], but might be incrementally better or slightly more accurate, and even more closely related to the signal you get with a tau PET scan,” Dr. Boxer said.
The researchers are now examining these issues in a larger group of participants (N = 617). Results for those analyses are expected to be published soon. In addition to tau and amyloid markers, the researchers are examining another potential biomarker of neurodegeneration: the triple protein neurofilament light chain.
It’s too early to say which biomarker or biomarkers will prove to be the most useful in diagnosing Alzheimer’s disease, Dr. Boxer noted. “It’s an open question whether it will be necessary to measure multiple P-taus plus beta amyloid plus neurofilament, or maybe just measuring one P-tau level will be sufficient,” he said.
Upcoming therapy?
Having a test that verifies Alzheimer’s disease is becoming all the more important now that a therapy might soon be available. Massachusetts-based biotech company Biogen has submitted aducanumab, a monoclonal antibody that targets amyloid-beta (Abeta), to the Food and Drug Administration for approval. Should that move forward, aducanumab would be the first disease-modifying therapy for Alzheimer’s disease.
“If that’s the case, it will be even more important to have simple ways to screen people, to see if they might eventually be eligible for treatment,” said Dr. Boxer. Even if the drug isn’t approved, many patients simply want to know what is causing their cognitive problems, he added. Knowing they have Alzheimer’s disease might impact their life planning. If they have mild symptoms, interventions such as exercise and reducing cardiovascular risk could improve their overall health and quality of life, he said.
If individuals have another type of dementia, such as FTLD, that, too, might determine a different approach. Some forms of FTLD are caused by “completely different biological processes,” which are now being studied, Dr. Boxer said. So knowing that patients have this condition would allow them to participate in relevant clinical trials.
Exciting aspect
Having a tau blood test will also help those in underserviced and minority communities who can’t easily access memory specialists, Dr. Boxer noted. “It might allow them to access care, and get help much more easily, and that is a really exciting aspect of this new technology,” he said. It’s not clear when such blood tests will be on the market, although many companies are “scrambling” to make them available, said Dr. Boxer.
P-tau217 also holds promise as a marker for early Alzheimer’s disease pathology, according to another study presented at AAIC 2020. A Swedish research team measured P-tau217 in more than 1,000 participants, including those who were unimpaired and those with mild cognitive impairment, Alzheimer’s disease dementia, or non-Alzheimer’s disease neurodegenerative diseases.
Results showed that plasma P-tau217 levels increase in early stages of Alzheimer’s disease when insoluble tau aggregates are not yet detectable with PET. They also predict subsequent increases in tau-PET, as well as conversion to Alzheimer’s disease dementia.
‘Incredible breakthrough’
Commenting on the research, Howard Fillit, MD, founding executive director and chief science officer of the Alzheimer’s Drug Discovery Foundation, called the study amazing and “an incredible breakthrough.
“Researchers are able to detect disease up to 20 years before symptoms. The blood test has very good characteristics in terms of sensitivity and specificity. It correlates with the spinal fluid, it’s better than the PET imaging, it correlates with the amyloid test, and the results are being confirmed in many different cohorts,” said Dr. Fillit, who was not involved with the research.
A tau blood test, especially for P-tau 217, has the potential to be as important to determining dementia risk as cholesterol is to gauging heart disease risk, he added.
Having a tau blood test will “make our clinical trials much more precise and more efficient and reduce costs tremendously,” Dr. Fillit said, adding that he thinks tau blood tests might come to market as early as within a year.
Also commenting on the research, Rebecca M. Edelmayer, PhD, director of scientific engagement for the Alzheimer’s Association, said the new studies illustrate the rapid progress being made “in the blood biomarker space.”
Even 5 years ago, researchers would “never have thought” that blood biomarkers could be used as a tool to detect brain changes related to Alzheimer’s disease, said Dr. Edelmayer.
These new studies are “filling a gap in our understanding around tau” in Alzheimer’s disease and other neurodegenerative diseases, she said. “Being able to distinguish between diseases is going to be very, very crucial for clinicians in the future,” she added.
Dr. Edelmayer foresees that in the future there will be a panel of blood biomarkers in addition to imaging tests to help clinicians make an accurate diagnosis.
The study was supported by the National Institutes of Health and the Tau Research Consortium. Dr. Boxer disclosed that the blood p-tau test was done as part of a research collaboration between UCSF and Eli Lilly. Dr. Fillit and Dr. Edelmayer have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
.
In one new development, experts at the University of California, San Francisco (UCSF) compared phosphorylated-tau181 (P-tau181) to a related form of tau called P-tau217 to determine which can best identify individuals with Alzheimer’s disease.
Results showed that the two biomarkers were similar overall, but P-tau 217 had a slight edge in terms of accuracy. Importantly, both tau isoforms distinguished frontotemporal lobar degeneration (FTLD).
“These new blood tests for P-tau are going to be really exciting because they will improve our ability to simply and inexpensively assess whether someone is at high risk for having Alzheimer’s disease,” said study author Adam L. Boxer, MD, PhD, professor in UCSF’s department of neurology.
With the approval of the first disease-modifying therapy for Alzheimer’s disease possibly around the corner, developing an accurate diagnostic blood test for this condition is even more urgent, added Dr. Boxer, who is also director of UCSF’s Neurosciences Clinical Research Unit and AD and FTD Clinical Trials Program.
The findings were presented at the virtual annual meeting of the Alzheimer’s Association International Conference.
Important implications
Currently, the only approved Alzheimer’s disease biomarkers are expensive positron emission tomography (PET) scans using agents that detect tau or amyloid, another hallmark Alzheimer’s disease protein, and cerebrospinal fluid levels of amyloid and tau, the measurement of which entails invasive lumbar puncture procedures. This limits the ability to easily confirm the underlying cause of dementia or cognitive impairment, which “obviously has important prognostic and therapeutic implications,” said Dr. Boxer.
Having a plasma biomarker, especially for tau, would be extremely useful. Patients with increased tau in the brain tend to exhibit Alzheimer’s disease symptoms while those with amyloid plaques do not always have clear signs, at least not immediately. “We think that P-tau is probably a better measure because it is much more closely related to symptoms of disease,” said Dr. Boxer.
Earlier this year, he and colleagues published a study in Nature Medicine showing that P-tau181 is more than three times as high in individuals with Alzheimer’s disease compared with healthy elderly people. It also differentiated Alzheimer’s disease from frontotemporal dementia (FTD). “We found that P-tau 181 was almost as good as a PET scan or lumbar puncture at identifying individuals with Alzheimer’s disease pathology in the brain,” said Dr. Boxer.
They next wanted to assess how well P-tau 217 held up as a possible biomarker.
The new retrospective study was composed of 210 participants: 37 who acted as healthy controls, 99 who had FTLD, 39 who had Alzheimer’s disease, and 35 who had mild cognitive impairment.
More accurate test
Results showed that plasma P-tau217 was increased 5.7-fold in the participants with Alzheimer’s disease compared with the healthy controls group, and increased fivefold compared with those who had FTLD (both comparisons, P < .001).
The increase in plasma P-tau181 was lower. It was increased only 4.5-times in participants with Alzheimer’s disease compared with the healthy controls and 3.8-times relative to those with FTLD (both, P < .001). In addition, P-tau217 was potentially superior in predicting whether a person had a tau positive FTP-PET brain scan.
“This newer P-tau 217 test produces very similar results to the previous test we published [on P-tau181], but might be incrementally better or slightly more accurate, and even more closely related to the signal you get with a tau PET scan,” Dr. Boxer said.
The researchers are now examining these issues in a larger group of participants (N = 617). Results for those analyses are expected to be published soon. In addition to tau and amyloid markers, the researchers are examining another potential biomarker of neurodegeneration: the triple protein neurofilament light chain.
It’s too early to say which biomarker or biomarkers will prove to be the most useful in diagnosing Alzheimer’s disease, Dr. Boxer noted. “It’s an open question whether it will be necessary to measure multiple P-taus plus beta amyloid plus neurofilament, or maybe just measuring one P-tau level will be sufficient,” he said.
Upcoming therapy?
Having a test that verifies Alzheimer’s disease is becoming all the more important now that a therapy might soon be available. Massachusetts-based biotech company Biogen has submitted aducanumab, a monoclonal antibody that targets amyloid-beta (Abeta), to the Food and Drug Administration for approval. Should that move forward, aducanumab would be the first disease-modifying therapy for Alzheimer’s disease.
“If that’s the case, it will be even more important to have simple ways to screen people, to see if they might eventually be eligible for treatment,” said Dr. Boxer. Even if the drug isn’t approved, many patients simply want to know what is causing their cognitive problems, he added. Knowing they have Alzheimer’s disease might impact their life planning. If they have mild symptoms, interventions such as exercise and reducing cardiovascular risk could improve their overall health and quality of life, he said.
If individuals have another type of dementia, such as FTLD, that, too, might determine a different approach. Some forms of FTLD are caused by “completely different biological processes,” which are now being studied, Dr. Boxer said. So knowing that patients have this condition would allow them to participate in relevant clinical trials.
Exciting aspect
Having a tau blood test will also help those in underserviced and minority communities who can’t easily access memory specialists, Dr. Boxer noted. “It might allow them to access care, and get help much more easily, and that is a really exciting aspect of this new technology,” he said. It’s not clear when such blood tests will be on the market, although many companies are “scrambling” to make them available, said Dr. Boxer.
P-tau217 also holds promise as a marker for early Alzheimer’s disease pathology, according to another study presented at AAIC 2020. A Swedish research team measured P-tau217 in more than 1,000 participants, including those who were unimpaired and those with mild cognitive impairment, Alzheimer’s disease dementia, or non-Alzheimer’s disease neurodegenerative diseases.
Results showed that plasma P-tau217 levels increase in early stages of Alzheimer’s disease when insoluble tau aggregates are not yet detectable with PET. They also predict subsequent increases in tau-PET, as well as conversion to Alzheimer’s disease dementia.
‘Incredible breakthrough’
Commenting on the research, Howard Fillit, MD, founding executive director and chief science officer of the Alzheimer’s Drug Discovery Foundation, called the study amazing and “an incredible breakthrough.
“Researchers are able to detect disease up to 20 years before symptoms. The blood test has very good characteristics in terms of sensitivity and specificity. It correlates with the spinal fluid, it’s better than the PET imaging, it correlates with the amyloid test, and the results are being confirmed in many different cohorts,” said Dr. Fillit, who was not involved with the research.
A tau blood test, especially for P-tau 217, has the potential to be as important to determining dementia risk as cholesterol is to gauging heart disease risk, he added.
Having a tau blood test will “make our clinical trials much more precise and more efficient and reduce costs tremendously,” Dr. Fillit said, adding that he thinks tau blood tests might come to market as early as within a year.
Also commenting on the research, Rebecca M. Edelmayer, PhD, director of scientific engagement for the Alzheimer’s Association, said the new studies illustrate the rapid progress being made “in the blood biomarker space.”
Even 5 years ago, researchers would “never have thought” that blood biomarkers could be used as a tool to detect brain changes related to Alzheimer’s disease, said Dr. Edelmayer.
These new studies are “filling a gap in our understanding around tau” in Alzheimer’s disease and other neurodegenerative diseases, she said. “Being able to distinguish between diseases is going to be very, very crucial for clinicians in the future,” she added.
Dr. Edelmayer foresees that in the future there will be a panel of blood biomarkers in addition to imaging tests to help clinicians make an accurate diagnosis.
The study was supported by the National Institutes of Health and the Tau Research Consortium. Dr. Boxer disclosed that the blood p-tau test was done as part of a research collaboration between UCSF and Eli Lilly. Dr. Fillit and Dr. Edelmayer have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
FROM AAIC 2020
New hope for ALS
. Both studies investigated potential benefits of suppressing the toxic activity in cells of a mutant gene (SOD1) that encodes superoxide dismutase 1 (SOD1) in patients with ALS.
One study investigated the antisense oligonucleotide (ASO) tofersen (Biogen); the other study examined viral vector–mediated gene suppression.
The studies’ promising results signal “the beginning of a new precision medicine–based approach towards treating ALS,” said Orla Hardiman, BSc, MB, BCh, BAO, MD, a consultant neurologist and professor of neurology at Trinity College and Beaumont Hospital in Dublin, Ireland. Dr. Hardiman co-authored an editorial that accompanied the two studies, which were published July 9 in the New England Journal of Medicine.
Genetic culprits
ALS is a disorder of progressive degeneration of upper and lower motor neurons. It typically leads to death from ventilatory failure within 5 years of symptom onset.
Genetic factors are responsible for about half the risk variance of ALS. In populations of European origin, variants in SOD1 account for an estimated 13% to 20% of familial ALS, although this rate varies around the world. Although SOD1 is not the most common variant in ALS, it is the one that researchers are most familiar with and has been studied in an animal model.
In the first study, investigators evaluated the safety, pharmacokinetics, and pharmacodynamics of the ASO tofersen in adults with ALS.
An ASO is a small piece of nucleic acid that enters neurons in the spinal cord and brain, explained co-investigator Toby A. Ferguson, MD, PhD, vice president and head of the neuromuscular development unit at Biogen.
ASO binds to the SOD1 gene and knocks down the SOD1 protein, which is the “toxic engine [that] drives the disease, kills neurons, and causes patients to have loss of function and eventually to die,” said Dr. Ferguson. “The ASO turns off the motor that produces that toxic protein,” he added.
Animal studies have shown that ASOs that target SOD1 messenger RNA transcripts prolong survival, improve motor performance, and reduce SOD1 protein concentrations.
The new phase 1/2 double-blind study included 50 adults at 18 sites in the United States, Canada, and four European countries. All had muscle weakness attributed to ALS and a documented SOD1 mutation. Participants were randomly assigned to receive one of four doses of tofersen—20, 40, 60, or 100 mg—or placebo. Treatment was administered via a lumbar intrathecal bolus injection. The study included a screening period followed by a 12-week intervention period and a 12-week follow-up.
Adverse events
A primary outcome was the incidence of adverse events (AEs) and serious AEs. Results showed that all participants reported one or more AEs. The most common AEs were headache, pain at the injection site, post–lumbar puncture syndrome, and falls. Three deaths occurred, one in the placebo group, one in the 20-mg dose group, and one in the 60-mg dose group. There were no serious AEs in the 100-mg group.
Although the investigators found an increase in cerebrospinal fluid (CSF) protein and white cell counts, there was no clear association between these observations and higher doses of tofersen or longer duration of exposure.
“We don’t know the implications of this, and it’s something we need to keep an eye on as we move these studies forward,” Dr. Ferguson said.
None of the AEs or CSF abnormalities led to trial discontinuation.
A secondary outcome was change in SOD1 protein concentration in CSF at day 85. The study showed that SOD1 concentrations decreased by 36% among the participants who received tofersen 100 mg and by lesser amounts in the patients who received lower doses. Concentrations in the placebo group were reduced by 3%.
The 36% reduction in the highest dose group is likely meaningful and “foundational to the concept of what this molecule can do,” Dr. Ferguson said.
“If the number one cause of SOD1 ALS is accumulation of toxic SOD1 protein, then the demonstration that we can reduce SOD1 protein in the CSF ... is saying that’s the first step on the way to showing the molecule is doing what it should do,” he added.
Emerging tool
In patients with ALS, neurofilament concentrations typically increase as the disease progresses. However, this study documented a reduction in these CSF concentrations. “One interpretation of that could be that there is less neurodegeneration or neuro injury” in patients treated with tofersen, Dr. Ferguson said.
He noted that neurofilament is “an emerging tool” for understanding neurodegeneration. It could also “be another sort of biochemical signal that the molecule is doing something important,” he added.
However, he noted that neurofilament concentration is still an exploratory marker.
Exploratory analyses suggested a possible slowing of functional loss, as measured by the ALS Functional Rating Scale–Revised (ALSFRS-R) score and the handheld dynamometry megascore. The latter assesses strength in 16 muscle groups in the arms and legs. The investigators noted that no conclusions can be drawn from these outcomes.
A post hoc analysis showed that among patients with SOD1 mutations associated with a fast-progressing disease course, the slope of clinical decline might have been gentler, and there was a greater decrease in CSF neurofilament concentration compared among those whose disease followed a slower course.
This suggests that “if you pick the right target,” even patients with severe disease can be treated, Dr. Ferguson said.
He acknowledged that in a relatively short study such as this one, it may be easier to see benefits in patients whose disease is progressing rapidly. However, he’s convinced that the treatment “would work for all SOD1 ALS patients, not just fast patients.”
Dr. Ferguson said the study investigators are encouraged by the new data, which “really suggest that we may be developing a meaningful treatment for SOD1 ALS.” However, “it’s still early” in terms of rolling out this therapy for patients with ALS, he said.
The safety and efficacy of tofersen are currently being evaluated in a phase 3, randomized, double-blind, placebo-controlled trial.
Limitations of the current study were the small number of participants, the short duration of treatment and follow-up, the exploratory nature of efficacy outcomes, and the post hoc methods for defining the fast-progressing subgroup.
Although an advantage of tofersen is that it can enter the nucleus of the cell, perhaps boosting effectiveness, a drawback might be that patients need several treatments administered via lumbar puncture. Following three initial doses, the drug is given every month.
An alternative approach might be a viral vector approach.
“Stunning” finding
In the second study, investigators assessed the safety of a single intrathecal infusion of a viral vector therapy designed to target SOD1 in two patients with familial ALS. The two patients were a 22-year-old man whose mother had died of ALS at age 45 and a 56-year-old man who had a family history of ALS.
The aim of the viral vector therapy is to continually suppress mutant gene activity, said study co-investigator Robert H. Brown, Jr, MD, professor of neurology, University of Massachusetts Medical School, Worcester.
“The virus essentially drops off a piece of DNA, and that DNA keeps making the agent that suppresses the gene,” Dr. Brown said.
He noted that the first patient had a mutation that causes a rapidly developing, “horribly devastating” disease.
Initially, the patient’s right leg, in which movement had been worsening over several weeks, “seemed to get stronger and remain strong for quite a long time. I’ve never seen that in this kind of mutation,” said Dr. Brown.
The patient died of ALS. At autopsy, there was evidence of suppression of SOD1 in the spinal cord. There was some preservation of motor neurons on the right side of the spinal cord, which Dr. Brown called a “stunning” finding.
“We have never seen preservation of motor neurons in an autopsy of a patient with this kind of mutation before,” he said.
Prior to the patient’s death, there were some initial signs of a decrease of SOD1 in CSF. However, the patient developed an inflammatory response in the lining of the CSF known as meningoradiculitis.
“In that setting, the SOD1 level went back up, so we could not say that we produced a significant lasting decrease,” Dr. Brown said.
One and done
Because meningoradiculitis occurred in the first patient, immunosuppressive drugs were administered to the second patient.
The functional status and vital capacity of the second patient were relatively stable during a 60-week period, a course that could be typical of the slow disease progression in patients with this SOD1 genotype.
As with the first patient, this man did not experience a substantial change in SOD1 protein levels in CSF, and he did not show clinical improvement.
The main advantage of a viral gene therapy is that it could be a one-time treatment; ideally, it could be used to replace a single missing gene in conditions such as cystic fibrosis. “The hope is that the virus will drop off the gene modulator or the gene itself of interest, depending on the disease, and that the gene will be there more or less indefinitely,” said Dr. Brown. “So the cliché is, ‘one and done’—if all goes well.”
This small study illustrates that gene therapy safely “turns off genes and that the extent of suppression of genes can be significant,” said Dr. Brown.
Most SOD1 mutations could be treated with this microRNA viral vector, he added. More than 180 such mutations have been identified in ALS.
Additional studies are now needed to determine the results of this method in a larger number of patients who have ALS with SOD1 mutations, the investigators wrote.
Within reach
Both studies are encouraging in that they show that a precision-medicine approach to ALS associated with single mutated genes “may be within reach,” said Dr. Hardiman.
She noted that gene therapies have been used successfully in other motor neuron conditions. For example, an ASO and a viral vector have “very significant efficacy” in a form of spinal muscular atrophy that occurs in infants. “So the underlying proof of principle is already there.”
The reduction in SOD1 levels among the highest-dose tofersen group in the first study indicates “target engagement,” Dr. Hardiman said.
In that study, the documented decreased protein in the CSF appeared to be dose related, as was the effect for neurofilaments, which is biomarker evidence of neuronal damage, she noted.
In the second study, the pathologic evidence from the first patient also suggests “evidence of target engagement,” Dr. Hardiman said.
However, she added, “We don’t know very much about the outcome of the second case other than immunosuppression seemed to be beneficial.”
New hope
Both studies have caveats, said Dr. Hardiman. For example, it is unclear whether the treatments would be beneficial for every variant in SOD1.
“These are very expensive therapies, and we will need to have some level of certainty in order to be able to determine whether this should be a treatment for a patient or not,” said Dr. Hardiman.
She also noted that the studies were not powered to provide evidence of efficacy and that they raise questions about the accuracy of the ALSFRS-R.
One issue is that the respiratory part of that scale is “very insensitive”; another is that the scale doesn’t capture nonmotor elements, such as cognition and behavior, she said.
Utilizing a combination of the ALSFRS-R slope and survival would “probably be more beneficial,” Dr. Hardiman said.
Understanding how to alter the genetic influence in a disorder is important to be able to identify successful treatments, Dr. Hardiman added. For example, the discovery of the BRCA gene led oncologists to develop a precision medicine approach to the treatment of breast cancer.
In regard to ALS, by starting with subgroups that have specific genomic features, “investigators are providing new hope for patients at genetic risk for this devastating fatal disease,” said Dr. Hardiman.
The first study was funded by Biogen. The second study was funded by a fellowship grant from the Alzheimer’s Association, a Jack Satter Foundation Award, the ALS Association, the Angel Fund for ALS Research, ALS Finding a Cure, ALS-One, Project ALS, the Massachusetts General Hospital, the Max Rosenfeld and Cellucci Funds for ALS Research, and several senior members of Bain Capital. Dr. Ferguson is employed by and holds stock in Biogen. Dr. Brown receives grant support from the National Institute of Neurological Disorders and Stroke. He is also co-founder of Apic Bio. Dr. Hardiman is the editor-in-chief of the Journal of Amyotrophic Lateral Sclerosis and Frontotemporal Degenerations, has consulted for Cytokinetics, Mitsubishi, and Wave, and holds research grants from Novartis and Merck. During the past 2 years, she has also been a principal investigator on ALS clinical trials sponsored by Orion and Cytokinetics and is currently on the data and safety monitoring board of Accelsior.
This article first appeared on Medscape.com.
. Both studies investigated potential benefits of suppressing the toxic activity in cells of a mutant gene (SOD1) that encodes superoxide dismutase 1 (SOD1) in patients with ALS.
One study investigated the antisense oligonucleotide (ASO) tofersen (Biogen); the other study examined viral vector–mediated gene suppression.
The studies’ promising results signal “the beginning of a new precision medicine–based approach towards treating ALS,” said Orla Hardiman, BSc, MB, BCh, BAO, MD, a consultant neurologist and professor of neurology at Trinity College and Beaumont Hospital in Dublin, Ireland. Dr. Hardiman co-authored an editorial that accompanied the two studies, which were published July 9 in the New England Journal of Medicine.
Genetic culprits
ALS is a disorder of progressive degeneration of upper and lower motor neurons. It typically leads to death from ventilatory failure within 5 years of symptom onset.
Genetic factors are responsible for about half the risk variance of ALS. In populations of European origin, variants in SOD1 account for an estimated 13% to 20% of familial ALS, although this rate varies around the world. Although SOD1 is not the most common variant in ALS, it is the one that researchers are most familiar with and has been studied in an animal model.
In the first study, investigators evaluated the safety, pharmacokinetics, and pharmacodynamics of the ASO tofersen in adults with ALS.
An ASO is a small piece of nucleic acid that enters neurons in the spinal cord and brain, explained co-investigator Toby A. Ferguson, MD, PhD, vice president and head of the neuromuscular development unit at Biogen.
ASO binds to the SOD1 gene and knocks down the SOD1 protein, which is the “toxic engine [that] drives the disease, kills neurons, and causes patients to have loss of function and eventually to die,” said Dr. Ferguson. “The ASO turns off the motor that produces that toxic protein,” he added.
Animal studies have shown that ASOs that target SOD1 messenger RNA transcripts prolong survival, improve motor performance, and reduce SOD1 protein concentrations.
The new phase 1/2 double-blind study included 50 adults at 18 sites in the United States, Canada, and four European countries. All had muscle weakness attributed to ALS and a documented SOD1 mutation. Participants were randomly assigned to receive one of four doses of tofersen—20, 40, 60, or 100 mg—or placebo. Treatment was administered via a lumbar intrathecal bolus injection. The study included a screening period followed by a 12-week intervention period and a 12-week follow-up.
Adverse events
A primary outcome was the incidence of adverse events (AEs) and serious AEs. Results showed that all participants reported one or more AEs. The most common AEs were headache, pain at the injection site, post–lumbar puncture syndrome, and falls. Three deaths occurred, one in the placebo group, one in the 20-mg dose group, and one in the 60-mg dose group. There were no serious AEs in the 100-mg group.
Although the investigators found an increase in cerebrospinal fluid (CSF) protein and white cell counts, there was no clear association between these observations and higher doses of tofersen or longer duration of exposure.
“We don’t know the implications of this, and it’s something we need to keep an eye on as we move these studies forward,” Dr. Ferguson said.
None of the AEs or CSF abnormalities led to trial discontinuation.
A secondary outcome was change in SOD1 protein concentration in CSF at day 85. The study showed that SOD1 concentrations decreased by 36% among the participants who received tofersen 100 mg and by lesser amounts in the patients who received lower doses. Concentrations in the placebo group were reduced by 3%.
The 36% reduction in the highest dose group is likely meaningful and “foundational to the concept of what this molecule can do,” Dr. Ferguson said.
“If the number one cause of SOD1 ALS is accumulation of toxic SOD1 protein, then the demonstration that we can reduce SOD1 protein in the CSF ... is saying that’s the first step on the way to showing the molecule is doing what it should do,” he added.
Emerging tool
In patients with ALS, neurofilament concentrations typically increase as the disease progresses. However, this study documented a reduction in these CSF concentrations. “One interpretation of that could be that there is less neurodegeneration or neuro injury” in patients treated with tofersen, Dr. Ferguson said.
He noted that neurofilament is “an emerging tool” for understanding neurodegeneration. It could also “be another sort of biochemical signal that the molecule is doing something important,” he added.
However, he noted that neurofilament concentration is still an exploratory marker.
Exploratory analyses suggested a possible slowing of functional loss, as measured by the ALS Functional Rating Scale–Revised (ALSFRS-R) score and the handheld dynamometry megascore. The latter assesses strength in 16 muscle groups in the arms and legs. The investigators noted that no conclusions can be drawn from these outcomes.
A post hoc analysis showed that among patients with SOD1 mutations associated with a fast-progressing disease course, the slope of clinical decline might have been gentler, and there was a greater decrease in CSF neurofilament concentration compared among those whose disease followed a slower course.
This suggests that “if you pick the right target,” even patients with severe disease can be treated, Dr. Ferguson said.
He acknowledged that in a relatively short study such as this one, it may be easier to see benefits in patients whose disease is progressing rapidly. However, he’s convinced that the treatment “would work for all SOD1 ALS patients, not just fast patients.”
Dr. Ferguson said the study investigators are encouraged by the new data, which “really suggest that we may be developing a meaningful treatment for SOD1 ALS.” However, “it’s still early” in terms of rolling out this therapy for patients with ALS, he said.
The safety and efficacy of tofersen are currently being evaluated in a phase 3, randomized, double-blind, placebo-controlled trial.
Limitations of the current study were the small number of participants, the short duration of treatment and follow-up, the exploratory nature of efficacy outcomes, and the post hoc methods for defining the fast-progressing subgroup.
Although an advantage of tofersen is that it can enter the nucleus of the cell, perhaps boosting effectiveness, a drawback might be that patients need several treatments administered via lumbar puncture. Following three initial doses, the drug is given every month.
An alternative approach might be a viral vector approach.
“Stunning” finding
In the second study, investigators assessed the safety of a single intrathecal infusion of a viral vector therapy designed to target SOD1 in two patients with familial ALS. The two patients were a 22-year-old man whose mother had died of ALS at age 45 and a 56-year-old man who had a family history of ALS.
The aim of the viral vector therapy is to continually suppress mutant gene activity, said study co-investigator Robert H. Brown, Jr, MD, professor of neurology, University of Massachusetts Medical School, Worcester.
“The virus essentially drops off a piece of DNA, and that DNA keeps making the agent that suppresses the gene,” Dr. Brown said.
He noted that the first patient had a mutation that causes a rapidly developing, “horribly devastating” disease.
Initially, the patient’s right leg, in which movement had been worsening over several weeks, “seemed to get stronger and remain strong for quite a long time. I’ve never seen that in this kind of mutation,” said Dr. Brown.
The patient died of ALS. At autopsy, there was evidence of suppression of SOD1 in the spinal cord. There was some preservation of motor neurons on the right side of the spinal cord, which Dr. Brown called a “stunning” finding.
“We have never seen preservation of motor neurons in an autopsy of a patient with this kind of mutation before,” he said.
Prior to the patient’s death, there were some initial signs of a decrease of SOD1 in CSF. However, the patient developed an inflammatory response in the lining of the CSF known as meningoradiculitis.
“In that setting, the SOD1 level went back up, so we could not say that we produced a significant lasting decrease,” Dr. Brown said.
One and done
Because meningoradiculitis occurred in the first patient, immunosuppressive drugs were administered to the second patient.
The functional status and vital capacity of the second patient were relatively stable during a 60-week period, a course that could be typical of the slow disease progression in patients with this SOD1 genotype.
As with the first patient, this man did not experience a substantial change in SOD1 protein levels in CSF, and he did not show clinical improvement.
The main advantage of a viral gene therapy is that it could be a one-time treatment; ideally, it could be used to replace a single missing gene in conditions such as cystic fibrosis. “The hope is that the virus will drop off the gene modulator or the gene itself of interest, depending on the disease, and that the gene will be there more or less indefinitely,” said Dr. Brown. “So the cliché is, ‘one and done’—if all goes well.”
This small study illustrates that gene therapy safely “turns off genes and that the extent of suppression of genes can be significant,” said Dr. Brown.
Most SOD1 mutations could be treated with this microRNA viral vector, he added. More than 180 such mutations have been identified in ALS.
Additional studies are now needed to determine the results of this method in a larger number of patients who have ALS with SOD1 mutations, the investigators wrote.
Within reach
Both studies are encouraging in that they show that a precision-medicine approach to ALS associated with single mutated genes “may be within reach,” said Dr. Hardiman.
She noted that gene therapies have been used successfully in other motor neuron conditions. For example, an ASO and a viral vector have “very significant efficacy” in a form of spinal muscular atrophy that occurs in infants. “So the underlying proof of principle is already there.”
The reduction in SOD1 levels among the highest-dose tofersen group in the first study indicates “target engagement,” Dr. Hardiman said.
In that study, the documented decreased protein in the CSF appeared to be dose related, as was the effect for neurofilaments, which is biomarker evidence of neuronal damage, she noted.
In the second study, the pathologic evidence from the first patient also suggests “evidence of target engagement,” Dr. Hardiman said.
However, she added, “We don’t know very much about the outcome of the second case other than immunosuppression seemed to be beneficial.”
New hope
Both studies have caveats, said Dr. Hardiman. For example, it is unclear whether the treatments would be beneficial for every variant in SOD1.
“These are very expensive therapies, and we will need to have some level of certainty in order to be able to determine whether this should be a treatment for a patient or not,” said Dr. Hardiman.
She also noted that the studies were not powered to provide evidence of efficacy and that they raise questions about the accuracy of the ALSFRS-R.
One issue is that the respiratory part of that scale is “very insensitive”; another is that the scale doesn’t capture nonmotor elements, such as cognition and behavior, she said.
Utilizing a combination of the ALSFRS-R slope and survival would “probably be more beneficial,” Dr. Hardiman said.
Understanding how to alter the genetic influence in a disorder is important to be able to identify successful treatments, Dr. Hardiman added. For example, the discovery of the BRCA gene led oncologists to develop a precision medicine approach to the treatment of breast cancer.
In regard to ALS, by starting with subgroups that have specific genomic features, “investigators are providing new hope for patients at genetic risk for this devastating fatal disease,” said Dr. Hardiman.
The first study was funded by Biogen. The second study was funded by a fellowship grant from the Alzheimer’s Association, a Jack Satter Foundation Award, the ALS Association, the Angel Fund for ALS Research, ALS Finding a Cure, ALS-One, Project ALS, the Massachusetts General Hospital, the Max Rosenfeld and Cellucci Funds for ALS Research, and several senior members of Bain Capital. Dr. Ferguson is employed by and holds stock in Biogen. Dr. Brown receives grant support from the National Institute of Neurological Disorders and Stroke. He is also co-founder of Apic Bio. Dr. Hardiman is the editor-in-chief of the Journal of Amyotrophic Lateral Sclerosis and Frontotemporal Degenerations, has consulted for Cytokinetics, Mitsubishi, and Wave, and holds research grants from Novartis and Merck. During the past 2 years, she has also been a principal investigator on ALS clinical trials sponsored by Orion and Cytokinetics and is currently on the data and safety monitoring board of Accelsior.
This article first appeared on Medscape.com.
. Both studies investigated potential benefits of suppressing the toxic activity in cells of a mutant gene (SOD1) that encodes superoxide dismutase 1 (SOD1) in patients with ALS.
One study investigated the antisense oligonucleotide (ASO) tofersen (Biogen); the other study examined viral vector–mediated gene suppression.
The studies’ promising results signal “the beginning of a new precision medicine–based approach towards treating ALS,” said Orla Hardiman, BSc, MB, BCh, BAO, MD, a consultant neurologist and professor of neurology at Trinity College and Beaumont Hospital in Dublin, Ireland. Dr. Hardiman co-authored an editorial that accompanied the two studies, which were published July 9 in the New England Journal of Medicine.
Genetic culprits
ALS is a disorder of progressive degeneration of upper and lower motor neurons. It typically leads to death from ventilatory failure within 5 years of symptom onset.
Genetic factors are responsible for about half the risk variance of ALS. In populations of European origin, variants in SOD1 account for an estimated 13% to 20% of familial ALS, although this rate varies around the world. Although SOD1 is not the most common variant in ALS, it is the one that researchers are most familiar with and has been studied in an animal model.
In the first study, investigators evaluated the safety, pharmacokinetics, and pharmacodynamics of the ASO tofersen in adults with ALS.
An ASO is a small piece of nucleic acid that enters neurons in the spinal cord and brain, explained co-investigator Toby A. Ferguson, MD, PhD, vice president and head of the neuromuscular development unit at Biogen.
ASO binds to the SOD1 gene and knocks down the SOD1 protein, which is the “toxic engine [that] drives the disease, kills neurons, and causes patients to have loss of function and eventually to die,” said Dr. Ferguson. “The ASO turns off the motor that produces that toxic protein,” he added.
Animal studies have shown that ASOs that target SOD1 messenger RNA transcripts prolong survival, improve motor performance, and reduce SOD1 protein concentrations.
The new phase 1/2 double-blind study included 50 adults at 18 sites in the United States, Canada, and four European countries. All had muscle weakness attributed to ALS and a documented SOD1 mutation. Participants were randomly assigned to receive one of four doses of tofersen—20, 40, 60, or 100 mg—or placebo. Treatment was administered via a lumbar intrathecal bolus injection. The study included a screening period followed by a 12-week intervention period and a 12-week follow-up.
Adverse events
A primary outcome was the incidence of adverse events (AEs) and serious AEs. Results showed that all participants reported one or more AEs. The most common AEs were headache, pain at the injection site, post–lumbar puncture syndrome, and falls. Three deaths occurred, one in the placebo group, one in the 20-mg dose group, and one in the 60-mg dose group. There were no serious AEs in the 100-mg group.
Although the investigators found an increase in cerebrospinal fluid (CSF) protein and white cell counts, there was no clear association between these observations and higher doses of tofersen or longer duration of exposure.
“We don’t know the implications of this, and it’s something we need to keep an eye on as we move these studies forward,” Dr. Ferguson said.
None of the AEs or CSF abnormalities led to trial discontinuation.
A secondary outcome was change in SOD1 protein concentration in CSF at day 85. The study showed that SOD1 concentrations decreased by 36% among the participants who received tofersen 100 mg and by lesser amounts in the patients who received lower doses. Concentrations in the placebo group were reduced by 3%.
The 36% reduction in the highest dose group is likely meaningful and “foundational to the concept of what this molecule can do,” Dr. Ferguson said.
“If the number one cause of SOD1 ALS is accumulation of toxic SOD1 protein, then the demonstration that we can reduce SOD1 protein in the CSF ... is saying that’s the first step on the way to showing the molecule is doing what it should do,” he added.
Emerging tool
In patients with ALS, neurofilament concentrations typically increase as the disease progresses. However, this study documented a reduction in these CSF concentrations. “One interpretation of that could be that there is less neurodegeneration or neuro injury” in patients treated with tofersen, Dr. Ferguson said.
He noted that neurofilament is “an emerging tool” for understanding neurodegeneration. It could also “be another sort of biochemical signal that the molecule is doing something important,” he added.
However, he noted that neurofilament concentration is still an exploratory marker.
Exploratory analyses suggested a possible slowing of functional loss, as measured by the ALS Functional Rating Scale–Revised (ALSFRS-R) score and the handheld dynamometry megascore. The latter assesses strength in 16 muscle groups in the arms and legs. The investigators noted that no conclusions can be drawn from these outcomes.
A post hoc analysis showed that among patients with SOD1 mutations associated with a fast-progressing disease course, the slope of clinical decline might have been gentler, and there was a greater decrease in CSF neurofilament concentration compared among those whose disease followed a slower course.
This suggests that “if you pick the right target,” even patients with severe disease can be treated, Dr. Ferguson said.
He acknowledged that in a relatively short study such as this one, it may be easier to see benefits in patients whose disease is progressing rapidly. However, he’s convinced that the treatment “would work for all SOD1 ALS patients, not just fast patients.”
Dr. Ferguson said the study investigators are encouraged by the new data, which “really suggest that we may be developing a meaningful treatment for SOD1 ALS.” However, “it’s still early” in terms of rolling out this therapy for patients with ALS, he said.
The safety and efficacy of tofersen are currently being evaluated in a phase 3, randomized, double-blind, placebo-controlled trial.
Limitations of the current study were the small number of participants, the short duration of treatment and follow-up, the exploratory nature of efficacy outcomes, and the post hoc methods for defining the fast-progressing subgroup.
Although an advantage of tofersen is that it can enter the nucleus of the cell, perhaps boosting effectiveness, a drawback might be that patients need several treatments administered via lumbar puncture. Following three initial doses, the drug is given every month.
An alternative approach might be a viral vector approach.
“Stunning” finding
In the second study, investigators assessed the safety of a single intrathecal infusion of a viral vector therapy designed to target SOD1 in two patients with familial ALS. The two patients were a 22-year-old man whose mother had died of ALS at age 45 and a 56-year-old man who had a family history of ALS.
The aim of the viral vector therapy is to continually suppress mutant gene activity, said study co-investigator Robert H. Brown, Jr, MD, professor of neurology, University of Massachusetts Medical School, Worcester.
“The virus essentially drops off a piece of DNA, and that DNA keeps making the agent that suppresses the gene,” Dr. Brown said.
He noted that the first patient had a mutation that causes a rapidly developing, “horribly devastating” disease.
Initially, the patient’s right leg, in which movement had been worsening over several weeks, “seemed to get stronger and remain strong for quite a long time. I’ve never seen that in this kind of mutation,” said Dr. Brown.
The patient died of ALS. At autopsy, there was evidence of suppression of SOD1 in the spinal cord. There was some preservation of motor neurons on the right side of the spinal cord, which Dr. Brown called a “stunning” finding.
“We have never seen preservation of motor neurons in an autopsy of a patient with this kind of mutation before,” he said.
Prior to the patient’s death, there were some initial signs of a decrease of SOD1 in CSF. However, the patient developed an inflammatory response in the lining of the CSF known as meningoradiculitis.
“In that setting, the SOD1 level went back up, so we could not say that we produced a significant lasting decrease,” Dr. Brown said.
One and done
Because meningoradiculitis occurred in the first patient, immunosuppressive drugs were administered to the second patient.
The functional status and vital capacity of the second patient were relatively stable during a 60-week period, a course that could be typical of the slow disease progression in patients with this SOD1 genotype.
As with the first patient, this man did not experience a substantial change in SOD1 protein levels in CSF, and he did not show clinical improvement.
The main advantage of a viral gene therapy is that it could be a one-time treatment; ideally, it could be used to replace a single missing gene in conditions such as cystic fibrosis. “The hope is that the virus will drop off the gene modulator or the gene itself of interest, depending on the disease, and that the gene will be there more or less indefinitely,” said Dr. Brown. “So the cliché is, ‘one and done’—if all goes well.”
This small study illustrates that gene therapy safely “turns off genes and that the extent of suppression of genes can be significant,” said Dr. Brown.
Most SOD1 mutations could be treated with this microRNA viral vector, he added. More than 180 such mutations have been identified in ALS.
Additional studies are now needed to determine the results of this method in a larger number of patients who have ALS with SOD1 mutations, the investigators wrote.
Within reach
Both studies are encouraging in that they show that a precision-medicine approach to ALS associated with single mutated genes “may be within reach,” said Dr. Hardiman.
She noted that gene therapies have been used successfully in other motor neuron conditions. For example, an ASO and a viral vector have “very significant efficacy” in a form of spinal muscular atrophy that occurs in infants. “So the underlying proof of principle is already there.”
The reduction in SOD1 levels among the highest-dose tofersen group in the first study indicates “target engagement,” Dr. Hardiman said.
In that study, the documented decreased protein in the CSF appeared to be dose related, as was the effect for neurofilaments, which is biomarker evidence of neuronal damage, she noted.
In the second study, the pathologic evidence from the first patient also suggests “evidence of target engagement,” Dr. Hardiman said.
However, she added, “We don’t know very much about the outcome of the second case other than immunosuppression seemed to be beneficial.”
New hope
Both studies have caveats, said Dr. Hardiman. For example, it is unclear whether the treatments would be beneficial for every variant in SOD1.
“These are very expensive therapies, and we will need to have some level of certainty in order to be able to determine whether this should be a treatment for a patient or not,” said Dr. Hardiman.
She also noted that the studies were not powered to provide evidence of efficacy and that they raise questions about the accuracy of the ALSFRS-R.
One issue is that the respiratory part of that scale is “very insensitive”; another is that the scale doesn’t capture nonmotor elements, such as cognition and behavior, she said.
Utilizing a combination of the ALSFRS-R slope and survival would “probably be more beneficial,” Dr. Hardiman said.
Understanding how to alter the genetic influence in a disorder is important to be able to identify successful treatments, Dr. Hardiman added. For example, the discovery of the BRCA gene led oncologists to develop a precision medicine approach to the treatment of breast cancer.
In regard to ALS, by starting with subgroups that have specific genomic features, “investigators are providing new hope for patients at genetic risk for this devastating fatal disease,” said Dr. Hardiman.
The first study was funded by Biogen. The second study was funded by a fellowship grant from the Alzheimer’s Association, a Jack Satter Foundation Award, the ALS Association, the Angel Fund for ALS Research, ALS Finding a Cure, ALS-One, Project ALS, the Massachusetts General Hospital, the Max Rosenfeld and Cellucci Funds for ALS Research, and several senior members of Bain Capital. Dr. Ferguson is employed by and holds stock in Biogen. Dr. Brown receives grant support from the National Institute of Neurological Disorders and Stroke. He is also co-founder of Apic Bio. Dr. Hardiman is the editor-in-chief of the Journal of Amyotrophic Lateral Sclerosis and Frontotemporal Degenerations, has consulted for Cytokinetics, Mitsubishi, and Wave, and holds research grants from Novartis and Merck. During the past 2 years, she has also been a principal investigator on ALS clinical trials sponsored by Orion and Cytokinetics and is currently on the data and safety monitoring board of Accelsior.
This article first appeared on Medscape.com.
FROM NEW ENGLAND JOURNAL OF MEDICINE
Does moderate drinking slow cognitive decline?
new research suggests. However, at least one expert urges caution in interpreting the findings.
Investigators found that consuming 10-14 alcoholic drinks per week had the strongest cognitive benefit. The findings “add more weight” to the growing body of research identifying beneficial cognitive effects of moderate alcohol consumption, said lead author, Ruiyuan Zhang, MD, of the department of epidemiology and biostatistics at the University of Georgia, Athens. However, Dr. Zhang emphasized that nondrinkers should not take up drinking to protect brain function, as alcohol can have negative effects.
The study was published online in JAMA Network Open.
Slower cognitive decline
The observational study was a secondary analysis of data from the Health and Retirement Study, a nationally representative U.S. survey of middle-aged and older adults. The survey, which began in 1992, is conducted every 2 years and collects health and economic data.
The current analysis used data from 1996 to 2008 and included information from individuals who participated in at least three surveys. The study included 19,887 participants, with a mean age 61.8 years. Most (60.1%) were women and white (85.2%). Mean follow-up was 9.1 years.
Researchers measured cognitive domains of mental status, word recall, and vocabulary. They also calculated a total cognition score, with higher scores indicating better cognitive abilities.
For each cognitive function measure, researchers categorized participants into a consistently low–trajectory group in which cognitive test scores from baseline through follow-up were consistently low or a consistently high–trajectory group, where cognitive test scores from baseline through follow-up were consistently high.
Based on self-reports, the investigators categorized participants as never drinkers (41.8%), former drinkers (39.5%), or current drinkers (18.7%). For current drinkers, researchers determined the number of drinking days per week and number of drinks per day. They further categorized these participants as low to moderate drinkers or heavy drinkers.
One drink was defined as a 12-ounce bottle of beer, a 5-ounce glass of wine, or a 1.5-ounce shot of spirits, said Dr. Zhang.
Women who consumed 8 or more drinks per week and men who drank 15 or more drinks per week were considered heavy drinkers. Other current drinkers were deemed low to moderate drinkers. Most current drinkers (85.2%) were low to moderate drinkers.
Other covariates included age, sex, race/ethnicity, years of education, marital status, tobacco smoking status, and body mass index.
Results showed moderate drinking was associated with relatively high cognitive test scores. After controlling for all covariates, compared with never drinkers, current low to moderate drinkers were significantly less likely to have consistently low trajectories for total cognitive score (odds ratio, 0.66; 95% confidence interval, 0.59-0.74), mental status (OR, 0.71; 95% CI, 0.63-0.81), word recall (OR, 0.74; 95% CI, 0.69-0.80), and vocabulary (OR, 0.64; 95% CI, 0.56-0.74) (all P < .001).
Former drinkers also had better cognitive outcomes for all cognitive domains. Heavy drinkers had lower odds of being in the consistently low trajectory group only for the vocabulary test.
Heavy drinking ‘risky’
Because few participants were deemed to be heavy drinkers, the power to identify an association between heavy drinking and cognitive function was limited. Dr. Zhang acknowledged, though he noted that heavy drinking is “risky.”
“We found that, after the drinking dosage passes the moderate level, the risk of low cognitive function increases very fast, which indicates that heavy drinking may harm cognitive function.” Limiting alcohol consumption “is still very important,” he said.
The associations of alcohol and cognitive functions differed by race/ethnicity. Low to moderate drinking was significantly associated with a lower odds of having a consistently low trajectory for all four cognitive function measures only among white participants.
A possible reason for this is that the study had so few African Americans (who made up only 14.8% of the sample), which limited the ability to identify relationships between alcohol intake and cognitive function, said Dr. Zhang. “Another reason is that the sensitivity to alcohol may be different between white and African American subjects.”
There was a significant U-shaped association between weekly amounts of alcohol and the odds of being in the consistently low–trajectory group for all cognitive functions. Depending on the function tested, the optimal number of weekly drinks ranged from 10-14.
Dr. Zhang noted that, when women were examined separately, alcohol consumption had a significant U-shaped relationship only with word recall, with the optimal dosage being around eight drinks.
U-shaped relationship an ‘important finding’
The U-shaped relationship is “an important finding,” said Dr. Zhang. “It shows that the human body may act differently to low and high doses of alcohol. Knowing why and how this happens is very important as it would help us understand how alcohol affects the function of the human body.”
Sensitivity analyses among participants with no chronic diseases showed the U-shaped association was still significant for scores of total word recall and vocabulary, but not for mental status or total cognition score.
The authors noted that 77.2% of participants had at least one chronic disease. They maintained that the association between alcohol consumption and cognitive function may be applicable both to healthy people and to those with a chronic disease.
The study also found that low to moderate drinkers had slower rates of cognitive decline over time for all cognition domains.
Although the mechanisms underlying the cognitive benefits of alcohol consumption are unclear, the authors believe it may be via cerebrovascular and cardiovascular pathways.
Alcohol may increase levels of brain-derived neurotrophic factor, a key regulator of neuronal plasticity and development in the dorsal striatum, they noted.
Balancing act
However, there’s also evidence that drinking, especially heavy drinking, increases the risk of hypertension, stroke, liver damage, and some cancers. “We think the role of alcohol drinking in cognitive function may be a balance of its beneficial and harmful effects on the cardiovascular system,” said Dr. Zhang.
“For the low to moderate drinker, the beneficial effects may outweigh the harmful effects on the small blood vessels in the brain. In this way, it could preserve cognition,” he added.
Dr. Zhang also noted that the study focused on middle-aged and older adults. “We can’t say whether or not moderate alcohol could benefit younger people” because they may have different characteristics, he said.
The findings of other studies examining the effects of alcohol on cognitive function are mixed. While studies have identified a beneficial effect, others have uncovered no, minimal, or adverse effects. This could be due to the use of different tests of cognitive function or different study populations, said Dr. Zhang.
A limitation of the current study was that assessment of alcohol consumption was based on self-report, which might have introduced recall bias. In addition, because individuals tend to underestimate their alcohol consumption, heavy drinkers could be misclassified as low to moderate drinkers, and low to moderate drinkers as former drinkers.
“This may make our study underestimate the association between low to moderate drinking and cognitive function,” said Dr. Zhang. In addition, alcohol consumption tended to change with time, and this change may be associated with other factors that led to changes in cognitive function, the authors noted.
Interpret with caution
Commenting on the study, Brent P. Forester, MD, chief of the Center of Excellence in Geriatric Psychiatry at McLean Hospital in Belmont, Mass., associate professor of psychiatry at Harvard Medical School, Boston, and a member of the American Psychiatric Association Council on Geriatric Psychiatry, said he views the study with some trepidation.
“As a clinician taking care of older adults, I would be very cautious about overinterpreting the beneficial effects of alcohol before we understand the mechanism better,” he said.
He noted that all of the risk factors associated with heart attack and stroke are also risk factors for Alzheimer’s disease and cognitive decline more broadly. “One of the issues here is how in the world does alcohol reduce cardiovascular and cerebrovascular risks, if you know it increases the risk of hypertension and stroke, regardless of dose.”
With regard to the possible impact of alcohol on brain-derived neurotrophic factor, Dr. Forester said, “it’s an interesting idea” but the actual mechanism is still unclear.
Even with dietary studies, such as those on the Mediterranean diet that include red wine, showing cognitive benefit, Dr. Forester said he’s still concerned about the adverse effects of alcohol on older people. These can include falls and sleep disturbances in addition to cognitive issues, and these effects can increase with age.
He was somewhat surprised at the level of alcohol that the study determined was beneficial. “Essentially, what they’re saying here is that, for men, it’s two drinks a day.” This could be “problematic” as two drinks per day can quickly escalate as individuals build tolerance.
He also pointed out that the study does not determine cause and effect, noting that it’s only an association.
Dr. Forester said the study raises a number of questions, including the type of alcohol study participants consumed and whether this has any impact on cognitive benefit. He also questioned whether the mediating effects of alcohol were associated with something that wasn’t measured, such as socioeconomic status.
Another question, he said, is what factors in individuals’ medical or psychiatric history determine whether they are more or less likely to benefit from low to moderate alcohol intake.
Perhaps alcohol should be recommended only for “select subpopulations” – for example, those who are healthy and have a family history of cognitive decline –but not for those with a history of substance abuse, including alcohol abuse, said Dr. Forester.
“For this population, the last thing you want to do is recommend alcohol to reduce risk of cognitive decline,” he cautioned.
The study was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health. The investigators and Dr. Forester have reported no relevant financial disclosures.
A version of this story originally appeared on Medscape.com.
new research suggests. However, at least one expert urges caution in interpreting the findings.
Investigators found that consuming 10-14 alcoholic drinks per week had the strongest cognitive benefit. The findings “add more weight” to the growing body of research identifying beneficial cognitive effects of moderate alcohol consumption, said lead author, Ruiyuan Zhang, MD, of the department of epidemiology and biostatistics at the University of Georgia, Athens. However, Dr. Zhang emphasized that nondrinkers should not take up drinking to protect brain function, as alcohol can have negative effects.
The study was published online in JAMA Network Open.
Slower cognitive decline
The observational study was a secondary analysis of data from the Health and Retirement Study, a nationally representative U.S. survey of middle-aged and older adults. The survey, which began in 1992, is conducted every 2 years and collects health and economic data.
The current analysis used data from 1996 to 2008 and included information from individuals who participated in at least three surveys. The study included 19,887 participants, with a mean age 61.8 years. Most (60.1%) were women and white (85.2%). Mean follow-up was 9.1 years.
Researchers measured cognitive domains of mental status, word recall, and vocabulary. They also calculated a total cognition score, with higher scores indicating better cognitive abilities.
For each cognitive function measure, researchers categorized participants into a consistently low–trajectory group in which cognitive test scores from baseline through follow-up were consistently low or a consistently high–trajectory group, where cognitive test scores from baseline through follow-up were consistently high.
Based on self-reports, the investigators categorized participants as never drinkers (41.8%), former drinkers (39.5%), or current drinkers (18.7%). For current drinkers, researchers determined the number of drinking days per week and number of drinks per day. They further categorized these participants as low to moderate drinkers or heavy drinkers.
One drink was defined as a 12-ounce bottle of beer, a 5-ounce glass of wine, or a 1.5-ounce shot of spirits, said Dr. Zhang.
Women who consumed 8 or more drinks per week and men who drank 15 or more drinks per week were considered heavy drinkers. Other current drinkers were deemed low to moderate drinkers. Most current drinkers (85.2%) were low to moderate drinkers.
Other covariates included age, sex, race/ethnicity, years of education, marital status, tobacco smoking status, and body mass index.
Results showed moderate drinking was associated with relatively high cognitive test scores. After controlling for all covariates, compared with never drinkers, current low to moderate drinkers were significantly less likely to have consistently low trajectories for total cognitive score (odds ratio, 0.66; 95% confidence interval, 0.59-0.74), mental status (OR, 0.71; 95% CI, 0.63-0.81), word recall (OR, 0.74; 95% CI, 0.69-0.80), and vocabulary (OR, 0.64; 95% CI, 0.56-0.74) (all P < .001).
Former drinkers also had better cognitive outcomes for all cognitive domains. Heavy drinkers had lower odds of being in the consistently low trajectory group only for the vocabulary test.
Heavy drinking ‘risky’
Because few participants were deemed to be heavy drinkers, the power to identify an association between heavy drinking and cognitive function was limited. Dr. Zhang acknowledged, though he noted that heavy drinking is “risky.”
“We found that, after the drinking dosage passes the moderate level, the risk of low cognitive function increases very fast, which indicates that heavy drinking may harm cognitive function.” Limiting alcohol consumption “is still very important,” he said.
The associations of alcohol and cognitive functions differed by race/ethnicity. Low to moderate drinking was significantly associated with a lower odds of having a consistently low trajectory for all four cognitive function measures only among white participants.
A possible reason for this is that the study had so few African Americans (who made up only 14.8% of the sample), which limited the ability to identify relationships between alcohol intake and cognitive function, said Dr. Zhang. “Another reason is that the sensitivity to alcohol may be different between white and African American subjects.”
There was a significant U-shaped association between weekly amounts of alcohol and the odds of being in the consistently low–trajectory group for all cognitive functions. Depending on the function tested, the optimal number of weekly drinks ranged from 10-14.
Dr. Zhang noted that, when women were examined separately, alcohol consumption had a significant U-shaped relationship only with word recall, with the optimal dosage being around eight drinks.
U-shaped relationship an ‘important finding’
The U-shaped relationship is “an important finding,” said Dr. Zhang. “It shows that the human body may act differently to low and high doses of alcohol. Knowing why and how this happens is very important as it would help us understand how alcohol affects the function of the human body.”
Sensitivity analyses among participants with no chronic diseases showed the U-shaped association was still significant for scores of total word recall and vocabulary, but not for mental status or total cognition score.
The authors noted that 77.2% of participants had at least one chronic disease. They maintained that the association between alcohol consumption and cognitive function may be applicable both to healthy people and to those with a chronic disease.
The study also found that low to moderate drinkers had slower rates of cognitive decline over time for all cognition domains.
Although the mechanisms underlying the cognitive benefits of alcohol consumption are unclear, the authors believe it may be via cerebrovascular and cardiovascular pathways.
Alcohol may increase levels of brain-derived neurotrophic factor, a key regulator of neuronal plasticity and development in the dorsal striatum, they noted.
Balancing act
However, there’s also evidence that drinking, especially heavy drinking, increases the risk of hypertension, stroke, liver damage, and some cancers. “We think the role of alcohol drinking in cognitive function may be a balance of its beneficial and harmful effects on the cardiovascular system,” said Dr. Zhang.
“For the low to moderate drinker, the beneficial effects may outweigh the harmful effects on the small blood vessels in the brain. In this way, it could preserve cognition,” he added.
Dr. Zhang also noted that the study focused on middle-aged and older adults. “We can’t say whether or not moderate alcohol could benefit younger people” because they may have different characteristics, he said.
The findings of other studies examining the effects of alcohol on cognitive function are mixed. While studies have identified a beneficial effect, others have uncovered no, minimal, or adverse effects. This could be due to the use of different tests of cognitive function or different study populations, said Dr. Zhang.
A limitation of the current study was that assessment of alcohol consumption was based on self-report, which might have introduced recall bias. In addition, because individuals tend to underestimate their alcohol consumption, heavy drinkers could be misclassified as low to moderate drinkers, and low to moderate drinkers as former drinkers.
“This may make our study underestimate the association between low to moderate drinking and cognitive function,” said Dr. Zhang. In addition, alcohol consumption tended to change with time, and this change may be associated with other factors that led to changes in cognitive function, the authors noted.
Interpret with caution
Commenting on the study, Brent P. Forester, MD, chief of the Center of Excellence in Geriatric Psychiatry at McLean Hospital in Belmont, Mass., associate professor of psychiatry at Harvard Medical School, Boston, and a member of the American Psychiatric Association Council on Geriatric Psychiatry, said he views the study with some trepidation.
“As a clinician taking care of older adults, I would be very cautious about overinterpreting the beneficial effects of alcohol before we understand the mechanism better,” he said.
He noted that all of the risk factors associated with heart attack and stroke are also risk factors for Alzheimer’s disease and cognitive decline more broadly. “One of the issues here is how in the world does alcohol reduce cardiovascular and cerebrovascular risks, if you know it increases the risk of hypertension and stroke, regardless of dose.”
With regard to the possible impact of alcohol on brain-derived neurotrophic factor, Dr. Forester said, “it’s an interesting idea” but the actual mechanism is still unclear.
Even with dietary studies, such as those on the Mediterranean diet that include red wine, showing cognitive benefit, Dr. Forester said he’s still concerned about the adverse effects of alcohol on older people. These can include falls and sleep disturbances in addition to cognitive issues, and these effects can increase with age.
He was somewhat surprised at the level of alcohol that the study determined was beneficial. “Essentially, what they’re saying here is that, for men, it’s two drinks a day.” This could be “problematic” as two drinks per day can quickly escalate as individuals build tolerance.
He also pointed out that the study does not determine cause and effect, noting that it’s only an association.
Dr. Forester said the study raises a number of questions, including the type of alcohol study participants consumed and whether this has any impact on cognitive benefit. He also questioned whether the mediating effects of alcohol were associated with something that wasn’t measured, such as socioeconomic status.
Another question, he said, is what factors in individuals’ medical or psychiatric history determine whether they are more or less likely to benefit from low to moderate alcohol intake.
Perhaps alcohol should be recommended only for “select subpopulations” – for example, those who are healthy and have a family history of cognitive decline –but not for those with a history of substance abuse, including alcohol abuse, said Dr. Forester.
“For this population, the last thing you want to do is recommend alcohol to reduce risk of cognitive decline,” he cautioned.
The study was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health. The investigators and Dr. Forester have reported no relevant financial disclosures.
A version of this story originally appeared on Medscape.com.
new research suggests. However, at least one expert urges caution in interpreting the findings.
Investigators found that consuming 10-14 alcoholic drinks per week had the strongest cognitive benefit. The findings “add more weight” to the growing body of research identifying beneficial cognitive effects of moderate alcohol consumption, said lead author, Ruiyuan Zhang, MD, of the department of epidemiology and biostatistics at the University of Georgia, Athens. However, Dr. Zhang emphasized that nondrinkers should not take up drinking to protect brain function, as alcohol can have negative effects.
The study was published online in JAMA Network Open.
Slower cognitive decline
The observational study was a secondary analysis of data from the Health and Retirement Study, a nationally representative U.S. survey of middle-aged and older adults. The survey, which began in 1992, is conducted every 2 years and collects health and economic data.
The current analysis used data from 1996 to 2008 and included information from individuals who participated in at least three surveys. The study included 19,887 participants, with a mean age 61.8 years. Most (60.1%) were women and white (85.2%). Mean follow-up was 9.1 years.
Researchers measured cognitive domains of mental status, word recall, and vocabulary. They also calculated a total cognition score, with higher scores indicating better cognitive abilities.
For each cognitive function measure, researchers categorized participants into a consistently low–trajectory group in which cognitive test scores from baseline through follow-up were consistently low or a consistently high–trajectory group, where cognitive test scores from baseline through follow-up were consistently high.
Based on self-reports, the investigators categorized participants as never drinkers (41.8%), former drinkers (39.5%), or current drinkers (18.7%). For current drinkers, researchers determined the number of drinking days per week and number of drinks per day. They further categorized these participants as low to moderate drinkers or heavy drinkers.
One drink was defined as a 12-ounce bottle of beer, a 5-ounce glass of wine, or a 1.5-ounce shot of spirits, said Dr. Zhang.
Women who consumed 8 or more drinks per week and men who drank 15 or more drinks per week were considered heavy drinkers. Other current drinkers were deemed low to moderate drinkers. Most current drinkers (85.2%) were low to moderate drinkers.
Other covariates included age, sex, race/ethnicity, years of education, marital status, tobacco smoking status, and body mass index.
Results showed moderate drinking was associated with relatively high cognitive test scores. After controlling for all covariates, compared with never drinkers, current low to moderate drinkers were significantly less likely to have consistently low trajectories for total cognitive score (odds ratio, 0.66; 95% confidence interval, 0.59-0.74), mental status (OR, 0.71; 95% CI, 0.63-0.81), word recall (OR, 0.74; 95% CI, 0.69-0.80), and vocabulary (OR, 0.64; 95% CI, 0.56-0.74) (all P < .001).
Former drinkers also had better cognitive outcomes for all cognitive domains. Heavy drinkers had lower odds of being in the consistently low trajectory group only for the vocabulary test.
Heavy drinking ‘risky’
Because few participants were deemed to be heavy drinkers, the power to identify an association between heavy drinking and cognitive function was limited. Dr. Zhang acknowledged, though he noted that heavy drinking is “risky.”
“We found that, after the drinking dosage passes the moderate level, the risk of low cognitive function increases very fast, which indicates that heavy drinking may harm cognitive function.” Limiting alcohol consumption “is still very important,” he said.
The associations of alcohol and cognitive functions differed by race/ethnicity. Low to moderate drinking was significantly associated with a lower odds of having a consistently low trajectory for all four cognitive function measures only among white participants.
A possible reason for this is that the study had so few African Americans (who made up only 14.8% of the sample), which limited the ability to identify relationships between alcohol intake and cognitive function, said Dr. Zhang. “Another reason is that the sensitivity to alcohol may be different between white and African American subjects.”
There was a significant U-shaped association between weekly amounts of alcohol and the odds of being in the consistently low–trajectory group for all cognitive functions. Depending on the function tested, the optimal number of weekly drinks ranged from 10-14.
Dr. Zhang noted that, when women were examined separately, alcohol consumption had a significant U-shaped relationship only with word recall, with the optimal dosage being around eight drinks.
U-shaped relationship an ‘important finding’
The U-shaped relationship is “an important finding,” said Dr. Zhang. “It shows that the human body may act differently to low and high doses of alcohol. Knowing why and how this happens is very important as it would help us understand how alcohol affects the function of the human body.”
Sensitivity analyses among participants with no chronic diseases showed the U-shaped association was still significant for scores of total word recall and vocabulary, but not for mental status or total cognition score.
The authors noted that 77.2% of participants had at least one chronic disease. They maintained that the association between alcohol consumption and cognitive function may be applicable both to healthy people and to those with a chronic disease.
The study also found that low to moderate drinkers had slower rates of cognitive decline over time for all cognition domains.
Although the mechanisms underlying the cognitive benefits of alcohol consumption are unclear, the authors believe it may be via cerebrovascular and cardiovascular pathways.
Alcohol may increase levels of brain-derived neurotrophic factor, a key regulator of neuronal plasticity and development in the dorsal striatum, they noted.
Balancing act
However, there’s also evidence that drinking, especially heavy drinking, increases the risk of hypertension, stroke, liver damage, and some cancers. “We think the role of alcohol drinking in cognitive function may be a balance of its beneficial and harmful effects on the cardiovascular system,” said Dr. Zhang.
“For the low to moderate drinker, the beneficial effects may outweigh the harmful effects on the small blood vessels in the brain. In this way, it could preserve cognition,” he added.
Dr. Zhang also noted that the study focused on middle-aged and older adults. “We can’t say whether or not moderate alcohol could benefit younger people” because they may have different characteristics, he said.
The findings of other studies examining the effects of alcohol on cognitive function are mixed. While studies have identified a beneficial effect, others have uncovered no, minimal, or adverse effects. This could be due to the use of different tests of cognitive function or different study populations, said Dr. Zhang.
A limitation of the current study was that assessment of alcohol consumption was based on self-report, which might have introduced recall bias. In addition, because individuals tend to underestimate their alcohol consumption, heavy drinkers could be misclassified as low to moderate drinkers, and low to moderate drinkers as former drinkers.
“This may make our study underestimate the association between low to moderate drinking and cognitive function,” said Dr. Zhang. In addition, alcohol consumption tended to change with time, and this change may be associated with other factors that led to changes in cognitive function, the authors noted.
Interpret with caution
Commenting on the study, Brent P. Forester, MD, chief of the Center of Excellence in Geriatric Psychiatry at McLean Hospital in Belmont, Mass., associate professor of psychiatry at Harvard Medical School, Boston, and a member of the American Psychiatric Association Council on Geriatric Psychiatry, said he views the study with some trepidation.
“As a clinician taking care of older adults, I would be very cautious about overinterpreting the beneficial effects of alcohol before we understand the mechanism better,” he said.
He noted that all of the risk factors associated with heart attack and stroke are also risk factors for Alzheimer’s disease and cognitive decline more broadly. “One of the issues here is how in the world does alcohol reduce cardiovascular and cerebrovascular risks, if you know it increases the risk of hypertension and stroke, regardless of dose.”
With regard to the possible impact of alcohol on brain-derived neurotrophic factor, Dr. Forester said, “it’s an interesting idea” but the actual mechanism is still unclear.
Even with dietary studies, such as those on the Mediterranean diet that include red wine, showing cognitive benefit, Dr. Forester said he’s still concerned about the adverse effects of alcohol on older people. These can include falls and sleep disturbances in addition to cognitive issues, and these effects can increase with age.
He was somewhat surprised at the level of alcohol that the study determined was beneficial. “Essentially, what they’re saying here is that, for men, it’s two drinks a day.” This could be “problematic” as two drinks per day can quickly escalate as individuals build tolerance.
He also pointed out that the study does not determine cause and effect, noting that it’s only an association.
Dr. Forester said the study raises a number of questions, including the type of alcohol study participants consumed and whether this has any impact on cognitive benefit. He also questioned whether the mediating effects of alcohol were associated with something that wasn’t measured, such as socioeconomic status.
Another question, he said, is what factors in individuals’ medical or psychiatric history determine whether they are more or less likely to benefit from low to moderate alcohol intake.
Perhaps alcohol should be recommended only for “select subpopulations” – for example, those who are healthy and have a family history of cognitive decline –but not for those with a history of substance abuse, including alcohol abuse, said Dr. Forester.
“For this population, the last thing you want to do is recommend alcohol to reduce risk of cognitive decline,” he cautioned.
The study was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health. The investigators and Dr. Forester have reported no relevant financial disclosures.
A version of this story originally appeared on Medscape.com.
Is cannabis gaining acceptance as a treatment for neuropathic pain?
, a recent debate on the topic suggests. During the debate, one expert argued for, and another against, there being sufficient evidence for the use of cannabis to treat neuropathic pain, but in the end, they agreed that some patients do benefit.
The discussion took place at the Congress of the European Academy of Neurology (EAN) 2020, which transitioned to a virtual online meeting because of the COVID-19 pandemic.
The cannabis plant has 460 constituents. The two main components are tetrahydrocannabinol (THC) and cannabidiol (CBD). It can be consumed by swallowing oil extracts, by the sublingual route, or by smoking or eating the plant. Cannabis medications already in use include oral THC (nabilone, dronabinol) and an oral mucosal spray, nabiximols (Sativex).
Arguing that therapeutic cannabis is helpful for neuropathic pain, Elon Eisenberg, MD, professor of neurology and pain medicine, Israel Institute of Technology, Haifa, cited a number of encouraging randomized, controlled trials and meta-analyses of studies on the subject.
Opioid substitute
Dr. Eisenberg discussed three relevant articles. One was a 2016 viewpoint article published in JAMA that concluded that “cannabis seems to be a substitute, a rather good one, for opioids,” said Dr. Eisenberg.
A “comprehensive” 440-page review, published by the National Academies Press in 2017, evaluated the evidence to that point and “came to the conclusion there is substantial evidence that cannabis is an effective treatment for chronic pain in adults,” said Dr. Eisenberg.
And a 2018 position paper from the European Pain Federation determined that “the quantity and quality of evidence is such that cannabis-based medicines may be reasonably considered for chronic neuropathic pain,” he said.
He noted that the most recent results from an Israeli prospective cohort registry study that is following more than 851 patients who are taking cannabis over 1 year are positive. Analyses show a steady reduction in pain intensity and improvements in catastrophizing and disability. Importantly, he said, participants are using fewer opioids. However, about 40% of patients in that registry study experienced some adverse event, although most were not serious, said Dr. Eisenberg.
Not convinced
Arguing on the other side – that therapeutic cannabis is not helpful for neuropathic pain – was Nadine Attal, MD, PhD, professor of therapeutics and pain at the University Versailles Saint Quentin, France. She questioned the quality of some of the research to date and stressed that studies should consider neuropathic pain as a primary outcome – not spasticity or pain in general. They should also be double-blind, randomized, and placebo controlled, she said.
In addition, she said these studies should enroll at least 10 patients per group and should continue for 3 weeks or longer.
Dr. Attal wondered which of the many plant derivatives (phytocannabinoids) are used in cannabis studies.
She discussed four meta-analyses or reviews on the topic, some of which she said are “heterogeneous” and don’t provide convincing evidence for cannabis use in neuropathic pain.
For example, one review examined only marijuana, and all studies in it were short term. One of the studies in this review was of spasticity. Another review included two studies of cancer pain, and the most positive study in NP used short-term inhaled THC.
“There is no evidence to date that cannabinoids, including nabiximols or oral THC, administered for at least 3 weeks are more effective than placebo in neuropathic pain,” she concluded.
Some responders
However, Dr. Attal acknowledged that cannabis might be effective for some patients. In her experience, which has been borne out by some observational studies, patients with paroxysmal pain, or sudden stabbing pain, seem to get more relief from cannabis. “It’s absolutely possible that there’s a subgroup of symptoms or a subgroup of patients with specific symptoms who are much better responders to cannabis than others,” she said.
Asked if patients experience increased pain after withdrawing from cannabis, Dr. Eisenberg said he has observed that many patients stop taking cannabis when they start feeling better, but he hasn’t seen severe withdrawal symptoms.
However, there are other concerns related to cannabis use, said Dr. Eisenberg. A major concern regards driving a vehicle. In Israel, getting behind the wheel is prohibited within 6 hours of using cannabis.
But Dr. Eisenberg pointed out that published data on the safety of cannabis and driving were based on recreational users. “We need to keep in mind that recreational users typically use other substances, so we’re not sure the data is accurate,” he said.
There are increasing reports of stroke, transient ischemic attack, and MI among cannabis users. This is especially concerning because many of these cases involve young male adults who have no risk factors, said Dr. Eisenberg.
One conference delegate asked whether legal issues make it difficult to properly investigate cannabis in large studies. Dr. Eisenberg noted that legal concerns may help explain why there have not been any new randomized, controlled trials for about 2 years. “In the U.S., you can’t do clinical trials; cannabis is still regarded as schedule I substance,” he said.
Some physicians “are reluctant to deal with cannabis unless they get better data,” he said. “Doing research on cannabis seems to be somehow out of the mainstream.” Moreover, the research is difficult to carry out, owing to the complexity of the cannabis plant, which has many constituents. Perhaps it’s a matter of identifying and adding particular components to better demonstrate reduced pain, said Dr. Eisenberg.
Another complicating factor is that bioavailability differs considerably from one patient to another, “sometimes even by 10-fold,” he said.
Dr. Attal’s group will be starting a study next January that will enroll a large sample of patients with neuropathic pain or spasticity. In that study, cannabis will be dispensed through pharmacies and primary care. The aim of the study is “to see how it works in a real-life setting,” she said
Those participating in the virtual session were asked to vote on which side they agreed with. About 57% voted in favor of cannabis use, 14% voted against, and 28% had no opinion.
Dr. Eisenberg has received research grants from Rafa Laboratories, Saga Medical Ltd., Israel Pain Association, and Teva Israel. Dr. Attal has received support from Merck Sharp & Dohme, Sanofi, Ipsen, Novartis, Aptinyx, Air Liquide, Lilly, and Grunenthal.
A version of this article originally appeared on Medscape.com.
, a recent debate on the topic suggests. During the debate, one expert argued for, and another against, there being sufficient evidence for the use of cannabis to treat neuropathic pain, but in the end, they agreed that some patients do benefit.
The discussion took place at the Congress of the European Academy of Neurology (EAN) 2020, which transitioned to a virtual online meeting because of the COVID-19 pandemic.
The cannabis plant has 460 constituents. The two main components are tetrahydrocannabinol (THC) and cannabidiol (CBD). It can be consumed by swallowing oil extracts, by the sublingual route, or by smoking or eating the plant. Cannabis medications already in use include oral THC (nabilone, dronabinol) and an oral mucosal spray, nabiximols (Sativex).
Arguing that therapeutic cannabis is helpful for neuropathic pain, Elon Eisenberg, MD, professor of neurology and pain medicine, Israel Institute of Technology, Haifa, cited a number of encouraging randomized, controlled trials and meta-analyses of studies on the subject.
Opioid substitute
Dr. Eisenberg discussed three relevant articles. One was a 2016 viewpoint article published in JAMA that concluded that “cannabis seems to be a substitute, a rather good one, for opioids,” said Dr. Eisenberg.
A “comprehensive” 440-page review, published by the National Academies Press in 2017, evaluated the evidence to that point and “came to the conclusion there is substantial evidence that cannabis is an effective treatment for chronic pain in adults,” said Dr. Eisenberg.
And a 2018 position paper from the European Pain Federation determined that “the quantity and quality of evidence is such that cannabis-based medicines may be reasonably considered for chronic neuropathic pain,” he said.
He noted that the most recent results from an Israeli prospective cohort registry study that is following more than 851 patients who are taking cannabis over 1 year are positive. Analyses show a steady reduction in pain intensity and improvements in catastrophizing and disability. Importantly, he said, participants are using fewer opioids. However, about 40% of patients in that registry study experienced some adverse event, although most were not serious, said Dr. Eisenberg.
Not convinced
Arguing on the other side – that therapeutic cannabis is not helpful for neuropathic pain – was Nadine Attal, MD, PhD, professor of therapeutics and pain at the University Versailles Saint Quentin, France. She questioned the quality of some of the research to date and stressed that studies should consider neuropathic pain as a primary outcome – not spasticity or pain in general. They should also be double-blind, randomized, and placebo controlled, she said.
In addition, she said these studies should enroll at least 10 patients per group and should continue for 3 weeks or longer.
Dr. Attal wondered which of the many plant derivatives (phytocannabinoids) are used in cannabis studies.
She discussed four meta-analyses or reviews on the topic, some of which she said are “heterogeneous” and don’t provide convincing evidence for cannabis use in neuropathic pain.
For example, one review examined only marijuana, and all studies in it were short term. One of the studies in this review was of spasticity. Another review included two studies of cancer pain, and the most positive study in NP used short-term inhaled THC.
“There is no evidence to date that cannabinoids, including nabiximols or oral THC, administered for at least 3 weeks are more effective than placebo in neuropathic pain,” she concluded.
Some responders
However, Dr. Attal acknowledged that cannabis might be effective for some patients. In her experience, which has been borne out by some observational studies, patients with paroxysmal pain, or sudden stabbing pain, seem to get more relief from cannabis. “It’s absolutely possible that there’s a subgroup of symptoms or a subgroup of patients with specific symptoms who are much better responders to cannabis than others,” she said.
Asked if patients experience increased pain after withdrawing from cannabis, Dr. Eisenberg said he has observed that many patients stop taking cannabis when they start feeling better, but he hasn’t seen severe withdrawal symptoms.
However, there are other concerns related to cannabis use, said Dr. Eisenberg. A major concern regards driving a vehicle. In Israel, getting behind the wheel is prohibited within 6 hours of using cannabis.
But Dr. Eisenberg pointed out that published data on the safety of cannabis and driving were based on recreational users. “We need to keep in mind that recreational users typically use other substances, so we’re not sure the data is accurate,” he said.
There are increasing reports of stroke, transient ischemic attack, and MI among cannabis users. This is especially concerning because many of these cases involve young male adults who have no risk factors, said Dr. Eisenberg.
One conference delegate asked whether legal issues make it difficult to properly investigate cannabis in large studies. Dr. Eisenberg noted that legal concerns may help explain why there have not been any new randomized, controlled trials for about 2 years. “In the U.S., you can’t do clinical trials; cannabis is still regarded as schedule I substance,” he said.
Some physicians “are reluctant to deal with cannabis unless they get better data,” he said. “Doing research on cannabis seems to be somehow out of the mainstream.” Moreover, the research is difficult to carry out, owing to the complexity of the cannabis plant, which has many constituents. Perhaps it’s a matter of identifying and adding particular components to better demonstrate reduced pain, said Dr. Eisenberg.
Another complicating factor is that bioavailability differs considerably from one patient to another, “sometimes even by 10-fold,” he said.
Dr. Attal’s group will be starting a study next January that will enroll a large sample of patients with neuropathic pain or spasticity. In that study, cannabis will be dispensed through pharmacies and primary care. The aim of the study is “to see how it works in a real-life setting,” she said
Those participating in the virtual session were asked to vote on which side they agreed with. About 57% voted in favor of cannabis use, 14% voted against, and 28% had no opinion.
Dr. Eisenberg has received research grants from Rafa Laboratories, Saga Medical Ltd., Israel Pain Association, and Teva Israel. Dr. Attal has received support from Merck Sharp & Dohme, Sanofi, Ipsen, Novartis, Aptinyx, Air Liquide, Lilly, and Grunenthal.
A version of this article originally appeared on Medscape.com.
, a recent debate on the topic suggests. During the debate, one expert argued for, and another against, there being sufficient evidence for the use of cannabis to treat neuropathic pain, but in the end, they agreed that some patients do benefit.
The discussion took place at the Congress of the European Academy of Neurology (EAN) 2020, which transitioned to a virtual online meeting because of the COVID-19 pandemic.
The cannabis plant has 460 constituents. The two main components are tetrahydrocannabinol (THC) and cannabidiol (CBD). It can be consumed by swallowing oil extracts, by the sublingual route, or by smoking or eating the plant. Cannabis medications already in use include oral THC (nabilone, dronabinol) and an oral mucosal spray, nabiximols (Sativex).
Arguing that therapeutic cannabis is helpful for neuropathic pain, Elon Eisenberg, MD, professor of neurology and pain medicine, Israel Institute of Technology, Haifa, cited a number of encouraging randomized, controlled trials and meta-analyses of studies on the subject.
Opioid substitute
Dr. Eisenberg discussed three relevant articles. One was a 2016 viewpoint article published in JAMA that concluded that “cannabis seems to be a substitute, a rather good one, for opioids,” said Dr. Eisenberg.
A “comprehensive” 440-page review, published by the National Academies Press in 2017, evaluated the evidence to that point and “came to the conclusion there is substantial evidence that cannabis is an effective treatment for chronic pain in adults,” said Dr. Eisenberg.
And a 2018 position paper from the European Pain Federation determined that “the quantity and quality of evidence is such that cannabis-based medicines may be reasonably considered for chronic neuropathic pain,” he said.
He noted that the most recent results from an Israeli prospective cohort registry study that is following more than 851 patients who are taking cannabis over 1 year are positive. Analyses show a steady reduction in pain intensity and improvements in catastrophizing and disability. Importantly, he said, participants are using fewer opioids. However, about 40% of patients in that registry study experienced some adverse event, although most were not serious, said Dr. Eisenberg.
Not convinced
Arguing on the other side – that therapeutic cannabis is not helpful for neuropathic pain – was Nadine Attal, MD, PhD, professor of therapeutics and pain at the University Versailles Saint Quentin, France. She questioned the quality of some of the research to date and stressed that studies should consider neuropathic pain as a primary outcome – not spasticity or pain in general. They should also be double-blind, randomized, and placebo controlled, she said.
In addition, she said these studies should enroll at least 10 patients per group and should continue for 3 weeks or longer.
Dr. Attal wondered which of the many plant derivatives (phytocannabinoids) are used in cannabis studies.
She discussed four meta-analyses or reviews on the topic, some of which she said are “heterogeneous” and don’t provide convincing evidence for cannabis use in neuropathic pain.
For example, one review examined only marijuana, and all studies in it were short term. One of the studies in this review was of spasticity. Another review included two studies of cancer pain, and the most positive study in NP used short-term inhaled THC.
“There is no evidence to date that cannabinoids, including nabiximols or oral THC, administered for at least 3 weeks are more effective than placebo in neuropathic pain,” she concluded.
Some responders
However, Dr. Attal acknowledged that cannabis might be effective for some patients. In her experience, which has been borne out by some observational studies, patients with paroxysmal pain, or sudden stabbing pain, seem to get more relief from cannabis. “It’s absolutely possible that there’s a subgroup of symptoms or a subgroup of patients with specific symptoms who are much better responders to cannabis than others,” she said.
Asked if patients experience increased pain after withdrawing from cannabis, Dr. Eisenberg said he has observed that many patients stop taking cannabis when they start feeling better, but he hasn’t seen severe withdrawal symptoms.
However, there are other concerns related to cannabis use, said Dr. Eisenberg. A major concern regards driving a vehicle. In Israel, getting behind the wheel is prohibited within 6 hours of using cannabis.
But Dr. Eisenberg pointed out that published data on the safety of cannabis and driving were based on recreational users. “We need to keep in mind that recreational users typically use other substances, so we’re not sure the data is accurate,” he said.
There are increasing reports of stroke, transient ischemic attack, and MI among cannabis users. This is especially concerning because many of these cases involve young male adults who have no risk factors, said Dr. Eisenberg.
One conference delegate asked whether legal issues make it difficult to properly investigate cannabis in large studies. Dr. Eisenberg noted that legal concerns may help explain why there have not been any new randomized, controlled trials for about 2 years. “In the U.S., you can’t do clinical trials; cannabis is still regarded as schedule I substance,” he said.
Some physicians “are reluctant to deal with cannabis unless they get better data,” he said. “Doing research on cannabis seems to be somehow out of the mainstream.” Moreover, the research is difficult to carry out, owing to the complexity of the cannabis plant, which has many constituents. Perhaps it’s a matter of identifying and adding particular components to better demonstrate reduced pain, said Dr. Eisenberg.
Another complicating factor is that bioavailability differs considerably from one patient to another, “sometimes even by 10-fold,” he said.
Dr. Attal’s group will be starting a study next January that will enroll a large sample of patients with neuropathic pain or spasticity. In that study, cannabis will be dispensed through pharmacies and primary care. The aim of the study is “to see how it works in a real-life setting,” she said
Those participating in the virtual session were asked to vote on which side they agreed with. About 57% voted in favor of cannabis use, 14% voted against, and 28% had no opinion.
Dr. Eisenberg has received research grants from Rafa Laboratories, Saga Medical Ltd., Israel Pain Association, and Teva Israel. Dr. Attal has received support from Merck Sharp & Dohme, Sanofi, Ipsen, Novartis, Aptinyx, Air Liquide, Lilly, and Grunenthal.
A version of this article originally appeared on Medscape.com.
FROM EAN 2020
Most adult epilepsy-related deaths could be avoided
The research shows that such avoidable deaths “remain common and have not declined over time, despite advances in treatment,” Gashirai Mbizvo, MBChB, PhD, clinical research fellow, Muir Maxwell Epilepsy Center, the University of Edinburgh, Scotland, told a press briefing.
The findings were presented at the Congress of the European Academy of Neurology (EAN) 2020, which is being conducted as a virtual/online meeting because of the COVID-19 pandemic.
As his PhD dissertation, Dr. Mbizvo is investigating the rates, causes, and risk factors for epilepsy-related deaths and the percentage of these that are potentially avoidable.
The National Health Service of Scotland contains various linked administrative data sets. Each resident of Scotland has a unique identifier that facilitates investigations across the health system.
Dr. Mbizvo investigated adults and adolescents aged 16 years and older who died because of epilepsy during 2009-2016. He compared this group to patients of similar age who were living with epilepsy to identify risk factors that might help focus resources. During the study period, 2,149 epilepsy-related deaths occurred. Nearly 60% involved at least one seizure-related hospital admission.
Heavy burden
Of the patients who died because of epilepsy, 24% were seen in an outpatient neurologic clinic. “So there’s this heavy burden of admissions not translating to neurology follow-up,” said Dr. Mbizvo.
During the study period, there was no reduction in mortality “despite advances in medical care,” said Dr. Mbizvo.
Younger people with epilepsy were found to be more likely to die. The standardized mortality rate was 6/100,000 (95% confidence interval, 2.3-9.7) among those aged 16-24 years. By contrast, among those aged 45-54 years, the rate was 2/100,000 (95% CI, 1.1-2.1); it was lower in older age groups.
“The overall mortality is not reducing; people are dying young, and neurologists are really not getting involved,” Dr. Mbizvo said.
Among the almost 600 deaths of those aged 16-54 years, 58% were from Scotland’s “most deprived areas,” he noted.
From medical records and antiepileptic drug (AED) use, Dr. Mbizvo looked for risk factors that may have contributed to these epilepsy-related deaths. The most common cause of death in the group aged 16- 54 years was sudden unexpected death in epilepsy (SUDEP), followed by respiratory disorders, such as aspiration pneumonia.
“We think this should be avoidable, in the sense that these are people that could perhaps be targeted early with, for example, antibiotics,” said Dr. Mbizvo.
The next most common cause of death was circulatory disease, largely cardiac arrest.
“The idea is that electroexcitation – an abnormality in the brain – and the heart are related, and maybe that’s translating to a risk of death,” said Dr. Mbizvo.
Worrisome group
Mental and behavioral disorders, largely alcohol related, were the next most common cause of death.
“This is a group I worry about,” said Dr. Mbizvo. “I think they’re seen in the acute services and discharged as alcohol-withdrawal seizures. It’s possible that some have epilepsy and are never referred to a neurologist, and this may translate into increased mortality.”
Dr. Mbizvo is analyzing how these results differ from what is seen in the general population of Scotland among those younger than 75 years.
The top cause of death in the general population is neoplasm of the lungs. Aspiration of the lung is near the top for those who died from epilepsy, but the mechanisms leading to lung-related deaths in these populations may differ, said Dr. Mbizvo.
By applying coding methodology from fields unrelated to epilepsy where this approach has been tried, he determined that 78% of epilepsy-related deaths among those younger than 55 years were potentially avoidable.
“As a method, this is still in its infancy and will require validation, but we see this as a start,” Dr. Mbizvo said.
He provided examples from medical records that illustrate avoidable factors that could contribute to death. These included cases in which patients were discharged with the wrong dose of AED and in which patients drowned in a bath after having not been appropriately educated about seizure safety.
Can’t plug in
Patients with a first seizure are typically referred quickly to an appropriate service, but Dr. Mbizvo is concerned about those with chronic, stable epilepsy. “These people may at some point decompensate, and there’s no channel to plug them back into neurology services to make it easy for them to access a neurologist,” he said.
Currently, experts tell discharged patients to call if a problem occurs, but the system “is rather ad hoc,” said Dr. Mbizvo.
Because of the COVID-19 crisis, the use of telemedicine is increasing. This is helping to improve the system. “We may be able to build a virtual community for people who are on antiepileptic drugs and who suddenly begin to experience seizures again, to enable them to quickly get help, alongside a defined pathway to an epilepsy specialist,” said Dr. Mbizvo.
He hopes to develop a risk index for epilepsy patients similar to one used in cardiology that assesses risks such as smoking, high cholesterol level, and obesity. Although such a risk score might be similar to the SUDEP risk indices being developed, it will take into account death from any epilepsy-related cause, said Dr. Mbizvo. “Having not yet completed the analysis, I’m not sure which aspects will confer the greatest risk,” he said.
He added that, anecdotally, he has noticed a slight trend toward high mortality among patients with epilepsy who present multiple times at emergency departments in a year.
If this trend is statistically valid, “it could help create a traffic light flagging system on A&Es [accident and emergency departments] in which individuals with epilepsy who, for example, have two or more attendances to A&E in a year become flagged as high risk of death and are plugged into a rapid access epilepsy specialist clinic,” he said.
For their part, neurologists should recognize drug-resistant epilepsy early and refer such patients for assessment for resective surgery. If successful, such surgery reduces the risk for premature mortality, said Dr. Mbizvo.
Patients should not become discouraged by drug resistance, either. Research shows that, with careful reassessment of epilepsy type and drug changes, some patients whose condition is thought to be intractable could experience significant improvement in seizure frequency or seizures could be stopped.
“We need to talk to our patients more about the importance of adherence and encourage them to be honest with us if they don’t like the drugs we’re giving them and, as a result, are not taking them as recommended,” Dr. Mbizvo said.
Physicians also need to screen for mood disorders, especially suicidal ideation. Increasingly, specialists are recognizing mental health as an important area of epilepsy care.
They should also conduct a “safety briefing” perhaps twice a year in which they discuss, for example, SUDEP risk, driving concerns, showering instead of bathing, ensuring that a life guard is present at a swimming pool, and other measures.
Commenting on the study, Josemir W. (Ley) Sander, MD, PhD, professor of neurology and clinical epilepsy at University College London, said he welcomes any effort that highlights the problem of premature death among people with epilepsy and that offers possible ways to mitigate it.
Although the study “shows that premature death among people with epilepsy is a major issue,” many health care providers are not fully aware of the extent of this problem, said Dr. Sander. “For many, epilepsy is just a benign condition in which people have seizures,” he said. A risk score that could identify those at high risk for death and establishing preventive measures “would go a long way to decrease the burden of epilepsy,” he noted.
The study was supported by Epilepsy Research UK and the Juliet Bergqvist Memorial Fund. Dr. Mbizvo and Dr. Sander have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
The research shows that such avoidable deaths “remain common and have not declined over time, despite advances in treatment,” Gashirai Mbizvo, MBChB, PhD, clinical research fellow, Muir Maxwell Epilepsy Center, the University of Edinburgh, Scotland, told a press briefing.
The findings were presented at the Congress of the European Academy of Neurology (EAN) 2020, which is being conducted as a virtual/online meeting because of the COVID-19 pandemic.
As his PhD dissertation, Dr. Mbizvo is investigating the rates, causes, and risk factors for epilepsy-related deaths and the percentage of these that are potentially avoidable.
The National Health Service of Scotland contains various linked administrative data sets. Each resident of Scotland has a unique identifier that facilitates investigations across the health system.
Dr. Mbizvo investigated adults and adolescents aged 16 years and older who died because of epilepsy during 2009-2016. He compared this group to patients of similar age who were living with epilepsy to identify risk factors that might help focus resources. During the study period, 2,149 epilepsy-related deaths occurred. Nearly 60% involved at least one seizure-related hospital admission.
Heavy burden
Of the patients who died because of epilepsy, 24% were seen in an outpatient neurologic clinic. “So there’s this heavy burden of admissions not translating to neurology follow-up,” said Dr. Mbizvo.
During the study period, there was no reduction in mortality “despite advances in medical care,” said Dr. Mbizvo.
Younger people with epilepsy were found to be more likely to die. The standardized mortality rate was 6/100,000 (95% confidence interval, 2.3-9.7) among those aged 16-24 years. By contrast, among those aged 45-54 years, the rate was 2/100,000 (95% CI, 1.1-2.1); it was lower in older age groups.
“The overall mortality is not reducing; people are dying young, and neurologists are really not getting involved,” Dr. Mbizvo said.
Among the almost 600 deaths of those aged 16-54 years, 58% were from Scotland’s “most deprived areas,” he noted.
From medical records and antiepileptic drug (AED) use, Dr. Mbizvo looked for risk factors that may have contributed to these epilepsy-related deaths. The most common cause of death in the group aged 16- 54 years was sudden unexpected death in epilepsy (SUDEP), followed by respiratory disorders, such as aspiration pneumonia.
“We think this should be avoidable, in the sense that these are people that could perhaps be targeted early with, for example, antibiotics,” said Dr. Mbizvo.
The next most common cause of death was circulatory disease, largely cardiac arrest.
“The idea is that electroexcitation – an abnormality in the brain – and the heart are related, and maybe that’s translating to a risk of death,” said Dr. Mbizvo.
Worrisome group
Mental and behavioral disorders, largely alcohol related, were the next most common cause of death.
“This is a group I worry about,” said Dr. Mbizvo. “I think they’re seen in the acute services and discharged as alcohol-withdrawal seizures. It’s possible that some have epilepsy and are never referred to a neurologist, and this may translate into increased mortality.”
Dr. Mbizvo is analyzing how these results differ from what is seen in the general population of Scotland among those younger than 75 years.
The top cause of death in the general population is neoplasm of the lungs. Aspiration of the lung is near the top for those who died from epilepsy, but the mechanisms leading to lung-related deaths in these populations may differ, said Dr. Mbizvo.
By applying coding methodology from fields unrelated to epilepsy where this approach has been tried, he determined that 78% of epilepsy-related deaths among those younger than 55 years were potentially avoidable.
“As a method, this is still in its infancy and will require validation, but we see this as a start,” Dr. Mbizvo said.
He provided examples from medical records that illustrate avoidable factors that could contribute to death. These included cases in which patients were discharged with the wrong dose of AED and in which patients drowned in a bath after having not been appropriately educated about seizure safety.
Can’t plug in
Patients with a first seizure are typically referred quickly to an appropriate service, but Dr. Mbizvo is concerned about those with chronic, stable epilepsy. “These people may at some point decompensate, and there’s no channel to plug them back into neurology services to make it easy for them to access a neurologist,” he said.
Currently, experts tell discharged patients to call if a problem occurs, but the system “is rather ad hoc,” said Dr. Mbizvo.
Because of the COVID-19 crisis, the use of telemedicine is increasing. This is helping to improve the system. “We may be able to build a virtual community for people who are on antiepileptic drugs and who suddenly begin to experience seizures again, to enable them to quickly get help, alongside a defined pathway to an epilepsy specialist,” said Dr. Mbizvo.
He hopes to develop a risk index for epilepsy patients similar to one used in cardiology that assesses risks such as smoking, high cholesterol level, and obesity. Although such a risk score might be similar to the SUDEP risk indices being developed, it will take into account death from any epilepsy-related cause, said Dr. Mbizvo. “Having not yet completed the analysis, I’m not sure which aspects will confer the greatest risk,” he said.
He added that, anecdotally, he has noticed a slight trend toward high mortality among patients with epilepsy who present multiple times at emergency departments in a year.
If this trend is statistically valid, “it could help create a traffic light flagging system on A&Es [accident and emergency departments] in which individuals with epilepsy who, for example, have two or more attendances to A&E in a year become flagged as high risk of death and are plugged into a rapid access epilepsy specialist clinic,” he said.
For their part, neurologists should recognize drug-resistant epilepsy early and refer such patients for assessment for resective surgery. If successful, such surgery reduces the risk for premature mortality, said Dr. Mbizvo.
Patients should not become discouraged by drug resistance, either. Research shows that, with careful reassessment of epilepsy type and drug changes, some patients whose condition is thought to be intractable could experience significant improvement in seizure frequency or seizures could be stopped.
“We need to talk to our patients more about the importance of adherence and encourage them to be honest with us if they don’t like the drugs we’re giving them and, as a result, are not taking them as recommended,” Dr. Mbizvo said.
Physicians also need to screen for mood disorders, especially suicidal ideation. Increasingly, specialists are recognizing mental health as an important area of epilepsy care.
They should also conduct a “safety briefing” perhaps twice a year in which they discuss, for example, SUDEP risk, driving concerns, showering instead of bathing, ensuring that a life guard is present at a swimming pool, and other measures.
Commenting on the study, Josemir W. (Ley) Sander, MD, PhD, professor of neurology and clinical epilepsy at University College London, said he welcomes any effort that highlights the problem of premature death among people with epilepsy and that offers possible ways to mitigate it.
Although the study “shows that premature death among people with epilepsy is a major issue,” many health care providers are not fully aware of the extent of this problem, said Dr. Sander. “For many, epilepsy is just a benign condition in which people have seizures,” he said. A risk score that could identify those at high risk for death and establishing preventive measures “would go a long way to decrease the burden of epilepsy,” he noted.
The study was supported by Epilepsy Research UK and the Juliet Bergqvist Memorial Fund. Dr. Mbizvo and Dr. Sander have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
The research shows that such avoidable deaths “remain common and have not declined over time, despite advances in treatment,” Gashirai Mbizvo, MBChB, PhD, clinical research fellow, Muir Maxwell Epilepsy Center, the University of Edinburgh, Scotland, told a press briefing.
The findings were presented at the Congress of the European Academy of Neurology (EAN) 2020, which is being conducted as a virtual/online meeting because of the COVID-19 pandemic.
As his PhD dissertation, Dr. Mbizvo is investigating the rates, causes, and risk factors for epilepsy-related deaths and the percentage of these that are potentially avoidable.
The National Health Service of Scotland contains various linked administrative data sets. Each resident of Scotland has a unique identifier that facilitates investigations across the health system.
Dr. Mbizvo investigated adults and adolescents aged 16 years and older who died because of epilepsy during 2009-2016. He compared this group to patients of similar age who were living with epilepsy to identify risk factors that might help focus resources. During the study period, 2,149 epilepsy-related deaths occurred. Nearly 60% involved at least one seizure-related hospital admission.
Heavy burden
Of the patients who died because of epilepsy, 24% were seen in an outpatient neurologic clinic. “So there’s this heavy burden of admissions not translating to neurology follow-up,” said Dr. Mbizvo.
During the study period, there was no reduction in mortality “despite advances in medical care,” said Dr. Mbizvo.
Younger people with epilepsy were found to be more likely to die. The standardized mortality rate was 6/100,000 (95% confidence interval, 2.3-9.7) among those aged 16-24 years. By contrast, among those aged 45-54 years, the rate was 2/100,000 (95% CI, 1.1-2.1); it was lower in older age groups.
“The overall mortality is not reducing; people are dying young, and neurologists are really not getting involved,” Dr. Mbizvo said.
Among the almost 600 deaths of those aged 16-54 years, 58% were from Scotland’s “most deprived areas,” he noted.
From medical records and antiepileptic drug (AED) use, Dr. Mbizvo looked for risk factors that may have contributed to these epilepsy-related deaths. The most common cause of death in the group aged 16- 54 years was sudden unexpected death in epilepsy (SUDEP), followed by respiratory disorders, such as aspiration pneumonia.
“We think this should be avoidable, in the sense that these are people that could perhaps be targeted early with, for example, antibiotics,” said Dr. Mbizvo.
The next most common cause of death was circulatory disease, largely cardiac arrest.
“The idea is that electroexcitation – an abnormality in the brain – and the heart are related, and maybe that’s translating to a risk of death,” said Dr. Mbizvo.
Worrisome group
Mental and behavioral disorders, largely alcohol related, were the next most common cause of death.
“This is a group I worry about,” said Dr. Mbizvo. “I think they’re seen in the acute services and discharged as alcohol-withdrawal seizures. It’s possible that some have epilepsy and are never referred to a neurologist, and this may translate into increased mortality.”
Dr. Mbizvo is analyzing how these results differ from what is seen in the general population of Scotland among those younger than 75 years.
The top cause of death in the general population is neoplasm of the lungs. Aspiration of the lung is near the top for those who died from epilepsy, but the mechanisms leading to lung-related deaths in these populations may differ, said Dr. Mbizvo.
By applying coding methodology from fields unrelated to epilepsy where this approach has been tried, he determined that 78% of epilepsy-related deaths among those younger than 55 years were potentially avoidable.
“As a method, this is still in its infancy and will require validation, but we see this as a start,” Dr. Mbizvo said.
He provided examples from medical records that illustrate avoidable factors that could contribute to death. These included cases in which patients were discharged with the wrong dose of AED and in which patients drowned in a bath after having not been appropriately educated about seizure safety.
Can’t plug in
Patients with a first seizure are typically referred quickly to an appropriate service, but Dr. Mbizvo is concerned about those with chronic, stable epilepsy. “These people may at some point decompensate, and there’s no channel to plug them back into neurology services to make it easy for them to access a neurologist,” he said.
Currently, experts tell discharged patients to call if a problem occurs, but the system “is rather ad hoc,” said Dr. Mbizvo.
Because of the COVID-19 crisis, the use of telemedicine is increasing. This is helping to improve the system. “We may be able to build a virtual community for people who are on antiepileptic drugs and who suddenly begin to experience seizures again, to enable them to quickly get help, alongside a defined pathway to an epilepsy specialist,” said Dr. Mbizvo.
He hopes to develop a risk index for epilepsy patients similar to one used in cardiology that assesses risks such as smoking, high cholesterol level, and obesity. Although such a risk score might be similar to the SUDEP risk indices being developed, it will take into account death from any epilepsy-related cause, said Dr. Mbizvo. “Having not yet completed the analysis, I’m not sure which aspects will confer the greatest risk,” he said.
He added that, anecdotally, he has noticed a slight trend toward high mortality among patients with epilepsy who present multiple times at emergency departments in a year.
If this trend is statistically valid, “it could help create a traffic light flagging system on A&Es [accident and emergency departments] in which individuals with epilepsy who, for example, have two or more attendances to A&E in a year become flagged as high risk of death and are plugged into a rapid access epilepsy specialist clinic,” he said.
For their part, neurologists should recognize drug-resistant epilepsy early and refer such patients for assessment for resective surgery. If successful, such surgery reduces the risk for premature mortality, said Dr. Mbizvo.
Patients should not become discouraged by drug resistance, either. Research shows that, with careful reassessment of epilepsy type and drug changes, some patients whose condition is thought to be intractable could experience significant improvement in seizure frequency or seizures could be stopped.
“We need to talk to our patients more about the importance of adherence and encourage them to be honest with us if they don’t like the drugs we’re giving them and, as a result, are not taking them as recommended,” Dr. Mbizvo said.
Physicians also need to screen for mood disorders, especially suicidal ideation. Increasingly, specialists are recognizing mental health as an important area of epilepsy care.
They should also conduct a “safety briefing” perhaps twice a year in which they discuss, for example, SUDEP risk, driving concerns, showering instead of bathing, ensuring that a life guard is present at a swimming pool, and other measures.
Commenting on the study, Josemir W. (Ley) Sander, MD, PhD, professor of neurology and clinical epilepsy at University College London, said he welcomes any effort that highlights the problem of premature death among people with epilepsy and that offers possible ways to mitigate it.
Although the study “shows that premature death among people with epilepsy is a major issue,” many health care providers are not fully aware of the extent of this problem, said Dr. Sander. “For many, epilepsy is just a benign condition in which people have seizures,” he said. A risk score that could identify those at high risk for death and establishing preventive measures “would go a long way to decrease the burden of epilepsy,” he noted.
The study was supported by Epilepsy Research UK and the Juliet Bergqvist Memorial Fund. Dr. Mbizvo and Dr. Sander have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
FROM EAN 2020
Sleep burden index predicts recurrent stroke
A sleep burden index that considers multiple sleep-wake disturbances (SWDs) predicts subsequent cardiocerebrovascular events during the 2 years after a stroke, preliminary results on an ongoing study suggest.
The index, which combines sleep duration, sleep disordered breathing, restless leg syndrome (RLS), insomnia, and sleep duration, is a better predictor of new events than a single sleep disorder alone.
With further evidence of its usefulness, “the sleep burden index could be integrated into clinical routine,” Simone B. Duss, PhD, of the department of neurology at Bern (Switzerland) University Hospital, told a press briefing.
The findings were presented online at the Congress of the European Academy of Neurology 2020, which transitioned to a virtual meeting because of the COVID-19 pandemic.
Sleep-wake disorders are very common in stroke patients and may preexist or appear de novo as a consequence of brain damage, said Dr. Duss. “They may also be a result of medical, psychological, or environmental challenges these patients face after a stroke.”
Clear Evidence
There’s “clear evidence” that sleep disordered breathing is a risk factor for stroke, and negatively affects stroke outcome if left untreated, said Dr. Duss.
But for other SWDs, such as insomnia, RLS, and long and short sleep duration, “the evidence is less compelling,” she said. “However, some studies still suggest they influence stroke risk and outcome.”
Experts believe that sleep disturbances after a stroke lead to sleep fragmentation, as well as decreased slow wave sleep and REM sleep.
“This negatively affects inflammatory neuroprotective and synaptic plasticity processes during the recovery process of a stroke,” said Dr. Duss. “In the end, this results in worse outcomes with regard to recurrent events but also in activities of daily living and mood.”
The new analysis aimed to assess the impact of sleep-wake disturbances on recurrent events and outcomes following a stroke or transient ischemic attack (TIA). It included 438 patients with acute stroke (85%) or TIA (15%). The mean age of the study population was 65 years, and 64% were male.
Researchers used the National Institutes of Health Stroke Scale (NIHSS) to assess stroke severity. At admission, the mean NIHSS score was 4. Most strokes (77.2%) were supratentorial.
About one-fifth of stroke patients and one-third of TIA patients had experienced a previous event.
Researchers used functional outcome scores to assess the clinical course of the stroke or TIA. In addition, they regularly asked patients about recurrence of cardiocerebrovascular events.
Investigators assessed sleep disordered breathing during the acute phase of stroke, so within the first few days, using respirography. They collected information on the presence of other sleep-wake disturbances from questionnaires and clinical interviews at 1 month, 3 months, 1 year, and 2 years after the event.
About 26% of subjects showed severe sleep disordered breathing, “meaning that they had more than 20 apnea-hypopnea events per hour,” said Dr. Duss.
More than a quarter of patients reported subclinical symptoms of insomnia (measured using the Insomnia Severity Index), and up to 10% reported severe insomnia symptoms corresponding to the clinical diagnosis of insomnia, she said.
About 9% of patients in the acute phase of stroke, and 6% in the more chronic phase, fulfilled the diagnostic criteria of RLS.
More ‘skewed’
The results for sleep duration were relatively “skewed,” said Dr. Duss. More patients reported longer sleep duration (more than 9 hours) at 1 month than at month 3, and more reported shorter sleep duration (4.0 hours or less) at month 3 than at month 1.
The researchers built a sleep burden index for the combined impact of the various sleep-wake disturbances.
They used this index as a predictor of subsequent cardiocerebrovascular events within 3 months after an event. They used a composite outcome that included recurrent stroke or TIA, MI, heart failure, and urgent revascularization, as well as new cardiocerebrovascular events, from 3 to 24 months.
The analysis showed that the mean sleep burden index was higher for stroke patients with a recurrent event, compared with stroke or TIA patients without a recurrent event (P = .0002).
A multiple logistical regression model with the presence or absence of a recurrent event as an outcome showed that the sleep burden index is a significant predictor of recurrent events (odds ratio, 2.10; P = .001). This was true even after controlling for age, gender, and baseline stroke severity.
The baseline apnea/hypopnea index and sleep duration were also significant predictors of new events. Importantly, though, the sleep burden index remained a significant predictor of recurrent events even after excluding the apnea/hypopnea index component, said Dr. Duss. “So the predictive power of the sleep burden index is not only driven by the apnea-hypopnea index at the beginning of a stroke.”
Sleep-wake disturbances “should be more carefully assessed and considered in comprehensive treatment approaches,” not only in stroke patients, but in neurologic patients in general, said Dr. Duss
She noted that these are preliminary observations from an ongoing study. The results need to be confirmed and should be when the study is finalized, she said.
Researchers are also analyzing MRI data to assess whether certain brain lesions are associated with sleep disturbances.
Jesse Dawson, MD, professor of stroke medicine at the University of Glasgow, said the clinical scoring system the study included “will be a big help in design and conduct of clinical trials.”
Although he and other stroke experts are aware of the high prevalence of sleep disorders after stroke, “we don’t routinely look for them as we’re uncertain whether intervention is of benefit,” said Dr. Dawson.
This new study “suggests there is an association with adverse outcome,” he said.
The research was supported by grants from the Swiss National Science Foundation and the Swiss Heart Foundation. Dr. Duss and Dr. Dawson disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
A sleep burden index that considers multiple sleep-wake disturbances (SWDs) predicts subsequent cardiocerebrovascular events during the 2 years after a stroke, preliminary results on an ongoing study suggest.
The index, which combines sleep duration, sleep disordered breathing, restless leg syndrome (RLS), insomnia, and sleep duration, is a better predictor of new events than a single sleep disorder alone.
With further evidence of its usefulness, “the sleep burden index could be integrated into clinical routine,” Simone B. Duss, PhD, of the department of neurology at Bern (Switzerland) University Hospital, told a press briefing.
The findings were presented online at the Congress of the European Academy of Neurology 2020, which transitioned to a virtual meeting because of the COVID-19 pandemic.
Sleep-wake disorders are very common in stroke patients and may preexist or appear de novo as a consequence of brain damage, said Dr. Duss. “They may also be a result of medical, psychological, or environmental challenges these patients face after a stroke.”
Clear Evidence
There’s “clear evidence” that sleep disordered breathing is a risk factor for stroke, and negatively affects stroke outcome if left untreated, said Dr. Duss.
But for other SWDs, such as insomnia, RLS, and long and short sleep duration, “the evidence is less compelling,” she said. “However, some studies still suggest they influence stroke risk and outcome.”
Experts believe that sleep disturbances after a stroke lead to sleep fragmentation, as well as decreased slow wave sleep and REM sleep.
“This negatively affects inflammatory neuroprotective and synaptic plasticity processes during the recovery process of a stroke,” said Dr. Duss. “In the end, this results in worse outcomes with regard to recurrent events but also in activities of daily living and mood.”
The new analysis aimed to assess the impact of sleep-wake disturbances on recurrent events and outcomes following a stroke or transient ischemic attack (TIA). It included 438 patients with acute stroke (85%) or TIA (15%). The mean age of the study population was 65 years, and 64% were male.
Researchers used the National Institutes of Health Stroke Scale (NIHSS) to assess stroke severity. At admission, the mean NIHSS score was 4. Most strokes (77.2%) were supratentorial.
About one-fifth of stroke patients and one-third of TIA patients had experienced a previous event.
Researchers used functional outcome scores to assess the clinical course of the stroke or TIA. In addition, they regularly asked patients about recurrence of cardiocerebrovascular events.
Investigators assessed sleep disordered breathing during the acute phase of stroke, so within the first few days, using respirography. They collected information on the presence of other sleep-wake disturbances from questionnaires and clinical interviews at 1 month, 3 months, 1 year, and 2 years after the event.
About 26% of subjects showed severe sleep disordered breathing, “meaning that they had more than 20 apnea-hypopnea events per hour,” said Dr. Duss.
More than a quarter of patients reported subclinical symptoms of insomnia (measured using the Insomnia Severity Index), and up to 10% reported severe insomnia symptoms corresponding to the clinical diagnosis of insomnia, she said.
About 9% of patients in the acute phase of stroke, and 6% in the more chronic phase, fulfilled the diagnostic criteria of RLS.
More ‘skewed’
The results for sleep duration were relatively “skewed,” said Dr. Duss. More patients reported longer sleep duration (more than 9 hours) at 1 month than at month 3, and more reported shorter sleep duration (4.0 hours or less) at month 3 than at month 1.
The researchers built a sleep burden index for the combined impact of the various sleep-wake disturbances.
They used this index as a predictor of subsequent cardiocerebrovascular events within 3 months after an event. They used a composite outcome that included recurrent stroke or TIA, MI, heart failure, and urgent revascularization, as well as new cardiocerebrovascular events, from 3 to 24 months.
The analysis showed that the mean sleep burden index was higher for stroke patients with a recurrent event, compared with stroke or TIA patients without a recurrent event (P = .0002).
A multiple logistical regression model with the presence or absence of a recurrent event as an outcome showed that the sleep burden index is a significant predictor of recurrent events (odds ratio, 2.10; P = .001). This was true even after controlling for age, gender, and baseline stroke severity.
The baseline apnea/hypopnea index and sleep duration were also significant predictors of new events. Importantly, though, the sleep burden index remained a significant predictor of recurrent events even after excluding the apnea/hypopnea index component, said Dr. Duss. “So the predictive power of the sleep burden index is not only driven by the apnea-hypopnea index at the beginning of a stroke.”
Sleep-wake disturbances “should be more carefully assessed and considered in comprehensive treatment approaches,” not only in stroke patients, but in neurologic patients in general, said Dr. Duss
She noted that these are preliminary observations from an ongoing study. The results need to be confirmed and should be when the study is finalized, she said.
Researchers are also analyzing MRI data to assess whether certain brain lesions are associated with sleep disturbances.
Jesse Dawson, MD, professor of stroke medicine at the University of Glasgow, said the clinical scoring system the study included “will be a big help in design and conduct of clinical trials.”
Although he and other stroke experts are aware of the high prevalence of sleep disorders after stroke, “we don’t routinely look for them as we’re uncertain whether intervention is of benefit,” said Dr. Dawson.
This new study “suggests there is an association with adverse outcome,” he said.
The research was supported by grants from the Swiss National Science Foundation and the Swiss Heart Foundation. Dr. Duss and Dr. Dawson disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
A sleep burden index that considers multiple sleep-wake disturbances (SWDs) predicts subsequent cardiocerebrovascular events during the 2 years after a stroke, preliminary results on an ongoing study suggest.
The index, which combines sleep duration, sleep disordered breathing, restless leg syndrome (RLS), insomnia, and sleep duration, is a better predictor of new events than a single sleep disorder alone.
With further evidence of its usefulness, “the sleep burden index could be integrated into clinical routine,” Simone B. Duss, PhD, of the department of neurology at Bern (Switzerland) University Hospital, told a press briefing.
The findings were presented online at the Congress of the European Academy of Neurology 2020, which transitioned to a virtual meeting because of the COVID-19 pandemic.
Sleep-wake disorders are very common in stroke patients and may preexist or appear de novo as a consequence of brain damage, said Dr. Duss. “They may also be a result of medical, psychological, or environmental challenges these patients face after a stroke.”
Clear Evidence
There’s “clear evidence” that sleep disordered breathing is a risk factor for stroke, and negatively affects stroke outcome if left untreated, said Dr. Duss.
But for other SWDs, such as insomnia, RLS, and long and short sleep duration, “the evidence is less compelling,” she said. “However, some studies still suggest they influence stroke risk and outcome.”
Experts believe that sleep disturbances after a stroke lead to sleep fragmentation, as well as decreased slow wave sleep and REM sleep.
“This negatively affects inflammatory neuroprotective and synaptic plasticity processes during the recovery process of a stroke,” said Dr. Duss. “In the end, this results in worse outcomes with regard to recurrent events but also in activities of daily living and mood.”
The new analysis aimed to assess the impact of sleep-wake disturbances on recurrent events and outcomes following a stroke or transient ischemic attack (TIA). It included 438 patients with acute stroke (85%) or TIA (15%). The mean age of the study population was 65 years, and 64% were male.
Researchers used the National Institutes of Health Stroke Scale (NIHSS) to assess stroke severity. At admission, the mean NIHSS score was 4. Most strokes (77.2%) were supratentorial.
About one-fifth of stroke patients and one-third of TIA patients had experienced a previous event.
Researchers used functional outcome scores to assess the clinical course of the stroke or TIA. In addition, they regularly asked patients about recurrence of cardiocerebrovascular events.
Investigators assessed sleep disordered breathing during the acute phase of stroke, so within the first few days, using respirography. They collected information on the presence of other sleep-wake disturbances from questionnaires and clinical interviews at 1 month, 3 months, 1 year, and 2 years after the event.
About 26% of subjects showed severe sleep disordered breathing, “meaning that they had more than 20 apnea-hypopnea events per hour,” said Dr. Duss.
More than a quarter of patients reported subclinical symptoms of insomnia (measured using the Insomnia Severity Index), and up to 10% reported severe insomnia symptoms corresponding to the clinical diagnosis of insomnia, she said.
About 9% of patients in the acute phase of stroke, and 6% in the more chronic phase, fulfilled the diagnostic criteria of RLS.
More ‘skewed’
The results for sleep duration were relatively “skewed,” said Dr. Duss. More patients reported longer sleep duration (more than 9 hours) at 1 month than at month 3, and more reported shorter sleep duration (4.0 hours or less) at month 3 than at month 1.
The researchers built a sleep burden index for the combined impact of the various sleep-wake disturbances.
They used this index as a predictor of subsequent cardiocerebrovascular events within 3 months after an event. They used a composite outcome that included recurrent stroke or TIA, MI, heart failure, and urgent revascularization, as well as new cardiocerebrovascular events, from 3 to 24 months.
The analysis showed that the mean sleep burden index was higher for stroke patients with a recurrent event, compared with stroke or TIA patients without a recurrent event (P = .0002).
A multiple logistical regression model with the presence or absence of a recurrent event as an outcome showed that the sleep burden index is a significant predictor of recurrent events (odds ratio, 2.10; P = .001). This was true even after controlling for age, gender, and baseline stroke severity.
The baseline apnea/hypopnea index and sleep duration were also significant predictors of new events. Importantly, though, the sleep burden index remained a significant predictor of recurrent events even after excluding the apnea/hypopnea index component, said Dr. Duss. “So the predictive power of the sleep burden index is not only driven by the apnea-hypopnea index at the beginning of a stroke.”
Sleep-wake disturbances “should be more carefully assessed and considered in comprehensive treatment approaches,” not only in stroke patients, but in neurologic patients in general, said Dr. Duss
She noted that these are preliminary observations from an ongoing study. The results need to be confirmed and should be when the study is finalized, she said.
Researchers are also analyzing MRI data to assess whether certain brain lesions are associated with sleep disturbances.
Jesse Dawson, MD, professor of stroke medicine at the University of Glasgow, said the clinical scoring system the study included “will be a big help in design and conduct of clinical trials.”
Although he and other stroke experts are aware of the high prevalence of sleep disorders after stroke, “we don’t routinely look for them as we’re uncertain whether intervention is of benefit,” said Dr. Dawson.
This new study “suggests there is an association with adverse outcome,” he said.
The research was supported by grants from the Swiss National Science Foundation and the Swiss Heart Foundation. Dr. Duss and Dr. Dawson disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
High levels of air pollution linked to increased MS risk
, new research suggests. A large cohort study of almost 550,000 individuals living in Italy showed that participants living in areas with high levels of pollutants had a significantly greater risk of developing MS than those who lived in areas with low levels of pollutants.
The findings further confirm a relationship between exposure to air pollutants and risk for MS that has been shown in previous research, said Roberto Bergamaschi, MD, PhD, director of the Multiple Sclerosis Center, IRCCS Mondino Foundation, Pavia, Italy.
“Countermeasures that cut air pollution can be important for public health, not only to reduce deaths related to cardiac and pulmonary diseases but also the risk of chronic autoimmune diseases such as MS,” Dr. Bergamaschi said.
The findings were presented at the Congress of the European Academy of Neurology (EAN) 2020, which transitioned to a virtual/online meeting because of the COVID-19 pandemic.
Toxic pollutants
Several environmental factors may trigger an abnormal immune response that manifests in MS. The most studied of these are low vitamin D level, cigarette smoking, and an unhealthy diet, Dr. Bergamaschi said. However, “other environmental factors deserve to be studied—pollution included,” he added.
Among the most toxic air pollutants are particulate matter (PM), which is a mixture of fine solid and liquid particles suspended in the earth’s atmosphere. PM may range from 2.5 microns (PM2.5) to 10 microns (PM10) in diameter.
The main sources of such pollutants are household and commercial heating (53%) and industrial activities (17%), followed by road vehicle and non–road vehicle use, agriculture, and electricity production.
The World Health Organization estimates that more than 3.2 million individuals worldwide die prematurely every year because of lung cancer, cardiovascular disease, and other diseases related to air pollutants, said Dr. Bergamaschi.
Epidemiologic research has uncovered a relationship between air pollution and MS. A large American study published in 2008 in Science of the Total Environment showed a significant association between MS prevalence and PM10 levels (P < 0.001). Other studies have shown an increase in the number of clinical relapses of MS that were linked to air pollution.
The current investigators assessed the association between PM2.5 levels and MS prevalence in the northern province of Pavia, which has a population of 547,251 individuals in 188 municipalities.
Peculiar features
Pavia is situated in a flat territory that encompasses the highly industrialized regions of Piedmont, Lombardy, Emilia-Romagna, and Veneto. It has a high level of anthropogenic emissions, or environmental pollutants, originating from human activity, Dr. Bergamaschi reported. The region also has “peculiar” geographical features that “favor the accumulation of pollutants,” such as the natural barrier of the Alps in the north and low wind speed, he said.
The researchers identified 927 individuals with MS (315 male and 612 female) in the province. The overall MS prevalence rate was 169.4 per 100,000 population (95% confidence interval [CI], 158.8 – 180.6), which is 10-fold higher than 50 years ago, Dr. Bergamaschi said. In addition, this MS prevalence is higher than that in the United States, which is about 150 per 100,000 population.
Using sophisticated Bayesian disease mapping, the investigators looked for clusters of MS. They also gathered emission data for PM2.5 from 2010 to 2017 from the European Monitoring and Evaluation Programme database. They then divided the region on the basis of average winter concentrations of PM2.5.
Three distinct lateral areas of air pollution were identified. The more northern region, which includes the large urban center of Milan, had the highest level of air pollution. Concentrations decreased the further south the investigators looked.
After adjusting for age, urbanization (population density), and deprivation index, results showed that living in areas with high levels of pollutants was associated with increased MS risk. When controlling for PM2.5 pollution, participants in urban areas had an increased risk for MS compared with rural dwellers (relative risk [RR], 1.16; 95% CI, 1.04 – 1.30; P = 0.003)
Dr. Bergamaschi said it is unclear whether this risk is higher for certain types of MS. “To my knowledge, no study has analyzed possible relationships between MS phenotypes and air pollution,” he noted.
Vitamin D’s role?
Several mechanisms might help explain the relationship between air pollution and MS risk, he added. These include oxidative stress, which results in cell damage, inflammation, and proinflammatory cytokine release. Vitamin D also likely plays some role, Dr. Bergamaschi said. Upon penetrating the lower strata of the earth’s atmosphere, ultraviolet B radiation is absorbed and scattered by suspended pollutants.
Several studies have highlighted the correlation between living in a polluted area and vitamin D hypovitaminosis; “so air pollution can contribute to increasing the risk of MS by reducing vitamin D synthesis,” he said.
Recent research has also shown that air pollution is associated with a higher risk for other autoimmune disorders, including systemic lupus erythematosus, rheumatoid arthritis, and type 1 diabetes mellitus.
However, pollution alone is only part of the picture. MS prevalence in highly populated and polluted countries such as China and India is low, with no more than 30 to 40 cases per 100,000 population, Dr. Bergamaschi noted. “This discrepancy is explained by different genetic backgrounds. While Caucasians are particularly susceptible to MS, Asians are not,” he said.
Study limitations cited included a possible bias because the analysis did not include other possible contributing risk factors, particularly other pollutants, Dr. Bergamaschi said.
Commenting on the research, Lily Jung Henson, MD, chief of neurology at Piedmont Healthcare in Stockbridge, Georgia, said the findings provide “a fascinating glimpse” into possible causative factors for MS and warrant further investigation.
“This research also suggests other opportunities to look at, such as progression of the degree of air pollution and the incidence of MS over time,” said Dr. Henson, who was not involved with the study.
Drs. Bergamaschi and Dr. Henson have reported no relevant financial relationships.
This article first appeared on Medscape.com.
, new research suggests. A large cohort study of almost 550,000 individuals living in Italy showed that participants living in areas with high levels of pollutants had a significantly greater risk of developing MS than those who lived in areas with low levels of pollutants.
The findings further confirm a relationship between exposure to air pollutants and risk for MS that has been shown in previous research, said Roberto Bergamaschi, MD, PhD, director of the Multiple Sclerosis Center, IRCCS Mondino Foundation, Pavia, Italy.
“Countermeasures that cut air pollution can be important for public health, not only to reduce deaths related to cardiac and pulmonary diseases but also the risk of chronic autoimmune diseases such as MS,” Dr. Bergamaschi said.
The findings were presented at the Congress of the European Academy of Neurology (EAN) 2020, which transitioned to a virtual/online meeting because of the COVID-19 pandemic.
Toxic pollutants
Several environmental factors may trigger an abnormal immune response that manifests in MS. The most studied of these are low vitamin D level, cigarette smoking, and an unhealthy diet, Dr. Bergamaschi said. However, “other environmental factors deserve to be studied—pollution included,” he added.
Among the most toxic air pollutants are particulate matter (PM), which is a mixture of fine solid and liquid particles suspended in the earth’s atmosphere. PM may range from 2.5 microns (PM2.5) to 10 microns (PM10) in diameter.
The main sources of such pollutants are household and commercial heating (53%) and industrial activities (17%), followed by road vehicle and non–road vehicle use, agriculture, and electricity production.
The World Health Organization estimates that more than 3.2 million individuals worldwide die prematurely every year because of lung cancer, cardiovascular disease, and other diseases related to air pollutants, said Dr. Bergamaschi.
Epidemiologic research has uncovered a relationship between air pollution and MS. A large American study published in 2008 in Science of the Total Environment showed a significant association between MS prevalence and PM10 levels (P < 0.001). Other studies have shown an increase in the number of clinical relapses of MS that were linked to air pollution.
The current investigators assessed the association between PM2.5 levels and MS prevalence in the northern province of Pavia, which has a population of 547,251 individuals in 188 municipalities.
Peculiar features
Pavia is situated in a flat territory that encompasses the highly industrialized regions of Piedmont, Lombardy, Emilia-Romagna, and Veneto. It has a high level of anthropogenic emissions, or environmental pollutants, originating from human activity, Dr. Bergamaschi reported. The region also has “peculiar” geographical features that “favor the accumulation of pollutants,” such as the natural barrier of the Alps in the north and low wind speed, he said.
The researchers identified 927 individuals with MS (315 male and 612 female) in the province. The overall MS prevalence rate was 169.4 per 100,000 population (95% confidence interval [CI], 158.8 – 180.6), which is 10-fold higher than 50 years ago, Dr. Bergamaschi said. In addition, this MS prevalence is higher than that in the United States, which is about 150 per 100,000 population.
Using sophisticated Bayesian disease mapping, the investigators looked for clusters of MS. They also gathered emission data for PM2.5 from 2010 to 2017 from the European Monitoring and Evaluation Programme database. They then divided the region on the basis of average winter concentrations of PM2.5.
Three distinct lateral areas of air pollution were identified. The more northern region, which includes the large urban center of Milan, had the highest level of air pollution. Concentrations decreased the further south the investigators looked.
After adjusting for age, urbanization (population density), and deprivation index, results showed that living in areas with high levels of pollutants was associated with increased MS risk. When controlling for PM2.5 pollution, participants in urban areas had an increased risk for MS compared with rural dwellers (relative risk [RR], 1.16; 95% CI, 1.04 – 1.30; P = 0.003)
Dr. Bergamaschi said it is unclear whether this risk is higher for certain types of MS. “To my knowledge, no study has analyzed possible relationships between MS phenotypes and air pollution,” he noted.
Vitamin D’s role?
Several mechanisms might help explain the relationship between air pollution and MS risk, he added. These include oxidative stress, which results in cell damage, inflammation, and proinflammatory cytokine release. Vitamin D also likely plays some role, Dr. Bergamaschi said. Upon penetrating the lower strata of the earth’s atmosphere, ultraviolet B radiation is absorbed and scattered by suspended pollutants.
Several studies have highlighted the correlation between living in a polluted area and vitamin D hypovitaminosis; “so air pollution can contribute to increasing the risk of MS by reducing vitamin D synthesis,” he said.
Recent research has also shown that air pollution is associated with a higher risk for other autoimmune disorders, including systemic lupus erythematosus, rheumatoid arthritis, and type 1 diabetes mellitus.
However, pollution alone is only part of the picture. MS prevalence in highly populated and polluted countries such as China and India is low, with no more than 30 to 40 cases per 100,000 population, Dr. Bergamaschi noted. “This discrepancy is explained by different genetic backgrounds. While Caucasians are particularly susceptible to MS, Asians are not,” he said.
Study limitations cited included a possible bias because the analysis did not include other possible contributing risk factors, particularly other pollutants, Dr. Bergamaschi said.
Commenting on the research, Lily Jung Henson, MD, chief of neurology at Piedmont Healthcare in Stockbridge, Georgia, said the findings provide “a fascinating glimpse” into possible causative factors for MS and warrant further investigation.
“This research also suggests other opportunities to look at, such as progression of the degree of air pollution and the incidence of MS over time,” said Dr. Henson, who was not involved with the study.
Drs. Bergamaschi and Dr. Henson have reported no relevant financial relationships.
This article first appeared on Medscape.com.
, new research suggests. A large cohort study of almost 550,000 individuals living in Italy showed that participants living in areas with high levels of pollutants had a significantly greater risk of developing MS than those who lived in areas with low levels of pollutants.
The findings further confirm a relationship between exposure to air pollutants and risk for MS that has been shown in previous research, said Roberto Bergamaschi, MD, PhD, director of the Multiple Sclerosis Center, IRCCS Mondino Foundation, Pavia, Italy.
“Countermeasures that cut air pollution can be important for public health, not only to reduce deaths related to cardiac and pulmonary diseases but also the risk of chronic autoimmune diseases such as MS,” Dr. Bergamaschi said.
The findings were presented at the Congress of the European Academy of Neurology (EAN) 2020, which transitioned to a virtual/online meeting because of the COVID-19 pandemic.
Toxic pollutants
Several environmental factors may trigger an abnormal immune response that manifests in MS. The most studied of these are low vitamin D level, cigarette smoking, and an unhealthy diet, Dr. Bergamaschi said. However, “other environmental factors deserve to be studied—pollution included,” he added.
Among the most toxic air pollutants are particulate matter (PM), which is a mixture of fine solid and liquid particles suspended in the earth’s atmosphere. PM may range from 2.5 microns (PM2.5) to 10 microns (PM10) in diameter.
The main sources of such pollutants are household and commercial heating (53%) and industrial activities (17%), followed by road vehicle and non–road vehicle use, agriculture, and electricity production.
The World Health Organization estimates that more than 3.2 million individuals worldwide die prematurely every year because of lung cancer, cardiovascular disease, and other diseases related to air pollutants, said Dr. Bergamaschi.
Epidemiologic research has uncovered a relationship between air pollution and MS. A large American study published in 2008 in Science of the Total Environment showed a significant association between MS prevalence and PM10 levels (P < 0.001). Other studies have shown an increase in the number of clinical relapses of MS that were linked to air pollution.
The current investigators assessed the association between PM2.5 levels and MS prevalence in the northern province of Pavia, which has a population of 547,251 individuals in 188 municipalities.
Peculiar features
Pavia is situated in a flat territory that encompasses the highly industrialized regions of Piedmont, Lombardy, Emilia-Romagna, and Veneto. It has a high level of anthropogenic emissions, or environmental pollutants, originating from human activity, Dr. Bergamaschi reported. The region also has “peculiar” geographical features that “favor the accumulation of pollutants,” such as the natural barrier of the Alps in the north and low wind speed, he said.
The researchers identified 927 individuals with MS (315 male and 612 female) in the province. The overall MS prevalence rate was 169.4 per 100,000 population (95% confidence interval [CI], 158.8 – 180.6), which is 10-fold higher than 50 years ago, Dr. Bergamaschi said. In addition, this MS prevalence is higher than that in the United States, which is about 150 per 100,000 population.
Using sophisticated Bayesian disease mapping, the investigators looked for clusters of MS. They also gathered emission data for PM2.5 from 2010 to 2017 from the European Monitoring and Evaluation Programme database. They then divided the region on the basis of average winter concentrations of PM2.5.
Three distinct lateral areas of air pollution were identified. The more northern region, which includes the large urban center of Milan, had the highest level of air pollution. Concentrations decreased the further south the investigators looked.
After adjusting for age, urbanization (population density), and deprivation index, results showed that living in areas with high levels of pollutants was associated with increased MS risk. When controlling for PM2.5 pollution, participants in urban areas had an increased risk for MS compared with rural dwellers (relative risk [RR], 1.16; 95% CI, 1.04 – 1.30; P = 0.003)
Dr. Bergamaschi said it is unclear whether this risk is higher for certain types of MS. “To my knowledge, no study has analyzed possible relationships between MS phenotypes and air pollution,” he noted.
Vitamin D’s role?
Several mechanisms might help explain the relationship between air pollution and MS risk, he added. These include oxidative stress, which results in cell damage, inflammation, and proinflammatory cytokine release. Vitamin D also likely plays some role, Dr. Bergamaschi said. Upon penetrating the lower strata of the earth’s atmosphere, ultraviolet B radiation is absorbed and scattered by suspended pollutants.
Several studies have highlighted the correlation between living in a polluted area and vitamin D hypovitaminosis; “so air pollution can contribute to increasing the risk of MS by reducing vitamin D synthesis,” he said.
Recent research has also shown that air pollution is associated with a higher risk for other autoimmune disorders, including systemic lupus erythematosus, rheumatoid arthritis, and type 1 diabetes mellitus.
However, pollution alone is only part of the picture. MS prevalence in highly populated and polluted countries such as China and India is low, with no more than 30 to 40 cases per 100,000 population, Dr. Bergamaschi noted. “This discrepancy is explained by different genetic backgrounds. While Caucasians are particularly susceptible to MS, Asians are not,” he said.
Study limitations cited included a possible bias because the analysis did not include other possible contributing risk factors, particularly other pollutants, Dr. Bergamaschi said.
Commenting on the research, Lily Jung Henson, MD, chief of neurology at Piedmont Healthcare in Stockbridge, Georgia, said the findings provide “a fascinating glimpse” into possible causative factors for MS and warrant further investigation.
“This research also suggests other opportunities to look at, such as progression of the degree of air pollution and the incidence of MS over time,” said Dr. Henson, who was not involved with the study.
Drs. Bergamaschi and Dr. Henson have reported no relevant financial relationships.
This article first appeared on Medscape.com.
FROM EAN 2020