Alzheimer's & Cognition

Biogen aims to file with the Food and Drug Administration for regulatory approval of aducanumab, an antibody under investigation for Alzheimer’s disease, in 2020 following largely positive results of a secondary analysis of two failed phase 3 trials, ENGAGE and EMERGE, the company announced Oct. 22.

Biogen’s plans reverse its March 21, 2019, decision with codeveloper Eisai to discontinue work on the drug after a futility analysis of the trials determined aducanumab was unlikely to yield significant benefit. Biogen announced the plan to file a biologic drug application following a new analysis of additional data that became available after the data lock on the futility analysis. But while primary and secondary endpoints were nearly all positive for EMERGE in the secondary analysis of the larger dataset, the same could not be said for the twin trial, ENGAGE, which had negative results for most of its endpoints. However, Biogen said that “results from a subset of patients in the phase 3 ENGAGE study who received sufficient exposure to high-dose aducanumab support the findings from EMERGE.”

Both the Alzheimer’s Association and researchers interpreted the announcement with a measured tone, saying it offered a hopeful sign for a field continually stymied in its quest for an effective treatment. More than 100 clinical trials have failed over the last 20 years.

“This really is very encouraging news,” Rebecca M. Edelmayer, PhD, director of scientific engagement at the Alzheimer’s Association, said in an interview. The secondary combined analyses showed “the largest reductions in clinical and functional decline we have seen. It’s an important moment for the patients with AD and their families, and for researchers all around the world. This deserves to be discussed and considered by the research community, but we really need to dig deep into the data. We expect to see more of them at the Clinical Trials on Alzheimer’s Disease conference,” which is set for early December.

Paul Aisen, MD, a consultant for Biogen and director of the Alzheimer’s Therapeutic Research Institute at the University of Southern California, Los Angeles, was similarly measured.

“There is an enormous amount of data here and they will be very challenging to interpret, especially since both trials were stopped in a futility analysis,” he said in an interview. “We’re now interpreting data that continue to be collected after the initial data lock. But I do believe there is evidence that supports the amyloid hypothesis and the development of aducanumab.”

A deep data dive is in order before the field completely embraces aducanumab’s advancement, agreed Michael Wolfe, PhD, the Mathias P. Mertes Professor of Medicinal Chemistry at the University of Kansas, Lawrence.

“We would have to see exactly how they came up with this new data set and analysis. I have felt for many years now that these companies would try to parse and shuffle the data around until they got a statistically significant result, just to get approval. They would make billions per year but not really make a difference in people’s lives. That being said, if aducanumab truly slows the decline in activities of daily living, keeping people independent longer, that would be a worthwhile clinical result.”

Still to be considered is whether aducanumab could confer enough benefits to be worth monthly, potentially lifelong, infusions of a pricey medication that still won’t stop disease progression.

“Whether the clinical impact will be worth the anticipated cost remains to be seen,” Richard J. Caselli, MD, said in an interview. “This is likely to be a very expensive treatment for a subgroup of individuals with the hope of slowing decline, but – unless there is a huge upside surprise in data yet to be released – it is not going to halt progression and will certainly increase the cost of care dramatically.”

Dr. Caselli, clinical core director of the Alzheimer’s Disease Center at the Mayo Clinic in Phoenix, continued: “I imagine if approved, there will be a number of insurance obstacles to overcome regarding who qualifies, for how long, etc. Scientifically, this certainly supports the long-held view that beta amyloid is important in the pathophysiology of Alzheimer’s disease. But, again, unless the impact is unexpectedly huge, I don’t think this quiets those who feel there is more to the story than only a gain of beta amyloid toxicity, though this does support the idea that it plays a role, which should not surprise anyone.”

Dr. Edelmayer said the Alzheimer’s Association has raised the issue of access and cost with Biogen.

“We have had many discussions about their capacity to roll this out,” if aducanumab is approved, she said. “Those who were in the studies will be the first recipients. But Biogen is making plans to move this into the general population if approved, to all patients who meet the diagnostic criteria.”

“There is precedent out there when it comes to doing infusion medicines, and those centers are part of the planning process. In terms of pricing, this is a problem we would be happy to see, because it would mean that we have a treatment. But we’ll cross that bridge when we come to it.”
 

Secondary analysis results

The new analysis comprised 2,066 patients who had the opportunity to complete the full 18-month trials by March 20, 2019. The full intent-to-treat population of the trials comprised 3,285 patients with mild cognitive impairment caused by Alzheimer’s disease or mild Alzheimer’s disease dementia.

In the secondary analysis of EMERGE’s intent-to-treat population, patients who took the highest dose of aducanumab (10 mg/kg every month) showed 23% lower functional and cognitive decline on the trial’s primary endpoint of Clinical Dementia Rating–Sum of Boxes (CDR-SB) at 18 months when compared with placebo. The rate of decline was slowed by a nonsignificant 14% among users of the lower dose (6 mg/kg monthly).Secondary endpoints for the high-dose group in EMERGE showed 27% slower cognitive decline on the 13-item cognitive subscale of the AD Assessment Scale (ADAS-Cog13) and 40% lower decline in function among patients with mild cognitive impairment based on the MCI version of the AD Cooperative Study–Activities of Daily Living Inventory (ADCS-ADL-MCI).

However, data from the ENGAGE trial, which had the same primary endpoint, were not positive. CDR-SB scores worsened 2% more among high-dose aducanumab users but low-dose users slowed decline by a nonsignificant 12% when compared with placebo.“Exposure to high-dose aducanumab was important for efficacy,” the company noted in a slide set presented at an Oct. 22 investors webcast. “Differences in exposure to high-dose aducanumab largely explain the different results between the futility analysis and the new analysis of this larger dataset, as well as the different results between the two studies.”

In EMERGE, changes in secondary endpoints among patients who had the opportunity to complete the full 18-month trials included:

• Mini Mental State Exam (MMSE): Significant 23% decrease in rate of decline in the high-dose group and nonsignificant 3% increase in decline in the low-dose group.
• ADAS-Cog13: Significant 25% decrease for high-dose users and nonsignificant 10% decrease for low dose.
• ADCS-ADL-MCI: Significant decreases of 46% for high-dose and 20% for low-dose users.

The ENGAGE secondary endpoints of high- vs. low-dose patients who completed the full trials were:

• MMSE: Significant 13% increase, nonsignificant 3% decrease.
• ADAS-Cog13: Nonsignificant 2% decrease, nonsignificant 1% decrease.
• ADCS-ADL-MCI: Significant 12% declines in both dosage groups.

All of the positive cognitive and functional results tracked along with results of amyloid PET imaging and CSF biomarkers. In EMERGE, amyloid plaque binding declined about 27% in the high-dose group and about 16% in the low-dose group, reflecting plaque clearance. Phosphorylated tau in CSF decreased by about 17 pg/mL and 10 pg/mL, respectively, and total tau decreased by 160 pg/mL and 120 pg/mL. Tau decreases indicate a slowing of neuronal damage.

In ENGAGE, amyloid plaque binding decreased by about 24% in the high-dose group and by about 16% in the low-dose group. Phosphorylated tau dropped by about 10 pg/mL and 11 pg/mL, respectively. But total tau dropped more in the low-dose group than in the high-dose group (about –100 pg/mL vs. –20 pg/mL).

Biogen said the amyloid PET imaging biomarker results and CDR-SB scores in both studies were consistent with each other in a subset of patients with “sufficient exposure to 10 mg/kg,” which was defined as “10 or more uninterrupted 10-mg/kg dosing intervals at steady-state.”

The most common adverse events were amyloid related imaging abnormalities–edema (ARIA-E), which occurred in 35%, and headache in 20%. The majority of patients who experienced ARIA-E (74%) were asymptomatic; episodes generally resolved within 4-16 weeks, typically without long-term sequelae.

Dr. Aisen is a consultant for Biogen and on the aducanumab steering committee. None of the other sources in this article have any financial relationship with Biogen or Eisai.

This article was updated 10/23/19.

[email protected]

Biogen aims to file with the Food and Drug Administration for regulatory approval of aducanumab, an antibody under investigation for Alzheimer’s disease, in 2020 following largely positive results of a secondary analysis of two failed phase 3 trials, ENGAGE and EMERGE, the company announced Oct. 22.

Biogen’s plans reverse its March 21, 2019, decision with codeveloper Eisai to discontinue work on the drug after a futility analysis of the trials determined aducanumab was unlikely to yield significant benefit. Biogen announced the plan to file a biologic drug application following a new analysis of additional data that became available after the data lock on the futility analysis. But while primary and secondary endpoints were nearly all positive for EMERGE in the secondary analysis of the larger dataset, the same could not be said for the twin trial, ENGAGE, which had negative results for most of its endpoints. However, Biogen said that “results from a subset of patients in the phase 3 ENGAGE study who received sufficient exposure to high-dose aducanumab support the findings from EMERGE.”

Both the Alzheimer’s Association and researchers interpreted the announcement with a measured tone, saying it offered a hopeful sign for a field continually stymied in its quest for an effective treatment. More than 100 clinical trials have failed over the last 20 years.

“This really is very encouraging news,” Rebecca M. Edelmayer, PhD, director of scientific engagement at the Alzheimer’s Association, said in an interview. The secondary combined analyses showed “the largest reductions in clinical and functional decline we have seen. It’s an important moment for the patients with AD and their families, and for researchers all around the world. This deserves to be discussed and considered by the research community, but we really need to dig deep into the data. We expect to see more of them at the Clinical Trials on Alzheimer’s Disease conference,” which is set for early December.

Paul Aisen, MD, a consultant for Biogen and director of the Alzheimer’s Therapeutic Research Institute at the University of Southern California, Los Angeles, was similarly measured.

“There is an enormous amount of data here and they will be very challenging to interpret, especially since both trials were stopped in a futility analysis,” he said in an interview. “We’re now interpreting data that continue to be collected after the initial data lock. But I do believe there is evidence that supports the amyloid hypothesis and the development of aducanumab.”

A deep data dive is in order before the field completely embraces aducanumab’s advancement, agreed Michael Wolfe, PhD, the Mathias P. Mertes Professor of Medicinal Chemistry at the University of Kansas, Lawrence.

“We would have to see exactly how they came up with this new data set and analysis. I have felt for many years now that these companies would try to parse and shuffle the data around until they got a statistically significant result, just to get approval. They would make billions per year but not really make a difference in people’s lives. That being said, if aducanumab truly slows the decline in activities of daily living, keeping people independent longer, that would be a worthwhile clinical result.”

Still to be considered is whether aducanumab could confer enough benefits to be worth monthly, potentially lifelong, infusions of a pricey medication that still won’t stop disease progression.

“Whether the clinical impact will be worth the anticipated cost remains to be seen,” Richard J. Caselli, MD, said in an interview. “This is likely to be a very expensive treatment for a subgroup of individuals with the hope of slowing decline, but – unless there is a huge upside surprise in data yet to be released – it is not going to halt progression and will certainly increase the cost of care dramatically.”

Dr. Caselli, clinical core director of the Alzheimer’s Disease Center at the Mayo Clinic in Phoenix, continued: “I imagine if approved, there will be a number of insurance obstacles to overcome regarding who qualifies, for how long, etc. Scientifically, this certainly supports the long-held view that beta amyloid is important in the pathophysiology of Alzheimer’s disease. But, again, unless the impact is unexpectedly huge, I don’t think this quiets those who feel there is more to the story than only a gain of beta amyloid toxicity, though this does support the idea that it plays a role, which should not surprise anyone.”

Dr. Edelmayer said the Alzheimer’s Association has raised the issue of access and cost with Biogen.

“We have had many discussions about their capacity to roll this out,” if aducanumab is approved, she said. “Those who were in the studies will be the first recipients. But Biogen is making plans to move this into the general population if approved, to all patients who meet the diagnostic criteria.”

“There is precedent out there when it comes to doing infusion medicines, and those centers are part of the planning process. In terms of pricing, this is a problem we would be happy to see, because it would mean that we have a treatment. But we’ll cross that bridge when we come to it.”
 

Secondary analysis results

The new analysis comprised 2,066 patients who had the opportunity to complete the full 18-month trials by March 20, 2019. The full intent-to-treat population of the trials comprised 3,285 patients with mild cognitive impairment caused by Alzheimer’s disease or mild Alzheimer’s disease dementia.

In the secondary analysis of EMERGE’s intent-to-treat population, patients who took the highest dose of aducanumab (10 mg/kg every month) showed 23% lower functional and cognitive decline on the trial’s primary endpoint of Clinical Dementia Rating–Sum of Boxes (CDR-SB) at 18 months when compared with placebo. The rate of decline was slowed by a nonsignificant 14% among users of the lower dose (6 mg/kg monthly).Secondary endpoints for the high-dose group in EMERGE showed 27% slower cognitive decline on the 13-item cognitive subscale of the AD Assessment Scale (ADAS-Cog13) and 40% lower decline in function among patients with mild cognitive impairment based on the MCI version of the AD Cooperative Study–Activities of Daily Living Inventory (ADCS-ADL-MCI).

However, data from the ENGAGE trial, which had the same primary endpoint, were not positive. CDR-SB scores worsened 2% more among high-dose aducanumab users but low-dose users slowed decline by a nonsignificant 12% when compared with placebo.“Exposure to high-dose aducanumab was important for efficacy,” the company noted in a slide set presented at an Oct. 22 investors webcast. “Differences in exposure to high-dose aducanumab largely explain the different results between the futility analysis and the new analysis of this larger dataset, as well as the different results between the two studies.”

In EMERGE, changes in secondary endpoints among patients who had the opportunity to complete the full 18-month trials included:

• Mini Mental State Exam (MMSE): Significant 23% decrease in rate of decline in the high-dose group and nonsignificant 3% increase in decline in the low-dose group.
• ADAS-Cog13: Significant 25% decrease for high-dose users and nonsignificant 10% decrease for low dose.
• ADCS-ADL-MCI: Significant decreases of 46% for high-dose and 20% for low-dose users.

The ENGAGE secondary endpoints of high- vs. low-dose patients who completed the full trials were:

• MMSE: Significant 13% increase, nonsignificant 3% decrease.
• ADAS-Cog13: Nonsignificant 2% decrease, nonsignificant 1% decrease.
• ADCS-ADL-MCI: Significant 12% declines in both dosage groups.

All of the positive cognitive and functional results tracked along with results of amyloid PET imaging and CSF biomarkers. In EMERGE, amyloid plaque binding declined about 27% in the high-dose group and about 16% in the low-dose group, reflecting plaque clearance. Phosphorylated tau in CSF decreased by about 17 pg/mL and 10 pg/mL, respectively, and total tau decreased by 160 pg/mL and 120 pg/mL. Tau decreases indicate a slowing of neuronal damage.

In ENGAGE, amyloid plaque binding decreased by about 24% in the high-dose group and by about 16% in the low-dose group. Phosphorylated tau dropped by about 10 pg/mL and 11 pg/mL, respectively. But total tau dropped more in the low-dose group than in the high-dose group (about –100 pg/mL vs. –20 pg/mL).

Biogen said the amyloid PET imaging biomarker results and CDR-SB scores in both studies were consistent with each other in a subset of patients with “sufficient exposure to 10 mg/kg,” which was defined as “10 or more uninterrupted 10-mg/kg dosing intervals at steady-state.”

The most common adverse events were amyloid related imaging abnormalities–edema (ARIA-E), which occurred in 35%, and headache in 20%. The majority of patients who experienced ARIA-E (74%) were asymptomatic; episodes generally resolved within 4-16 weeks, typically without long-term sequelae.

Dr. Aisen is a consultant for Biogen and on the aducanumab steering committee. None of the other sources in this article have any financial relationship with Biogen or Eisai.

This article was updated 10/23/19.

[email protected]

Biogen aims to file with the Food and Drug Administration for regulatory approval of aducanumab, an antibody under investigation for Alzheimer’s disease, in 2020 following largely positive results of a secondary analysis of two failed phase 3 trials, ENGAGE and EMERGE, the company announced Oct. 22.

Biogen’s plans reverse its March 21, 2019, decision with codeveloper Eisai to discontinue work on the drug after a futility analysis of the trials determined aducanumab was unlikely to yield significant benefit. Biogen announced the plan to file a biologic drug application following a new analysis of additional data that became available after the data lock on the futility analysis. But while primary and secondary endpoints were nearly all positive for EMERGE in the secondary analysis of the larger dataset, the same could not be said for the twin trial, ENGAGE, which had negative results for most of its endpoints. However, Biogen said that “results from a subset of patients in the phase 3 ENGAGE study who received sufficient exposure to high-dose aducanumab support the findings from EMERGE.”

Both the Alzheimer’s Association and researchers interpreted the announcement with a measured tone, saying it offered a hopeful sign for a field continually stymied in its quest for an effective treatment. More than 100 clinical trials have failed over the last 20 years.

“This really is very encouraging news,” Rebecca M. Edelmayer, PhD, director of scientific engagement at the Alzheimer’s Association, said in an interview. The secondary combined analyses showed “the largest reductions in clinical and functional decline we have seen. It’s an important moment for the patients with AD and their families, and for researchers all around the world. This deserves to be discussed and considered by the research community, but we really need to dig deep into the data. We expect to see more of them at the Clinical Trials on Alzheimer’s Disease conference,” which is set for early December.

Paul Aisen, MD, a consultant for Biogen and director of the Alzheimer’s Therapeutic Research Institute at the University of Southern California, Los Angeles, was similarly measured.

“There is an enormous amount of data here and they will be very challenging to interpret, especially since both trials were stopped in a futility analysis,” he said in an interview. “We’re now interpreting data that continue to be collected after the initial data lock. But I do believe there is evidence that supports the amyloid hypothesis and the development of aducanumab.”

A deep data dive is in order before the field completely embraces aducanumab’s advancement, agreed Michael Wolfe, PhD, the Mathias P. Mertes Professor of Medicinal Chemistry at the University of Kansas, Lawrence.

“We would have to see exactly how they came up with this new data set and analysis. I have felt for many years now that these companies would try to parse and shuffle the data around until they got a statistically significant result, just to get approval. They would make billions per year but not really make a difference in people’s lives. That being said, if aducanumab truly slows the decline in activities of daily living, keeping people independent longer, that would be a worthwhile clinical result.”

Still to be considered is whether aducanumab could confer enough benefits to be worth monthly, potentially lifelong, infusions of a pricey medication that still won’t stop disease progression.

“Whether the clinical impact will be worth the anticipated cost remains to be seen,” Richard J. Caselli, MD, said in an interview. “This is likely to be a very expensive treatment for a subgroup of individuals with the hope of slowing decline, but – unless there is a huge upside surprise in data yet to be released – it is not going to halt progression and will certainly increase the cost of care dramatically.”

Dr. Caselli, clinical core director of the Alzheimer’s Disease Center at the Mayo Clinic in Phoenix, continued: “I imagine if approved, there will be a number of insurance obstacles to overcome regarding who qualifies, for how long, etc. Scientifically, this certainly supports the long-held view that beta amyloid is important in the pathophysiology of Alzheimer’s disease. But, again, unless the impact is unexpectedly huge, I don’t think this quiets those who feel there is more to the story than only a gain of beta amyloid toxicity, though this does support the idea that it plays a role, which should not surprise anyone.”

Dr. Edelmayer said the Alzheimer’s Association has raised the issue of access and cost with Biogen.

“We have had many discussions about their capacity to roll this out,” if aducanumab is approved, she said. “Those who were in the studies will be the first recipients. But Biogen is making plans to move this into the general population if approved, to all patients who meet the diagnostic criteria.”

“There is precedent out there when it comes to doing infusion medicines, and those centers are part of the planning process. In terms of pricing, this is a problem we would be happy to see, because it would mean that we have a treatment. But we’ll cross that bridge when we come to it.”
 

Secondary analysis results

The new analysis comprised 2,066 patients who had the opportunity to complete the full 18-month trials by March 20, 2019. The full intent-to-treat population of the trials comprised 3,285 patients with mild cognitive impairment caused by Alzheimer’s disease or mild Alzheimer’s disease dementia.

In the secondary analysis of EMERGE’s intent-to-treat population, patients who took the highest dose of aducanumab (10 mg/kg every month) showed 23% lower functional and cognitive decline on the trial’s primary endpoint of Clinical Dementia Rating–Sum of Boxes (CDR-SB) at 18 months when compared with placebo. The rate of decline was slowed by a nonsignificant 14% among users of the lower dose (6 mg/kg monthly).Secondary endpoints for the high-dose group in EMERGE showed 27% slower cognitive decline on the 13-item cognitive subscale of the AD Assessment Scale (ADAS-Cog13) and 40% lower decline in function among patients with mild cognitive impairment based on the MCI version of the AD Cooperative Study–Activities of Daily Living Inventory (ADCS-ADL-MCI).

However, data from the ENGAGE trial, which had the same primary endpoint, were not positive. CDR-SB scores worsened 2% more among high-dose aducanumab users but low-dose users slowed decline by a nonsignificant 12% when compared with placebo.“Exposure to high-dose aducanumab was important for efficacy,” the company noted in a slide set presented at an Oct. 22 investors webcast. “Differences in exposure to high-dose aducanumab largely explain the different results between the futility analysis and the new analysis of this larger dataset, as well as the different results between the two studies.”

In EMERGE, changes in secondary endpoints among patients who had the opportunity to complete the full 18-month trials included:

• Mini Mental State Exam (MMSE): Significant 23% decrease in rate of decline in the high-dose group and nonsignificant 3% increase in decline in the low-dose group.
• ADAS-Cog13: Significant 25% decrease for high-dose users and nonsignificant 10% decrease for low dose.
• ADCS-ADL-MCI: Significant decreases of 46% for high-dose and 20% for low-dose users.

The ENGAGE secondary endpoints of high- vs. low-dose patients who completed the full trials were:

• MMSE: Significant 13% increase, nonsignificant 3% decrease.
• ADAS-Cog13: Nonsignificant 2% decrease, nonsignificant 1% decrease.
• ADCS-ADL-MCI: Significant 12% declines in both dosage groups.

All of the positive cognitive and functional results tracked along with results of amyloid PET imaging and CSF biomarkers. In EMERGE, amyloid plaque binding declined about 27% in the high-dose group and about 16% in the low-dose group, reflecting plaque clearance. Phosphorylated tau in CSF decreased by about 17 pg/mL and 10 pg/mL, respectively, and total tau decreased by 160 pg/mL and 120 pg/mL. Tau decreases indicate a slowing of neuronal damage.

In ENGAGE, amyloid plaque binding decreased by about 24% in the high-dose group and by about 16% in the low-dose group. Phosphorylated tau dropped by about 10 pg/mL and 11 pg/mL, respectively. But total tau dropped more in the low-dose group than in the high-dose group (about –100 pg/mL vs. –20 pg/mL).

Biogen said the amyloid PET imaging biomarker results and CDR-SB scores in both studies were consistent with each other in a subset of patients with “sufficient exposure to 10 mg/kg,” which was defined as “10 or more uninterrupted 10-mg/kg dosing intervals at steady-state.”

The most common adverse events were amyloid related imaging abnormalities–edema (ARIA-E), which occurred in 35%, and headache in 20%. The majority of patients who experienced ARIA-E (74%) were asymptomatic; episodes generally resolved within 4-16 weeks, typically without long-term sequelae.

Dr. Aisen is a consultant for Biogen and on the aducanumab steering committee. None of the other sources in this article have any financial relationship with Biogen or Eisai.

This article was updated 10/23/19.

[email protected]

Mortality risk associated with neurodegenerative disease is higher, and mortality risk associated with other causes lower, among former Scottish professional soccer players versus matched controls, findings from a retrospective epidemiologic analysis suggest.

Nikada/Getty Images

Former professional soccer players included in the analysis also received more dementia-related medication prescriptions than did controls, Daniel F. Mackay, PhD, of the Institute of Health and Wellbeing at the University of Glasgow (Scotland) and his colleagues reported online Oct. 21 in The New England Journal of Medicine.

Overall mortality during a median follow-up of 18 years from study entry at the age of 40 years was 15.4% among 7,676 former players, and 16.5% among 23,028 controls matched based on age, sex, and degree of social deprivation. All-cause mortality was lower among players versus controls before age 70 years, and was higher thereafter, and the mortality rates associated with ischemic heart disease and lung cancer were lower among the players (hazard ratios, 0.80 and 0.53, respectively), the investigators found.

Mortality rates from stroke or cerebrovascular disease were similar in the players and controls (HR, 0.88), they noted.

However, mortality with neurodegenerative disease listed as the primary cause was 1.7% in players versus 0.5% in controls (HR adjusted for competing risks of death, 3.45), they said. The estimated risk of death with neurodegenerative disease was highest among those with Alzheimer’s disease and lowest for those with Parkinson’s disease (HRs, 5.07 and 2.15, respectively).

Dementia-related medications also were prescribed more frequently for players vs. controls (odds ratio, 4.90).

A subgroup analysis showed no significant difference between goalkeepers and outfielders with respect to mortality with neurodegenerative disease listed as a factor (HR, 0.73), but dementia-related medications were prescribed less often to goalkeepers (OR, 0.41).

Concerns about the risk of neurodegenerative diseases among participants in contact sports have been raised, in part because of the recognition of pathologic changes of chronic traumatic encephalopathy among participants across a range of such sports, the investigators explained, noting that data regarding the risk of neurodegenerative disease among former professional soccer players are limited.

The findings of the current study, in terms of lower all-cause mortality up to the age of 70 years, are similar to those in previous studies involving elite athletes across a range of sports, and “may reflect higher levels of physical activity and lower levels of obesity and smoking in elite athletes than in the general population,” they noted.

“In contrast, mortality from neurodegenerative disease was higher among former soccer players, a finding consistent with studies involving former players in the U.S. National Football League,” they added, concluding that the findings, which “may be valuable to inform the management of risks in the sport,” require confirmation in prospective studies.

This study was supported by the Football Association and Professional Footballers’ Association, and by an NHS Research Scotland Career Researcher Fellowship. Dr. Mackay reported having no relevant financial disclosures.

[email protected]

SOURCE: Mackay D et al. N Engl J Med. 2019 Oct 21. doi: 10.1056/NEJMoa1908483.

Mortality risk associated with neurodegenerative disease is higher, and mortality risk associated with other causes lower, among former Scottish professional soccer players versus matched controls, findings from a retrospective epidemiologic analysis suggest.

Nikada/Getty Images

Former professional soccer players included in the analysis also received more dementia-related medication prescriptions than did controls, Daniel F. Mackay, PhD, of the Institute of Health and Wellbeing at the University of Glasgow (Scotland) and his colleagues reported online Oct. 21 in The New England Journal of Medicine.

Overall mortality during a median follow-up of 18 years from study entry at the age of 40 years was 15.4% among 7,676 former players, and 16.5% among 23,028 controls matched based on age, sex, and degree of social deprivation. All-cause mortality was lower among players versus controls before age 70 years, and was higher thereafter, and the mortality rates associated with ischemic heart disease and lung cancer were lower among the players (hazard ratios, 0.80 and 0.53, respectively), the investigators found.

Mortality rates from stroke or cerebrovascular disease were similar in the players and controls (HR, 0.88), they noted.

However, mortality with neurodegenerative disease listed as the primary cause was 1.7% in players versus 0.5% in controls (HR adjusted for competing risks of death, 3.45), they said. The estimated risk of death with neurodegenerative disease was highest among those with Alzheimer’s disease and lowest for those with Parkinson’s disease (HRs, 5.07 and 2.15, respectively).

Dementia-related medications also were prescribed more frequently for players vs. controls (odds ratio, 4.90).

A subgroup analysis showed no significant difference between goalkeepers and outfielders with respect to mortality with neurodegenerative disease listed as a factor (HR, 0.73), but dementia-related medications were prescribed less often to goalkeepers (OR, 0.41).

Concerns about the risk of neurodegenerative diseases among participants in contact sports have been raised, in part because of the recognition of pathologic changes of chronic traumatic encephalopathy among participants across a range of such sports, the investigators explained, noting that data regarding the risk of neurodegenerative disease among former professional soccer players are limited.

The findings of the current study, in terms of lower all-cause mortality up to the age of 70 years, are similar to those in previous studies involving elite athletes across a range of sports, and “may reflect higher levels of physical activity and lower levels of obesity and smoking in elite athletes than in the general population,” they noted.

“In contrast, mortality from neurodegenerative disease was higher among former soccer players, a finding consistent with studies involving former players in the U.S. National Football League,” they added, concluding that the findings, which “may be valuable to inform the management of risks in the sport,” require confirmation in prospective studies.

This study was supported by the Football Association and Professional Footballers’ Association, and by an NHS Research Scotland Career Researcher Fellowship. Dr. Mackay reported having no relevant financial disclosures.

[email protected]

SOURCE: Mackay D et al. N Engl J Med. 2019 Oct 21. doi: 10.1056/NEJMoa1908483.

Mortality risk associated with neurodegenerative disease is higher, and mortality risk associated with other causes lower, among former Scottish professional soccer players versus matched controls, findings from a retrospective epidemiologic analysis suggest.

Nikada/Getty Images

Former professional soccer players included in the analysis also received more dementia-related medication prescriptions than did controls, Daniel F. Mackay, PhD, of the Institute of Health and Wellbeing at the University of Glasgow (Scotland) and his colleagues reported online Oct. 21 in The New England Journal of Medicine.

Overall mortality during a median follow-up of 18 years from study entry at the age of 40 years was 15.4% among 7,676 former players, and 16.5% among 23,028 controls matched based on age, sex, and degree of social deprivation. All-cause mortality was lower among players versus controls before age 70 years, and was higher thereafter, and the mortality rates associated with ischemic heart disease and lung cancer were lower among the players (hazard ratios, 0.80 and 0.53, respectively), the investigators found.

Mortality rates from stroke or cerebrovascular disease were similar in the players and controls (HR, 0.88), they noted.

However, mortality with neurodegenerative disease listed as the primary cause was 1.7% in players versus 0.5% in controls (HR adjusted for competing risks of death, 3.45), they said. The estimated risk of death with neurodegenerative disease was highest among those with Alzheimer’s disease and lowest for those with Parkinson’s disease (HRs, 5.07 and 2.15, respectively).

Dementia-related medications also were prescribed more frequently for players vs. controls (odds ratio, 4.90).

A subgroup analysis showed no significant difference between goalkeepers and outfielders with respect to mortality with neurodegenerative disease listed as a factor (HR, 0.73), but dementia-related medications were prescribed less often to goalkeepers (OR, 0.41).

Concerns about the risk of neurodegenerative diseases among participants in contact sports have been raised, in part because of the recognition of pathologic changes of chronic traumatic encephalopathy among participants across a range of such sports, the investigators explained, noting that data regarding the risk of neurodegenerative disease among former professional soccer players are limited.

The findings of the current study, in terms of lower all-cause mortality up to the age of 70 years, are similar to those in previous studies involving elite athletes across a range of sports, and “may reflect higher levels of physical activity and lower levels of obesity and smoking in elite athletes than in the general population,” they noted.

“In contrast, mortality from neurodegenerative disease was higher among former soccer players, a finding consistent with studies involving former players in the U.S. National Football League,” they added, concluding that the findings, which “may be valuable to inform the management of risks in the sport,” require confirmation in prospective studies.

This study was supported by the Football Association and Professional Footballers’ Association, and by an NHS Research Scotland Career Researcher Fellowship. Dr. Mackay reported having no relevant financial disclosures.

[email protected]

SOURCE: Mackay D et al. N Engl J Med. 2019 Oct 21. doi: 10.1056/NEJMoa1908483.

COPENHAGEN – Selected antidiabetes medications appear to blunt the increased risk of dementia associated with type 2 diabetes, according to a Danish national case control registry study.

Boarding1Now/Thinkstock

This benefit applies to the newer antidiabetic agents – specifically, the dipeptidyl peptidase 4 (DPP4) inhibitors, the glucagon-like peptide 1 (GLP1) analogs, and the sodium-glucose transport protein 2 (SGLT2) inhibitors – and metformin as well, Merete Osler, MD, PhD, reported at the annual congress of the European College of Neuropsychopharmacology.

In contrast, neither insulin nor the sulfonylureas showed any signal of a protective effect against development of dementia. In fact, the use of sulfonylureas was associated with a small but statistically significant 7% increased risk, added Dr. Osler, of the University of Copenhagen.

Elsewhere at the meeting, investigators tapped a Swedish national registry to demonstrate that individuals with type 1 diabetes have a sharply reduced risk of developing schizophrenia.
 

Type 2 diabetes medications and dementia

Dr. Osler and colleagues are among several groups of investigators who have previously shown that patients with type 2 diabetes have an increased risk of dementia.

“This has raised the question of the role of dysregulated glucose metabolism in the development of this neurodegenerative disorder, and the possible effect of antidiabetic medications,” she noted.

To further explore this issue, which links two great ongoing global epidemics, Dr. Osler and coinvestigators conducted a nested case-control study including all 176,250 patients with type 2 diabetes in the comprehensive Danish National Diabetes Register for 1995-2012. The 11,619 patients with type 2 diabetes who received a dementia diagnosis were matched with 46,476 type 2 diabetes patients without dementia. The objective was to determine associations between dementia and ever-use and cumulative dose of antidiabetes drugs, alone and in combination, in logistic regression analyses adjusted for demographics, comorbid conditions, marital status, diabetic complications, and year of dementia diagnosis.

Patients who had ever used metformin had an adjusted 6% reduction in the likelihood of dementia compared with metformin nonusers, a modest but statistically significant difference. Those on a DPP4 inhibitor had a 20% reduction in risk. The GLP1 analogs were associated with a 42% decrease in risk. So were the SGLT2 inhibitors. A dose-response relationship was evident: The higher the cumulative exposure to these agents, the lower the odds of dementia.

Combination therapy is common in type 2 diabetes, so the investigators scrutinized the impact of a variety of multidrug combinations. The clear winner in terms of the magnitude of associated reduction in dementia risk were the combinations including an SGLT2 inhibitor, with a 62% relative risk reduction. Combinations including a DPP4 inhibitor or GLP1 analog were also associated with significantly reduced dementia risk.

Records of glycemic control in the form of hemoglobin A_1c values were available on only 1,446 type 2 diabetic dementia patients and 4,003 matched controls. An analysis that incorporated this variable showed that the observed anti-dementia effect of selected diabetes drugs was independent of glycemic control, according to Dr. Osler.

The protective effect appeared to extend to both Alzheimer’s disease and vascular dementias, although firm conclusions can’t be drawn on this score because the study was insufficiently powered to address that issue.

Dr. Osler noted that the Danish study confirms a recent Taiwanese study showing an apparent protective effect against dementia for metformin in patients with type 2 diabetes (Aging Dis. 2019 Feb 1;10(1):37-48).

“Ours is the first study on the newer diabetic drugs, so our results need to be confirmed,” she pointed out.

If confirmed, however, it would warrant exploration of these drugs more generally as potential interventions to prevent dementia. That could open a whole new chapter in the remarkable story of the SGLT2 inhibitors, a class of drugs originally developed for treatment of type 2 diabetes but which in major randomized clinical trials later proved to be so effective in the treatment of heart failure that they are now considered cardiology drugs first.

Asked if she thinks these antidiabetes agents have a general neuroprotective effect or, instead, that the observed reduced risk of dementia is a function of patients being treated better early on with modern drugs, the psychiatrist replied, “I think it might be a combination of both, especially because we find different risk estimates between the drugs.”

Dr. Osler reported having no financial conflicts of interest regarding the study, which was funded by the Danish Diabetes Foundation, the Danish Medical Association, and several other foundations.

The full study details were published online shortly before her presentation at ECNP 2019 (Eur J Endocrinol. 2019 Aug 1. pii: EJE-19-0259.R1. doi: 10.1530/EJE-19-0259).

Type 1 diabetes and schizophrenia risk

Kristina Melkersson, MD, PhD, presented a cohort study that utilized Swedish national registries to examine the relationship between type 1 diabetes and schizophrenia. The study comprised 1,745,977 individuals, of whom 10,117 had type 1 diabetes, who were followed for a median of 9.7 and maximum of 18 years from their 13th birthday. During follow-up, 1,280 individuals were diagnosed with schizophrenia and 649 others with schizoaffective disorder. The adjusted risk of schizophrenia was 70% lower in patients with type 1 diabetes. However, there was no difference in the risk of schizoaffective disorder in the type 1 diabetic versus nondiabetic subjects.

The Swedish data confirm the findings of an earlier Finnish national study showing that the risk of schizophrenia is reduced in patients with type 1 diabetes (Arch Gen Psychiatry. 2007 Aug;64(8):894-9). These findings raise the intriguing possibility that autoimmunity somehow figures into the etiology of the psychiatric disorder. Other investigators have previously reported a reduced prevalence of rheumatoid arthritis in patients with schizophrenia, noted Dr. Melkersson of the Karolinska Institute in Stockholm.

She reported having no financial conflicts regarding her study.

[email protected]

SOURCE: Osler M. ECNP Abstract P180. Melkersson K. Abstract 81.

COPENHAGEN – Selected antidiabetes medications appear to blunt the increased risk of dementia associated with type 2 diabetes, according to a Danish national case control registry study.

Boarding1Now/Thinkstock

This benefit applies to the newer antidiabetic agents – specifically, the dipeptidyl peptidase 4 (DPP4) inhibitors, the glucagon-like peptide 1 (GLP1) analogs, and the sodium-glucose transport protein 2 (SGLT2) inhibitors – and metformin as well, Merete Osler, MD, PhD, reported at the annual congress of the European College of Neuropsychopharmacology.

In contrast, neither insulin nor the sulfonylureas showed any signal of a protective effect against development of dementia. In fact, the use of sulfonylureas was associated with a small but statistically significant 7% increased risk, added Dr. Osler, of the University of Copenhagen.

Elsewhere at the meeting, investigators tapped a Swedish national registry to demonstrate that individuals with type 1 diabetes have a sharply reduced risk of developing schizophrenia.
 

Type 2 diabetes medications and dementia

Dr. Osler and colleagues are among several groups of investigators who have previously shown that patients with type 2 diabetes have an increased risk of dementia.

“This has raised the question of the role of dysregulated glucose metabolism in the development of this neurodegenerative disorder, and the possible effect of antidiabetic medications,” she noted.

To further explore this issue, which links two great ongoing global epidemics, Dr. Osler and coinvestigators conducted a nested case-control study including all 176,250 patients with type 2 diabetes in the comprehensive Danish National Diabetes Register for 1995-2012. The 11,619 patients with type 2 diabetes who received a dementia diagnosis were matched with 46,476 type 2 diabetes patients without dementia. The objective was to determine associations between dementia and ever-use and cumulative dose of antidiabetes drugs, alone and in combination, in logistic regression analyses adjusted for demographics, comorbid conditions, marital status, diabetic complications, and year of dementia diagnosis.

Patients who had ever used metformin had an adjusted 6% reduction in the likelihood of dementia compared with metformin nonusers, a modest but statistically significant difference. Those on a DPP4 inhibitor had a 20% reduction in risk. The GLP1 analogs were associated with a 42% decrease in risk. So were the SGLT2 inhibitors. A dose-response relationship was evident: The higher the cumulative exposure to these agents, the lower the odds of dementia.

Combination therapy is common in type 2 diabetes, so the investigators scrutinized the impact of a variety of multidrug combinations. The clear winner in terms of the magnitude of associated reduction in dementia risk were the combinations including an SGLT2 inhibitor, with a 62% relative risk reduction. Combinations including a DPP4 inhibitor or GLP1 analog were also associated with significantly reduced dementia risk.

Records of glycemic control in the form of hemoglobin A_1c values were available on only 1,446 type 2 diabetic dementia patients and 4,003 matched controls. An analysis that incorporated this variable showed that the observed anti-dementia effect of selected diabetes drugs was independent of glycemic control, according to Dr. Osler.

The protective effect appeared to extend to both Alzheimer’s disease and vascular dementias, although firm conclusions can’t be drawn on this score because the study was insufficiently powered to address that issue.

Dr. Osler noted that the Danish study confirms a recent Taiwanese study showing an apparent protective effect against dementia for metformin in patients with type 2 diabetes (Aging Dis. 2019 Feb 1;10(1):37-48).

“Ours is the first study on the newer diabetic drugs, so our results need to be confirmed,” she pointed out.

If confirmed, however, it would warrant exploration of these drugs more generally as potential interventions to prevent dementia. That could open a whole new chapter in the remarkable story of the SGLT2 inhibitors, a class of drugs originally developed for treatment of type 2 diabetes but which in major randomized clinical trials later proved to be so effective in the treatment of heart failure that they are now considered cardiology drugs first.

Asked if she thinks these antidiabetes agents have a general neuroprotective effect or, instead, that the observed reduced risk of dementia is a function of patients being treated better early on with modern drugs, the psychiatrist replied, “I think it might be a combination of both, especially because we find different risk estimates between the drugs.”

Dr. Osler reported having no financial conflicts of interest regarding the study, which was funded by the Danish Diabetes Foundation, the Danish Medical Association, and several other foundations.

The full study details were published online shortly before her presentation at ECNP 2019 (Eur J Endocrinol. 2019 Aug 1. pii: EJE-19-0259.R1. doi: 10.1530/EJE-19-0259).

Type 1 diabetes and schizophrenia risk

Kristina Melkersson, MD, PhD, presented a cohort study that utilized Swedish national registries to examine the relationship between type 1 diabetes and schizophrenia. The study comprised 1,745,977 individuals, of whom 10,117 had type 1 diabetes, who were followed for a median of 9.7 and maximum of 18 years from their 13th birthday. During follow-up, 1,280 individuals were diagnosed with schizophrenia and 649 others with schizoaffective disorder. The adjusted risk of schizophrenia was 70% lower in patients with type 1 diabetes. However, there was no difference in the risk of schizoaffective disorder in the type 1 diabetic versus nondiabetic subjects.

The Swedish data confirm the findings of an earlier Finnish national study showing that the risk of schizophrenia is reduced in patients with type 1 diabetes (Arch Gen Psychiatry. 2007 Aug;64(8):894-9). These findings raise the intriguing possibility that autoimmunity somehow figures into the etiology of the psychiatric disorder. Other investigators have previously reported a reduced prevalence of rheumatoid arthritis in patients with schizophrenia, noted Dr. Melkersson of the Karolinska Institute in Stockholm.

She reported having no financial conflicts regarding her study.

[email protected]

SOURCE: Osler M. ECNP Abstract P180. Melkersson K. Abstract 81.

COPENHAGEN – Selected antidiabetes medications appear to blunt the increased risk of dementia associated with type 2 diabetes, according to a Danish national case control registry study.

Boarding1Now/Thinkstock

This benefit applies to the newer antidiabetic agents – specifically, the dipeptidyl peptidase 4 (DPP4) inhibitors, the glucagon-like peptide 1 (GLP1) analogs, and the sodium-glucose transport protein 2 (SGLT2) inhibitors – and metformin as well, Merete Osler, MD, PhD, reported at the annual congress of the European College of Neuropsychopharmacology.

In contrast, neither insulin nor the sulfonylureas showed any signal of a protective effect against development of dementia. In fact, the use of sulfonylureas was associated with a small but statistically significant 7% increased risk, added Dr. Osler, of the University of Copenhagen.

Elsewhere at the meeting, investigators tapped a Swedish national registry to demonstrate that individuals with type 1 diabetes have a sharply reduced risk of developing schizophrenia.
 

Type 2 diabetes medications and dementia

Dr. Osler and colleagues are among several groups of investigators who have previously shown that patients with type 2 diabetes have an increased risk of dementia.

“This has raised the question of the role of dysregulated glucose metabolism in the development of this neurodegenerative disorder, and the possible effect of antidiabetic medications,” she noted.

To further explore this issue, which links two great ongoing global epidemics, Dr. Osler and coinvestigators conducted a nested case-control study including all 176,250 patients with type 2 diabetes in the comprehensive Danish National Diabetes Register for 1995-2012. The 11,619 patients with type 2 diabetes who received a dementia diagnosis were matched with 46,476 type 2 diabetes patients without dementia. The objective was to determine associations between dementia and ever-use and cumulative dose of antidiabetes drugs, alone and in combination, in logistic regression analyses adjusted for demographics, comorbid conditions, marital status, diabetic complications, and year of dementia diagnosis.

Patients who had ever used metformin had an adjusted 6% reduction in the likelihood of dementia compared with metformin nonusers, a modest but statistically significant difference. Those on a DPP4 inhibitor had a 20% reduction in risk. The GLP1 analogs were associated with a 42% decrease in risk. So were the SGLT2 inhibitors. A dose-response relationship was evident: The higher the cumulative exposure to these agents, the lower the odds of dementia.

Combination therapy is common in type 2 diabetes, so the investigators scrutinized the impact of a variety of multidrug combinations. The clear winner in terms of the magnitude of associated reduction in dementia risk were the combinations including an SGLT2 inhibitor, with a 62% relative risk reduction. Combinations including a DPP4 inhibitor or GLP1 analog were also associated with significantly reduced dementia risk.

Records of glycemic control in the form of hemoglobin A_1c values were available on only 1,446 type 2 diabetic dementia patients and 4,003 matched controls. An analysis that incorporated this variable showed that the observed anti-dementia effect of selected diabetes drugs was independent of glycemic control, according to Dr. Osler.

The protective effect appeared to extend to both Alzheimer’s disease and vascular dementias, although firm conclusions can’t be drawn on this score because the study was insufficiently powered to address that issue.

Dr. Osler noted that the Danish study confirms a recent Taiwanese study showing an apparent protective effect against dementia for metformin in patients with type 2 diabetes (Aging Dis. 2019 Feb 1;10(1):37-48).

“Ours is the first study on the newer diabetic drugs, so our results need to be confirmed,” she pointed out.

If confirmed, however, it would warrant exploration of these drugs more generally as potential interventions to prevent dementia. That could open a whole new chapter in the remarkable story of the SGLT2 inhibitors, a class of drugs originally developed for treatment of type 2 diabetes but which in major randomized clinical trials later proved to be so effective in the treatment of heart failure that they are now considered cardiology drugs first.

Asked if she thinks these antidiabetes agents have a general neuroprotective effect or, instead, that the observed reduced risk of dementia is a function of patients being treated better early on with modern drugs, the psychiatrist replied, “I think it might be a combination of both, especially because we find different risk estimates between the drugs.”

Dr. Osler reported having no financial conflicts of interest regarding the study, which was funded by the Danish Diabetes Foundation, the Danish Medical Association, and several other foundations.

The full study details were published online shortly before her presentation at ECNP 2019 (Eur J Endocrinol. 2019 Aug 1. pii: EJE-19-0259.R1. doi: 10.1530/EJE-19-0259).

Type 1 diabetes and schizophrenia risk

Kristina Melkersson, MD, PhD, presented a cohort study that utilized Swedish national registries to examine the relationship between type 1 diabetes and schizophrenia. The study comprised 1,745,977 individuals, of whom 10,117 had type 1 diabetes, who were followed for a median of 9.7 and maximum of 18 years from their 13th birthday. During follow-up, 1,280 individuals were diagnosed with schizophrenia and 649 others with schizoaffective disorder. The adjusted risk of schizophrenia was 70% lower in patients with type 1 diabetes. However, there was no difference in the risk of schizoaffective disorder in the type 1 diabetic versus nondiabetic subjects.

The Swedish data confirm the findings of an earlier Finnish national study showing that the risk of schizophrenia is reduced in patients with type 1 diabetes (Arch Gen Psychiatry. 2007 Aug;64(8):894-9). These findings raise the intriguing possibility that autoimmunity somehow figures into the etiology of the psychiatric disorder. Other investigators have previously reported a reduced prevalence of rheumatoid arthritis in patients with schizophrenia, noted Dr. Melkersson of the Karolinska Institute in Stockholm.

She reported having no financial conflicts regarding her study.

[email protected]

SOURCE: Osler M. ECNP Abstract P180. Melkersson K. Abstract 81.

Imagine the clinical care consequences if patients seen in specialty or primary care practices did not have ready access to laboratory, other medical tests, and/or consultative services deemed critical to quickly establishing diagnostic status and the development of an appropriate treatment plan. For instance, what would be the implications if a dentistry practice did not employ a dental hygienist; an otolaryngology group was not staffed with an audiologist; or a gastroenterology practice had no one available for digestive/nutritional consultation support.

ipopba/Getty Images

Consider a neurologist who suspects that a patient has a potentially life-threatening brain condition, but the patient has to wait months for brain imaging or – even worse – is tasked to find their own provider for this diagnostic test only to be told that the neuroimaging service does not take their insurance and/or there are no available appointments for several months.

Situations of this kind would not be – and should not be – tolerated by medical professionals or their patients.

A common “real-world” scenario: After evaluation, a psychiatrist needs clarification regarding a possible subtle psychotic process, or, in another instance, suspects that there is an early degenerative cognitive change underlying recent changes in mood and personality. However, the psychiatrist has no dependable access to an assessment psychologist to assist in cases of this kind.

Patients are frequently told by psychiatrists and other physicians that they should have psychodiagnostic testing to arrive at a clearer picture of their clinical status and treatment needs. However, most medical practices, in particular, psychiatry, pediatrics, neurology, and neurosurgery, who see substantial numbers of patients who could benefit from testing, do not employ psychologists. When they do, many do not possess the requisite assessment skills to address the reason(s) for referral.

If the patient needing testing services is fortunate enough, he/she is referred to a well-trained psychologist within commuting distance who takes the patient’s insurance and is able to set up a timely appointment – an unlikely set of circumstances in today’s health care environment.

Many patients are left to research this matter on their own, using the Internet or relying on “word of mouth.” Some state psychological associations allow for a “matching service” of sorts in the form of announcements in the organization’s listserv, which reviews the referral and includes a back channel for psychologists to contact the patient regarding their availability for testing.

Over the past 2 decades, significant advancements have been made in the integration of primary and mental health care. Those need to continue to include colocating assessment psychologists in medical specialty practices, such as psychiatry, which make frequent referrals for psychodiagnostic testing or would like to but have no place to turn.

Dr. Pollak is affiliated with the Seacoast Mental Health Center in Portsmouth, N.H.

Imagine the clinical care consequences if patients seen in specialty or primary care practices did not have ready access to laboratory, other medical tests, and/or consultative services deemed critical to quickly establishing diagnostic status and the development of an appropriate treatment plan. For instance, what would be the implications if a dentistry practice did not employ a dental hygienist; an otolaryngology group was not staffed with an audiologist; or a gastroenterology practice had no one available for digestive/nutritional consultation support.

ipopba/Getty Images

Consider a neurologist who suspects that a patient has a potentially life-threatening brain condition, but the patient has to wait months for brain imaging or – even worse – is tasked to find their own provider for this diagnostic test only to be told that the neuroimaging service does not take their insurance and/or there are no available appointments for several months.

Situations of this kind would not be – and should not be – tolerated by medical professionals or their patients.

A common “real-world” scenario: After evaluation, a psychiatrist needs clarification regarding a possible subtle psychotic process, or, in another instance, suspects that there is an early degenerative cognitive change underlying recent changes in mood and personality. However, the psychiatrist has no dependable access to an assessment psychologist to assist in cases of this kind.

Patients are frequently told by psychiatrists and other physicians that they should have psychodiagnostic testing to arrive at a clearer picture of their clinical status and treatment needs. However, most medical practices, in particular, psychiatry, pediatrics, neurology, and neurosurgery, who see substantial numbers of patients who could benefit from testing, do not employ psychologists. When they do, many do not possess the requisite assessment skills to address the reason(s) for referral.

If the patient needing testing services is fortunate enough, he/she is referred to a well-trained psychologist within commuting distance who takes the patient’s insurance and is able to set up a timely appointment – an unlikely set of circumstances in today’s health care environment.

Many patients are left to research this matter on their own, using the Internet or relying on “word of mouth.” Some state psychological associations allow for a “matching service” of sorts in the form of announcements in the organization’s listserv, which reviews the referral and includes a back channel for psychologists to contact the patient regarding their availability for testing.

Over the past 2 decades, significant advancements have been made in the integration of primary and mental health care. Those need to continue to include colocating assessment psychologists in medical specialty practices, such as psychiatry, which make frequent referrals for psychodiagnostic testing or would like to but have no place to turn.

Dr. Pollak is affiliated with the Seacoast Mental Health Center in Portsmouth, N.H.

Imagine the clinical care consequences if patients seen in specialty or primary care practices did not have ready access to laboratory, other medical tests, and/or consultative services deemed critical to quickly establishing diagnostic status and the development of an appropriate treatment plan. For instance, what would be the implications if a dentistry practice did not employ a dental hygienist; an otolaryngology group was not staffed with an audiologist; or a gastroenterology practice had no one available for digestive/nutritional consultation support.

ipopba/Getty Images

Consider a neurologist who suspects that a patient has a potentially life-threatening brain condition, but the patient has to wait months for brain imaging or – even worse – is tasked to find their own provider for this diagnostic test only to be told that the neuroimaging service does not take their insurance and/or there are no available appointments for several months.

Situations of this kind would not be – and should not be – tolerated by medical professionals or their patients.

A common “real-world” scenario: After evaluation, a psychiatrist needs clarification regarding a possible subtle psychotic process, or, in another instance, suspects that there is an early degenerative cognitive change underlying recent changes in mood and personality. However, the psychiatrist has no dependable access to an assessment psychologist to assist in cases of this kind.

Patients are frequently told by psychiatrists and other physicians that they should have psychodiagnostic testing to arrive at a clearer picture of their clinical status and treatment needs. However, most medical practices, in particular, psychiatry, pediatrics, neurology, and neurosurgery, who see substantial numbers of patients who could benefit from testing, do not employ psychologists. When they do, many do not possess the requisite assessment skills to address the reason(s) for referral.

If the patient needing testing services is fortunate enough, he/she is referred to a well-trained psychologist within commuting distance who takes the patient’s insurance and is able to set up a timely appointment – an unlikely set of circumstances in today’s health care environment.

Many patients are left to research this matter on their own, using the Internet or relying on “word of mouth.” Some state psychological associations allow for a “matching service” of sorts in the form of announcements in the organization’s listserv, which reviews the referral and includes a back channel for psychologists to contact the patient regarding their availability for testing.

Over the past 2 decades, significant advancements have been made in the integration of primary and mental health care. Those need to continue to include colocating assessment psychologists in medical specialty practices, such as psychiatry, which make frequent referrals for psychodiagnostic testing or would like to but have no place to turn.

Dr. Pollak is affiliated with the Seacoast Mental Health Center in Portsmouth, N.H.

Applying diagnostic criteria for amnestic mild cognitive impairment (aMCI) that do not account for sex differences in verbal memory performance leads to an approximately 20% rate of misdiagnosis, according to an investigation published Oct. 9 in Neurology. Using sex-specific cut scores to define verbal memory impairment improves diagnostic accuracy and “may result in earlier detection of memory impairment in women and avoid false diagnoses in men,” wrote Erin E. Sundermann, PhD, assistant project scientist in psychiatry at the University of California, San Diego, and colleagues.

A diagnosis of aMCI generally requires a verbal memory deficit. Ample research demonstrates a female advantage on verbal memory tests, but normative data for these tests usually do not adjust for sex. Dr. Sundermann and colleagues previously showed that among men and women with aMCI and similar disease burden, women perform better on tests of verbal memory. Given these results, the investigators initiated a new study to test the hypothesis that using sex-specific norms and cut scores to identify memory impairment improves the accuracy of aMCI diagnosis, compared with non–sex-specific norms and cut scores.
 

An examination of ADNI data

Dr. Sundermann’s group extracted cross-sectional data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database in October 2016. They included participants without dementia for whom neuropsychologic and Alzheimer’s disease pathologic marker data were available at baseline. They excluded patients with a non-aMCI diagnosis based on typical and sex-specific criteria.

The researchers’ primary outcome was the Rey Auditory Verbal Learning Test (RAVLT). They also determined the presence or absence of the APOE e4 allele for each participant. Biomarker outcomes included the CSF ratio of hyperphosphorylated tau (p-tau) to beta-amyloid (A-beta), and cortical A-beta deposition.

Dr. Sundermann and colleagues applied the Jak/Bondi actuarial neuropsychologic diagnostic method to baseline data. This method relies on six neuropsychologic tests, including the RAVLT Learning and Delayed Recall. They subsequently derived two sets of normative data for the RAVLT outcomes in a normative sample of 1,620 patients enrolled in the Mayo Clinic Study of Aging (MCSA). The latter patients were considered normal controls at baseline and at least two follow-up visits at 15 months apart. One set of normative data was specific for age and education, and the other was specific for age, education, and sex. Dr. Sundermann’s group next applied the typical Jak/Bondi method and the sex-specific Jak/Bondi method to all ADNI participants’ data.
 

Biomarker analysis supported the hypothesis

The researchers included 985 participants (453 women) in their final sample. Approximately 94% of the population was white. Mean age was 72.9 years, and mean education duration was 16.3 years. Overall, women had a significantly lower mean age (71.9 years vs. 73.6 years), significantly fewer mean years of education (15.7 years vs. 16.7 years), and a significantly higher mean Mini-Mental State Examination score (28 vs. 28.1) compared with men. Compared with men’s scores, women’s scores on the RAVLT Learning (mean 42.3 vs. mean 35.6) and Delayed Recall (mean 6.2 vs. mean 4.5) were significantly higher.

When Dr. Sundermann and colleagues used typical cut scores, the frequency of aMCI diagnosis was significantly higher in men. Using sex-specific cut scores eliminated this sex difference, however. Among men, 184 (35%) were categorized as true positive, 293 (55%) as true negative, and 55 (10%) as false positive. No men were categorized as false negative. Among women, 120 (26%) were categorized as true positive, 288 (64%) as true negative, and 45 (10%) as false negative. No women were categorized as false positive.

The likelihood of cortical amyloid positivity in false negative women was 3.6 times greater than in true negative women but did not differ from that in true positive women. The likelihood of positivity for the CSF p-tau/A-beta ratio in false negative women was more than two times higher than in true negative women but did not differ from that in true positive women. The likelihood of having an APOE e4 allele in false negative women was almost fivefold higher than in true negative women but did not differ from that in true positive women.

The likelihood of cortical amyloid positivity in false positive men was less than that in true positive men (odds ratio [OR], 0.45) but did not differ from that in true negative men. The likelihood of positivity for CSF p-tau/A-beta ratio in false positive men was significantly less than in true positive men (OR, 0.47) but did not differ from that in true negative men. The likelihood of having the APOE e4 allele in false positive men was lower than that in true positive men (OR, 0.63) and higher than that in true negative men (OR, 1.50), but not significantly.
 

Results have implications for treatment

“If these results are confirmed, they have vital implications,” Dr. Sundermann said in a press release. “If women are inaccurately identified as having no problems with memory and thinking skills when they actually have MCI, then treatments are not being started, and they and their families are not planning ahead for their care or their financial or legal situations. And for men who are inaccurately diagnosed with MCI, they can be exposed to unneeded medications along with undue stress for them and their families.”

Among the limitations that the investigators acknowledged was the study’s cross-sectional, rather than longitudinal, design. In addition, the ADNI population that the researchers examined is a convenience sample of predominantly white and well-educated volunteers. The results therefore may not be generalizable to the broader U.S. population, wrote the authors.

Grants from the National Institutes of Health funded the study. Several of the investigators reported receiving honoraria from various pharmaceutical companies such as Mylan. One investigator sits on the editorial board for Neurology.

[email protected]

SOURCE: Sundermann EE et al. Neurology. 2019 Oct 9.

Applying diagnostic criteria for amnestic mild cognitive impairment (aMCI) that do not account for sex differences in verbal memory performance leads to an approximately 20% rate of misdiagnosis, according to an investigation published Oct. 9 in Neurology. Using sex-specific cut scores to define verbal memory impairment improves diagnostic accuracy and “may result in earlier detection of memory impairment in women and avoid false diagnoses in men,” wrote Erin E. Sundermann, PhD, assistant project scientist in psychiatry at the University of California, San Diego, and colleagues.

A diagnosis of aMCI generally requires a verbal memory deficit. Ample research demonstrates a female advantage on verbal memory tests, but normative data for these tests usually do not adjust for sex. Dr. Sundermann and colleagues previously showed that among men and women with aMCI and similar disease burden, women perform better on tests of verbal memory. Given these results, the investigators initiated a new study to test the hypothesis that using sex-specific norms and cut scores to identify memory impairment improves the accuracy of aMCI diagnosis, compared with non–sex-specific norms and cut scores.
 

An examination of ADNI data

Dr. Sundermann’s group extracted cross-sectional data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database in October 2016. They included participants without dementia for whom neuropsychologic and Alzheimer’s disease pathologic marker data were available at baseline. They excluded patients with a non-aMCI diagnosis based on typical and sex-specific criteria.

The researchers’ primary outcome was the Rey Auditory Verbal Learning Test (RAVLT). They also determined the presence or absence of the APOE e4 allele for each participant. Biomarker outcomes included the CSF ratio of hyperphosphorylated tau (p-tau) to beta-amyloid (A-beta), and cortical A-beta deposition.

Dr. Sundermann and colleagues applied the Jak/Bondi actuarial neuropsychologic diagnostic method to baseline data. This method relies on six neuropsychologic tests, including the RAVLT Learning and Delayed Recall. They subsequently derived two sets of normative data for the RAVLT outcomes in a normative sample of 1,620 patients enrolled in the Mayo Clinic Study of Aging (MCSA). The latter patients were considered normal controls at baseline and at least two follow-up visits at 15 months apart. One set of normative data was specific for age and education, and the other was specific for age, education, and sex. Dr. Sundermann’s group next applied the typical Jak/Bondi method and the sex-specific Jak/Bondi method to all ADNI participants’ data.
 

Biomarker analysis supported the hypothesis

The researchers included 985 participants (453 women) in their final sample. Approximately 94% of the population was white. Mean age was 72.9 years, and mean education duration was 16.3 years. Overall, women had a significantly lower mean age (71.9 years vs. 73.6 years), significantly fewer mean years of education (15.7 years vs. 16.7 years), and a significantly higher mean Mini-Mental State Examination score (28 vs. 28.1) compared with men. Compared with men’s scores, women’s scores on the RAVLT Learning (mean 42.3 vs. mean 35.6) and Delayed Recall (mean 6.2 vs. mean 4.5) were significantly higher.

When Dr. Sundermann and colleagues used typical cut scores, the frequency of aMCI diagnosis was significantly higher in men. Using sex-specific cut scores eliminated this sex difference, however. Among men, 184 (35%) were categorized as true positive, 293 (55%) as true negative, and 55 (10%) as false positive. No men were categorized as false negative. Among women, 120 (26%) were categorized as true positive, 288 (64%) as true negative, and 45 (10%) as false negative. No women were categorized as false positive.

The likelihood of cortical amyloid positivity in false negative women was 3.6 times greater than in true negative women but did not differ from that in true positive women. The likelihood of positivity for the CSF p-tau/A-beta ratio in false negative women was more than two times higher than in true negative women but did not differ from that in true positive women. The likelihood of having an APOE e4 allele in false negative women was almost fivefold higher than in true negative women but did not differ from that in true positive women.

The likelihood of cortical amyloid positivity in false positive men was less than that in true positive men (odds ratio [OR], 0.45) but did not differ from that in true negative men. The likelihood of positivity for CSF p-tau/A-beta ratio in false positive men was significantly less than in true positive men (OR, 0.47) but did not differ from that in true negative men. The likelihood of having the APOE e4 allele in false positive men was lower than that in true positive men (OR, 0.63) and higher than that in true negative men (OR, 1.50), but not significantly.
 

Results have implications for treatment

“If these results are confirmed, they have vital implications,” Dr. Sundermann said in a press release. “If women are inaccurately identified as having no problems with memory and thinking skills when they actually have MCI, then treatments are not being started, and they and their families are not planning ahead for their care or their financial or legal situations. And for men who are inaccurately diagnosed with MCI, they can be exposed to unneeded medications along with undue stress for them and their families.”

Among the limitations that the investigators acknowledged was the study’s cross-sectional, rather than longitudinal, design. In addition, the ADNI population that the researchers examined is a convenience sample of predominantly white and well-educated volunteers. The results therefore may not be generalizable to the broader U.S. population, wrote the authors.

Grants from the National Institutes of Health funded the study. Several of the investigators reported receiving honoraria from various pharmaceutical companies such as Mylan. One investigator sits on the editorial board for Neurology.

[email protected]

SOURCE: Sundermann EE et al. Neurology. 2019 Oct 9.

Applying diagnostic criteria for amnestic mild cognitive impairment (aMCI) that do not account for sex differences in verbal memory performance leads to an approximately 20% rate of misdiagnosis, according to an investigation published Oct. 9 in Neurology. Using sex-specific cut scores to define verbal memory impairment improves diagnostic accuracy and “may result in earlier detection of memory impairment in women and avoid false diagnoses in men,” wrote Erin E. Sundermann, PhD, assistant project scientist in psychiatry at the University of California, San Diego, and colleagues.

A diagnosis of aMCI generally requires a verbal memory deficit. Ample research demonstrates a female advantage on verbal memory tests, but normative data for these tests usually do not adjust for sex. Dr. Sundermann and colleagues previously showed that among men and women with aMCI and similar disease burden, women perform better on tests of verbal memory. Given these results, the investigators initiated a new study to test the hypothesis that using sex-specific norms and cut scores to identify memory impairment improves the accuracy of aMCI diagnosis, compared with non–sex-specific norms and cut scores.
 

An examination of ADNI data

Dr. Sundermann’s group extracted cross-sectional data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database in October 2016. They included participants without dementia for whom neuropsychologic and Alzheimer’s disease pathologic marker data were available at baseline. They excluded patients with a non-aMCI diagnosis based on typical and sex-specific criteria.

The researchers’ primary outcome was the Rey Auditory Verbal Learning Test (RAVLT). They also determined the presence or absence of the APOE e4 allele for each participant. Biomarker outcomes included the CSF ratio of hyperphosphorylated tau (p-tau) to beta-amyloid (A-beta), and cortical A-beta deposition.

Dr. Sundermann and colleagues applied the Jak/Bondi actuarial neuropsychologic diagnostic method to baseline data. This method relies on six neuropsychologic tests, including the RAVLT Learning and Delayed Recall. They subsequently derived two sets of normative data for the RAVLT outcomes in a normative sample of 1,620 patients enrolled in the Mayo Clinic Study of Aging (MCSA). The latter patients were considered normal controls at baseline and at least two follow-up visits at 15 months apart. One set of normative data was specific for age and education, and the other was specific for age, education, and sex. Dr. Sundermann’s group next applied the typical Jak/Bondi method and the sex-specific Jak/Bondi method to all ADNI participants’ data.
 

Biomarker analysis supported the hypothesis

The researchers included 985 participants (453 women) in their final sample. Approximately 94% of the population was white. Mean age was 72.9 years, and mean education duration was 16.3 years. Overall, women had a significantly lower mean age (71.9 years vs. 73.6 years), significantly fewer mean years of education (15.7 years vs. 16.7 years), and a significantly higher mean Mini-Mental State Examination score (28 vs. 28.1) compared with men. Compared with men’s scores, women’s scores on the RAVLT Learning (mean 42.3 vs. mean 35.6) and Delayed Recall (mean 6.2 vs. mean 4.5) were significantly higher.

When Dr. Sundermann and colleagues used typical cut scores, the frequency of aMCI diagnosis was significantly higher in men. Using sex-specific cut scores eliminated this sex difference, however. Among men, 184 (35%) were categorized as true positive, 293 (55%) as true negative, and 55 (10%) as false positive. No men were categorized as false negative. Among women, 120 (26%) were categorized as true positive, 288 (64%) as true negative, and 45 (10%) as false negative. No women were categorized as false positive.

The likelihood of cortical amyloid positivity in false negative women was 3.6 times greater than in true negative women but did not differ from that in true positive women. The likelihood of positivity for the CSF p-tau/A-beta ratio in false negative women was more than two times higher than in true negative women but did not differ from that in true positive women. The likelihood of having an APOE e4 allele in false negative women was almost fivefold higher than in true negative women but did not differ from that in true positive women.

The likelihood of cortical amyloid positivity in false positive men was less than that in true positive men (odds ratio [OR], 0.45) but did not differ from that in true negative men. The likelihood of positivity for CSF p-tau/A-beta ratio in false positive men was significantly less than in true positive men (OR, 0.47) but did not differ from that in true negative men. The likelihood of having the APOE e4 allele in false positive men was lower than that in true positive men (OR, 0.63) and higher than that in true negative men (OR, 1.50), but not significantly.
 

Results have implications for treatment

“If these results are confirmed, they have vital implications,” Dr. Sundermann said in a press release. “If women are inaccurately identified as having no problems with memory and thinking skills when they actually have MCI, then treatments are not being started, and they and their families are not planning ahead for their care or their financial or legal situations. And for men who are inaccurately diagnosed with MCI, they can be exposed to unneeded medications along with undue stress for them and their families.”

Among the limitations that the investigators acknowledged was the study’s cross-sectional, rather than longitudinal, design. In addition, the ADNI population that the researchers examined is a convenience sample of predominantly white and well-educated volunteers. The results therefore may not be generalizable to the broader U.S. population, wrote the authors.

Grants from the National Institutes of Health funded the study. Several of the investigators reported receiving honoraria from various pharmaceutical companies such as Mylan. One investigator sits on the editorial board for Neurology.

[email protected]

SOURCE: Sundermann EE et al. Neurology. 2019 Oct 9.

The shortage of psychiatrists, other mental health clinicians, and primary care physicians who treat patients with mental illness is a profound problem in the United States and around the world. What would happen to those trends if psychiatrists incorporated a functional medicine approach to treating patients?

In functional medicine, we look for underlying causes, physiological damage that results from those causes, clinical body system imbalances, and ultimately, symptoms that patients are experiencing. By addressing the root causes of chronic problems, treating physiological damage, and creating balance in body systems, psychiatrists and other physicians can help our patients achieve optimal health.

For example, a functional medicine approach to treating a child with ADHD might focus on encouraging behavioral changes such as improving sleep hygiene,¹ increasing hydration,² changing nutrition, or prescribing adjunctive meditation rather than medication alone. A functional medicine approach to Alzheimer’s prevention, for example, could include “prescribing” an increase in the amount of regular physical exercise.³ In other words, functional medicine uses a different lens to prevent, arrest, and in some cases, reverse certain diseases.

Medicine has long recognized the links between inflammation and chronic illness. Autoimmune conditions, asthma, heart disease, stroke, diabetes, obesity, peripheral neuropathy, thyroid problems, joint pain, and cancer all are chronic inflammatory diseases. Because inflammation affects the brain, it has been theorized and is being investigated that psychiatric disorders such as depression, schizophrenia, anxiety, panic attacks, dementia, and autism might result.^4,5,6,7

Besides the brain, the GI tract is the only organ system that has its own nervous system, which is called the enteric nervous system, or ENS. The ENS functions independently from the central nervous system, and transmits important messages to and from the brain. When one feels stressed, the brain communicates to the hormonal system and floods the body with stress hormones, such as cortisol, which by themselves, can cause increased intestinal permeability. In addition, the gut produces its own neurotransmitters that affect the brain. In fact, every class of neurotransmitter found in the brain also is found in the GI tract. For example, serotonin is an important neurotransmitter for feeling happy and optimistic. Ninety-five percent of the body’s serotonin is produced in the gut. It is produced from 5-HTP, which is derived from tryptophan. However, in the presence of inflammation in the body, tryptophan is converted into kynurenate and quinolate. Both cause fatigue, and quinolate causes neurotoxicity. The subsequent depletion of serotonin produces symptoms of depression. Problems in the gut can lead to problems in the brain and the whole body.

Other problems affecting patients are tied to toxins in the environment. The air we breathe, food we eat, water we drink, and clothing we wear all are sources of toxins. Toxins include biotoxins, dioxine, phthalates, PCBs, and heavy metals, such as mercury, lead, cadmium, aluminum. About 2,000 new chemicals have been introduced into our environment each year since the 1940s, and it is estimated that we are exposed to more than 80,000 chemicals on a regular basis.⁸

The Environmental Working Group, a nonprofit organization dedicated to educating the public about the environment, has estimated that average babies are born with 287 chemicals in their body, 217 of which are neurotoxins.⁹ As children grow up, their body accumulates more toxins. According to the Centers for Disease Control and Prevention, every American has hundreds of neurotoxins in their bodies right now.

As we become more aware of the many changes in our environment, functional medicine brings a new way of thinking about and looking at chronic disease. As physicians, we can continue treating symptoms, and we should. But we can look deeper and ask ourselves what has changed in our lives that has caused such a decline in human mental and physical health. Your training as psychiatrists makes you uniquely positioned to understand these connections. I urge psychiatrists to help lead the way.
 

Dr. Gaitour, a physiatrist, trained at NYU Langone Medical Center in New York. She is a functional medicine practitioner.
 

References

1. Peppers KH et al. J Pediatr Health Care. 2016 Nov-Dec;30(6):e43-8.

2. Martin EB and PG Hammerness. ADHD, stimulant medication, and dehydration. CHADD.org. 2014 Aug.

3. Guitar NA et al. Ageing Res Rev. 2018 Nov;47:159-67.

4. Mørch RH et al. Acta Psychiatr Scand. 2017 Oct;136(4):400-8.

5. Dooley LN et al. Neurosci Biobehav Rev. 2018 Nov;94:219-37.

6. Yang L et al. Brain Behav Immun. 2016 Aug;56:352-62.

7. Doenyas C. Neuroscience. 2018 Mar 15;374:271-86.

8. PBS News Hour. 2016 Jun 22.

9. Houlihan J. Environmental Working Group. 2005 Jul 14.
 

The shortage of psychiatrists, other mental health clinicians, and primary care physicians who treat patients with mental illness is a profound problem in the United States and around the world. What would happen to those trends if psychiatrists incorporated a functional medicine approach to treating patients?

In functional medicine, we look for underlying causes, physiological damage that results from those causes, clinical body system imbalances, and ultimately, symptoms that patients are experiencing. By addressing the root causes of chronic problems, treating physiological damage, and creating balance in body systems, psychiatrists and other physicians can help our patients achieve optimal health.

For example, a functional medicine approach to treating a child with ADHD might focus on encouraging behavioral changes such as improving sleep hygiene,¹ increasing hydration,² changing nutrition, or prescribing adjunctive meditation rather than medication alone. A functional medicine approach to Alzheimer’s prevention, for example, could include “prescribing” an increase in the amount of regular physical exercise.³ In other words, functional medicine uses a different lens to prevent, arrest, and in some cases, reverse certain diseases.

Medicine has long recognized the links between inflammation and chronic illness. Autoimmune conditions, asthma, heart disease, stroke, diabetes, obesity, peripheral neuropathy, thyroid problems, joint pain, and cancer all are chronic inflammatory diseases. Because inflammation affects the brain, it has been theorized and is being investigated that psychiatric disorders such as depression, schizophrenia, anxiety, panic attacks, dementia, and autism might result.^4,5,6,7

Besides the brain, the GI tract is the only organ system that has its own nervous system, which is called the enteric nervous system, or ENS. The ENS functions independently from the central nervous system, and transmits important messages to and from the brain. When one feels stressed, the brain communicates to the hormonal system and floods the body with stress hormones, such as cortisol, which by themselves, can cause increased intestinal permeability. In addition, the gut produces its own neurotransmitters that affect the brain. In fact, every class of neurotransmitter found in the brain also is found in the GI tract. For example, serotonin is an important neurotransmitter for feeling happy and optimistic. Ninety-five percent of the body’s serotonin is produced in the gut. It is produced from 5-HTP, which is derived from tryptophan. However, in the presence of inflammation in the body, tryptophan is converted into kynurenate and quinolate. Both cause fatigue, and quinolate causes neurotoxicity. The subsequent depletion of serotonin produces symptoms of depression. Problems in the gut can lead to problems in the brain and the whole body.

Other problems affecting patients are tied to toxins in the environment. The air we breathe, food we eat, water we drink, and clothing we wear all are sources of toxins. Toxins include biotoxins, dioxine, phthalates, PCBs, and heavy metals, such as mercury, lead, cadmium, aluminum. About 2,000 new chemicals have been introduced into our environment each year since the 1940s, and it is estimated that we are exposed to more than 80,000 chemicals on a regular basis.⁸

The Environmental Working Group, a nonprofit organization dedicated to educating the public about the environment, has estimated that average babies are born with 287 chemicals in their body, 217 of which are neurotoxins.⁹ As children grow up, their body accumulates more toxins. According to the Centers for Disease Control and Prevention, every American has hundreds of neurotoxins in their bodies right now.

As we become more aware of the many changes in our environment, functional medicine brings a new way of thinking about and looking at chronic disease. As physicians, we can continue treating symptoms, and we should. But we can look deeper and ask ourselves what has changed in our lives that has caused such a decline in human mental and physical health. Your training as psychiatrists makes you uniquely positioned to understand these connections. I urge psychiatrists to help lead the way.
 

Dr. Gaitour, a physiatrist, trained at NYU Langone Medical Center in New York. She is a functional medicine practitioner.
 

References

1. Peppers KH et al. J Pediatr Health Care. 2016 Nov-Dec;30(6):e43-8.

2. Martin EB and PG Hammerness. ADHD, stimulant medication, and dehydration. CHADD.org. 2014 Aug.

3. Guitar NA et al. Ageing Res Rev. 2018 Nov;47:159-67.

4. Mørch RH et al. Acta Psychiatr Scand. 2017 Oct;136(4):400-8.

5. Dooley LN et al. Neurosci Biobehav Rev. 2018 Nov;94:219-37.

6. Yang L et al. Brain Behav Immun. 2016 Aug;56:352-62.

7. Doenyas C. Neuroscience. 2018 Mar 15;374:271-86.

8. PBS News Hour. 2016 Jun 22.

9. Houlihan J. Environmental Working Group. 2005 Jul 14.
 

The shortage of psychiatrists, other mental health clinicians, and primary care physicians who treat patients with mental illness is a profound problem in the United States and around the world. What would happen to those trends if psychiatrists incorporated a functional medicine approach to treating patients?

In functional medicine, we look for underlying causes, physiological damage that results from those causes, clinical body system imbalances, and ultimately, symptoms that patients are experiencing. By addressing the root causes of chronic problems, treating physiological damage, and creating balance in body systems, psychiatrists and other physicians can help our patients achieve optimal health.

For example, a functional medicine approach to treating a child with ADHD might focus on encouraging behavioral changes such as improving sleep hygiene,¹ increasing hydration,² changing nutrition, or prescribing adjunctive meditation rather than medication alone. A functional medicine approach to Alzheimer’s prevention, for example, could include “prescribing” an increase in the amount of regular physical exercise.³ In other words, functional medicine uses a different lens to prevent, arrest, and in some cases, reverse certain diseases.

Medicine has long recognized the links between inflammation and chronic illness. Autoimmune conditions, asthma, heart disease, stroke, diabetes, obesity, peripheral neuropathy, thyroid problems, joint pain, and cancer all are chronic inflammatory diseases. Because inflammation affects the brain, it has been theorized and is being investigated that psychiatric disorders such as depression, schizophrenia, anxiety, panic attacks, dementia, and autism might result.^4,5,6,7

Besides the brain, the GI tract is the only organ system that has its own nervous system, which is called the enteric nervous system, or ENS. The ENS functions independently from the central nervous system, and transmits important messages to and from the brain. When one feels stressed, the brain communicates to the hormonal system and floods the body with stress hormones, such as cortisol, which by themselves, can cause increased intestinal permeability. In addition, the gut produces its own neurotransmitters that affect the brain. In fact, every class of neurotransmitter found in the brain also is found in the GI tract. For example, serotonin is an important neurotransmitter for feeling happy and optimistic. Ninety-five percent of the body’s serotonin is produced in the gut. It is produced from 5-HTP, which is derived from tryptophan. However, in the presence of inflammation in the body, tryptophan is converted into kynurenate and quinolate. Both cause fatigue, and quinolate causes neurotoxicity. The subsequent depletion of serotonin produces symptoms of depression. Problems in the gut can lead to problems in the brain and the whole body.

Other problems affecting patients are tied to toxins in the environment. The air we breathe, food we eat, water we drink, and clothing we wear all are sources of toxins. Toxins include biotoxins, dioxine, phthalates, PCBs, and heavy metals, such as mercury, lead, cadmium, aluminum. About 2,000 new chemicals have been introduced into our environment each year since the 1940s, and it is estimated that we are exposed to more than 80,000 chemicals on a regular basis.⁸

The Environmental Working Group, a nonprofit organization dedicated to educating the public about the environment, has estimated that average babies are born with 287 chemicals in their body, 217 of which are neurotoxins.⁹ As children grow up, their body accumulates more toxins. According to the Centers for Disease Control and Prevention, every American has hundreds of neurotoxins in their bodies right now.

As we become more aware of the many changes in our environment, functional medicine brings a new way of thinking about and looking at chronic disease. As physicians, we can continue treating symptoms, and we should. But we can look deeper and ask ourselves what has changed in our lives that has caused such a decline in human mental and physical health. Your training as psychiatrists makes you uniquely positioned to understand these connections. I urge psychiatrists to help lead the way.
 

Dr. Gaitour, a physiatrist, trained at NYU Langone Medical Center in New York. She is a functional medicine practitioner.
 

References

1. Peppers KH et al. J Pediatr Health Care. 2016 Nov-Dec;30(6):e43-8.

2. Martin EB and PG Hammerness. ADHD, stimulant medication, and dehydration. CHADD.org. 2014 Aug.

3. Guitar NA et al. Ageing Res Rev. 2018 Nov;47:159-67.

4. Mørch RH et al. Acta Psychiatr Scand. 2017 Oct;136(4):400-8.

5. Dooley LN et al. Neurosci Biobehav Rev. 2018 Nov;94:219-37.

6. Yang L et al. Brain Behav Immun. 2016 Aug;56:352-62.

7. Doenyas C. Neuroscience. 2018 Mar 15;374:271-86.

8. PBS News Hour. 2016 Jun 22.

9. Houlihan J. Environmental Working Group. 2005 Jul 14.
 

Mr. Z, an obese adult with a history of portal hypertension and cirrhosis from alcoholism, visits your clinic because he is having difficulty sleeping and concentrating at work. He recently reduced his alcohol use and has improved support from his spouse. He walks into your office with an unremarkable gait before stopping to jot down a note in crisp, neat handwriting. He sits facing you, making good eye contact and exhibiting no involuntary movements. As has been the case at previous visits, Mr. Z is fully oriented to person, place, and time. You can follow one another’s train of thought and collaborate on treatment decisions. You’ve ruled out hepatic encephalopathy. Could you be missing something?

Hepatic encephalopathy is a neuropsychiatric condition caused by metabolic changes secondary to liver dysfunction and/or by blood flow bypassing the portal venous system. Signs and symptoms of hepatic encephalopathy range from subtle changes in cognition and affect to coma.Pathophysiologic mechanisms involved in hepatic encephalopathy include inflammation, neurotoxins, oxidative stress, permeability changes in the blood-brain barrier, and impaired brain energy metabolism.¹

Patients with poor liver function commonly have psychometrically detectable cognitive and psychomotor deficits that can substantially affect their lives. When such deficits are undetectable by routine physical and mental status examinations, the condition is called minimal hepatic encephalopathy (MHE), or latent hepatic encephalopathy. Minimal hepatic encephalopathy is associated with a reduced quality of life, sleep disturbances, fall risk, impaired ability to work and/or drive, and a risk of developing overt hepatic encephalopathy.¹

Approximately 22% to 74% of patients with liver dysfunction develop MHE.² Prevalence estimates vary widely because of the poor standardization of diagnostic criteria and potential underdiagnosis due to a lack of obvious symptoms.²

How is MHE diagnosed?

The most commonly administered psychometric test to assess for MHE is the Psychometric Hepatic Encephalopathy Score, a written test that measures motor speed and accuracy, concentration, attention, visual perception, visual-spatial orientation, visual construction, and memory.^3,4 Other methods for evaluating MHE, including EEG, MRI, single-photon emission CT, positron emission tomography, and determining a patient’s frequency threshold of perceiving a flickering light, have predictive power, but they do not have a well-defined, standardized role in the diagnosis of MHE.² Although ammonia levels can correlate with severity of impairment in episodic hepatic encephalopathy, they are not well correlated with the deficits in MHE, and often it is not feasible to properly measure ammonia concentrations in outpatient settings.²

Limited treatment options

Few studies have investigated interventions specifically for MHE. The best­studied treatments are lactulose⁵ and rifaximin.⁶ Lactulose reduces the formation of ammonia and the absorption of both ammonia and glutamine in the colonic lumen.⁵ In addition to improving MHE, lactulose helps prevent the recurrence of episodic overt hepatic encephalopathy.⁵ The antibiotic rifaximin kills ammonia-producing gut bacteria because it is minimally absorbed in the digestive system. No studies investigating rifaximin have observed antibiotic resistance, even with prolonged use. Rifaximin improves cognitive ability, driving ability, and quality of life in patients with MHE. Adding rifaximin to a treatment regimen that includes lactulose also can reduce the recurrence of overt hepatic encephalopathy.⁶ Branched chain amino acids, L-carnitine, L-ornithine aspartate, treating a comorbid zinc deficiency, probiotics, and increasing vegetable protein intake relative to animal protein intake may also have roles in treating MHE.²

Mr. Z, an obese adult with a history of portal hypertension and cirrhosis from alcoholism, visits your clinic because he is having difficulty sleeping and concentrating at work. He recently reduced his alcohol use and has improved support from his spouse. He walks into your office with an unremarkable gait before stopping to jot down a note in crisp, neat handwriting. He sits facing you, making good eye contact and exhibiting no involuntary movements. As has been the case at previous visits, Mr. Z is fully oriented to person, place, and time. You can follow one another’s train of thought and collaborate on treatment decisions. You’ve ruled out hepatic encephalopathy. Could you be missing something?

Hepatic encephalopathy is a neuropsychiatric condition caused by metabolic changes secondary to liver dysfunction and/or by blood flow bypassing the portal venous system. Signs and symptoms of hepatic encephalopathy range from subtle changes in cognition and affect to coma.Pathophysiologic mechanisms involved in hepatic encephalopathy include inflammation, neurotoxins, oxidative stress, permeability changes in the blood-brain barrier, and impaired brain energy metabolism.¹

Patients with poor liver function commonly have psychometrically detectable cognitive and psychomotor deficits that can substantially affect their lives. When such deficits are undetectable by routine physical and mental status examinations, the condition is called minimal hepatic encephalopathy (MHE), or latent hepatic encephalopathy. Minimal hepatic encephalopathy is associated with a reduced quality of life, sleep disturbances, fall risk, impaired ability to work and/or drive, and a risk of developing overt hepatic encephalopathy.¹

Approximately 22% to 74% of patients with liver dysfunction develop MHE.² Prevalence estimates vary widely because of the poor standardization of diagnostic criteria and potential underdiagnosis due to a lack of obvious symptoms.²

How is MHE diagnosed?

The most commonly administered psychometric test to assess for MHE is the Psychometric Hepatic Encephalopathy Score, a written test that measures motor speed and accuracy, concentration, attention, visual perception, visual-spatial orientation, visual construction, and memory.^3,4 Other methods for evaluating MHE, including EEG, MRI, single-photon emission CT, positron emission tomography, and determining a patient’s frequency threshold of perceiving a flickering light, have predictive power, but they do not have a well-defined, standardized role in the diagnosis of MHE.² Although ammonia levels can correlate with severity of impairment in episodic hepatic encephalopathy, they are not well correlated with the deficits in MHE, and often it is not feasible to properly measure ammonia concentrations in outpatient settings.²

Limited treatment options

Few studies have investigated interventions specifically for MHE. The best­studied treatments are lactulose⁵ and rifaximin.⁶ Lactulose reduces the formation of ammonia and the absorption of both ammonia and glutamine in the colonic lumen.⁵ In addition to improving MHE, lactulose helps prevent the recurrence of episodic overt hepatic encephalopathy.⁵ The antibiotic rifaximin kills ammonia-producing gut bacteria because it is minimally absorbed in the digestive system. No studies investigating rifaximin have observed antibiotic resistance, even with prolonged use. Rifaximin improves cognitive ability, driving ability, and quality of life in patients with MHE. Adding rifaximin to a treatment regimen that includes lactulose also can reduce the recurrence of overt hepatic encephalopathy.⁶ Branched chain amino acids, L-carnitine, L-ornithine aspartate, treating a comorbid zinc deficiency, probiotics, and increasing vegetable protein intake relative to animal protein intake may also have roles in treating MHE.²

Mr. Z, an obese adult with a history of portal hypertension and cirrhosis from alcoholism, visits your clinic because he is having difficulty sleeping and concentrating at work. He recently reduced his alcohol use and has improved support from his spouse. He walks into your office with an unremarkable gait before stopping to jot down a note in crisp, neat handwriting. He sits facing you, making good eye contact and exhibiting no involuntary movements. As has been the case at previous visits, Mr. Z is fully oriented to person, place, and time. You can follow one another’s train of thought and collaborate on treatment decisions. You’ve ruled out hepatic encephalopathy. Could you be missing something?

Hepatic encephalopathy is a neuropsychiatric condition caused by metabolic changes secondary to liver dysfunction and/or by blood flow bypassing the portal venous system. Signs and symptoms of hepatic encephalopathy range from subtle changes in cognition and affect to coma.Pathophysiologic mechanisms involved in hepatic encephalopathy include inflammation, neurotoxins, oxidative stress, permeability changes in the blood-brain barrier, and impaired brain energy metabolism.¹

Patients with poor liver function commonly have psychometrically detectable cognitive and psychomotor deficits that can substantially affect their lives. When such deficits are undetectable by routine physical and mental status examinations, the condition is called minimal hepatic encephalopathy (MHE), or latent hepatic encephalopathy. Minimal hepatic encephalopathy is associated with a reduced quality of life, sleep disturbances, fall risk, impaired ability to work and/or drive, and a risk of developing overt hepatic encephalopathy.¹

Approximately 22% to 74% of patients with liver dysfunction develop MHE.² Prevalence estimates vary widely because of the poor standardization of diagnostic criteria and potential underdiagnosis due to a lack of obvious symptoms.²

How is MHE diagnosed?

The most commonly administered psychometric test to assess for MHE is the Psychometric Hepatic Encephalopathy Score, a written test that measures motor speed and accuracy, concentration, attention, visual perception, visual-spatial orientation, visual construction, and memory.^3,4 Other methods for evaluating MHE, including EEG, MRI, single-photon emission CT, positron emission tomography, and determining a patient’s frequency threshold of perceiving a flickering light, have predictive power, but they do not have a well-defined, standardized role in the diagnosis of MHE.² Although ammonia levels can correlate with severity of impairment in episodic hepatic encephalopathy, they are not well correlated with the deficits in MHE, and often it is not feasible to properly measure ammonia concentrations in outpatient settings.²

Limited treatment options

Few studies have investigated interventions specifically for MHE. The best­studied treatments are lactulose⁵ and rifaximin.⁶ Lactulose reduces the formation of ammonia and the absorption of both ammonia and glutamine in the colonic lumen.⁵ In addition to improving MHE, lactulose helps prevent the recurrence of episodic overt hepatic encephalopathy.⁵ The antibiotic rifaximin kills ammonia-producing gut bacteria because it is minimally absorbed in the digestive system. No studies investigating rifaximin have observed antibiotic resistance, even with prolonged use. Rifaximin improves cognitive ability, driving ability, and quality of life in patients with MHE. Adding rifaximin to a treatment regimen that includes lactulose also can reduce the recurrence of overt hepatic encephalopathy.⁶ Branched chain amino acids, L-carnitine, L-ornithine aspartate, treating a comorbid zinc deficiency, probiotics, and increasing vegetable protein intake relative to animal protein intake may also have roles in treating MHE.²

Mild cognitive impairment (MCI) may influence the relationship between alcohol consumption and dementia risk, a study of more than 3,000 adults suggests. In addition, alcohol dose and the frequency of alcohol intake correlate with cognitive decline and the risk of dementia, according to the study, which was published in JAMA Network Open.

Thinkstockphotos.com

“The associations of self-reported alcohol consumption with dementia risk and cognitive decline were more consistently adverse among individuals with MCI than those with normal cognition,” reported Manja Koch, PhD, a researcher in the department of nutrition at Harvard T.H. Chan School of Public Health in Boston and colleagues. “This was particularly true for the subset of individuals [with MCI] who drank more than 14.0 servings per week, whose rate of cognitive decline and risk of dementia were the highest of any subgroup.”

Among older adults with normal cognition, the results generally were consistent with those of a recent meta-analysis that found a U-shaped relationship between drinking and dementia, the researchers said (Eur J Epidemiol. 2017 Jan;32[1]:31-42.).

“Our results did not show significant associations and clearly do not suffice to suggest a clinical benefit from even limited alcohol use,” said Dr. Koch and colleagues. “Nonetheless, our findings provide some reassurance that alcohol consumed within recommended limits was not associated with an increased risk of dementia among older adults with normal baseline cognition.”

GEMS data

To study whether alcohol consumption is associated with the risk of dementia and cognitive decline in older adults with and without MCI, the investigators analyzed data from the Ginkgo Evaluation of Memory Study (GEMS). GEMS was a randomized controlled trial conducted between 2000 and 2008 that found no overall association between ginkgo biloba and dementia prevention. During the trial, participants completed the Modified Mini-Mental State Examination, the Clinical Dementia Rating scale, and the cognitive portion of the Alzheimer’s Disease Assessment Scale.

In the present study, the investigators analyzed data from 3,021 participants aged 72 years and older who were free of dementia at baseline and had provided information about their alcohol intake. Their median age was 78 years, and 46.2% were female. Fifty-eight percent consumed alcohol, including 45% of the participants with MCI at baseline.

During follow-up, 512 cases of dementia occurred. Among the 473 participants with MCI at baseline, the adjusted hazard ratio (HR) for dementia was 1.72 for those who consumed more than 14 drinks per week, compared with light drinkers who consumed less than 1 drink per week. For participants who consumed between 7 and 14 drinks per week, the adjusted HR for dementia was 0.63 among those without MCI and 0.93 among those with MCI, relative to light drinkers who consumed less than 1 drink per week.

Among adults with normal cognition at baseline, daily low-quantity drinking was associated with lower dementia risk, compared with infrequent higher-quantity drinking (HR, 0.45).
 

Trial excluded adults with excessive alcohol use

Limitations of the study include a lack of data about any changes in alcohol consumption over time. In addition, the original trial excluded people with a known history of excessive alcohol use. Furthermore, it is possible that the “long preclinical phase of dementia” and other health issues affect drinking behavior, the authors said. “At present, our findings cannot be directly translated into clinical recommendations,” the authors said. Nevertheless, the results “suggest that, while caring for older adults, physicians should carefully assess the full dimensions of drinking behavior and cognition when providing guidance to patients about alcohol consumption,” they said.

The study was supported by grants from the National Center for Complementary and Alternative Medicine; the National Institute of Neurological Disorders and Stroke; the Office of Dietary Supplements of the National Institute on Aging; the National Heart, Lung, and Blood Institute; the University of Pittsburgh Alzheimer’s Disease Research Center; the Roena Kulynych Center for Memory and Cognition Research; and Wake Forest University School of Medicine. In addition, the researchers used plasma samples from the National Cell Repository for Alzheimer’s Disease, which receives support from the National Institute on Aging. Dr. Koch had no conflicts of interest. Coauthors disclosed university and government grants and personal fees from pharmaceutical companies outside the study. One author was an employee of Genentech at the time of publication, but Genentech did not contribute to the study.

[email protected]

SOURCE: Koch M et al. JAMA Network Open. 2019 Sep 27. doi: 10.1001/jamanetworkopen.2019.10319.

Mild cognitive impairment (MCI) may influence the relationship between alcohol consumption and dementia risk, a study of more than 3,000 adults suggests. In addition, alcohol dose and the frequency of alcohol intake correlate with cognitive decline and the risk of dementia, according to the study, which was published in JAMA Network Open.

Thinkstockphotos.com

“The associations of self-reported alcohol consumption with dementia risk and cognitive decline were more consistently adverse among individuals with MCI than those with normal cognition,” reported Manja Koch, PhD, a researcher in the department of nutrition at Harvard T.H. Chan School of Public Health in Boston and colleagues. “This was particularly true for the subset of individuals [with MCI] who drank more than 14.0 servings per week, whose rate of cognitive decline and risk of dementia were the highest of any subgroup.”

Among older adults with normal cognition, the results generally were consistent with those of a recent meta-analysis that found a U-shaped relationship between drinking and dementia, the researchers said (Eur J Epidemiol. 2017 Jan;32[1]:31-42.).

“Our results did not show significant associations and clearly do not suffice to suggest a clinical benefit from even limited alcohol use,” said Dr. Koch and colleagues. “Nonetheless, our findings provide some reassurance that alcohol consumed within recommended limits was not associated with an increased risk of dementia among older adults with normal baseline cognition.”

GEMS data

To study whether alcohol consumption is associated with the risk of dementia and cognitive decline in older adults with and without MCI, the investigators analyzed data from the Ginkgo Evaluation of Memory Study (GEMS). GEMS was a randomized controlled trial conducted between 2000 and 2008 that found no overall association between ginkgo biloba and dementia prevention. During the trial, participants completed the Modified Mini-Mental State Examination, the Clinical Dementia Rating scale, and the cognitive portion of the Alzheimer’s Disease Assessment Scale.

In the present study, the investigators analyzed data from 3,021 participants aged 72 years and older who were free of dementia at baseline and had provided information about their alcohol intake. Their median age was 78 years, and 46.2% were female. Fifty-eight percent consumed alcohol, including 45% of the participants with MCI at baseline.

During follow-up, 512 cases of dementia occurred. Among the 473 participants with MCI at baseline, the adjusted hazard ratio (HR) for dementia was 1.72 for those who consumed more than 14 drinks per week, compared with light drinkers who consumed less than 1 drink per week. For participants who consumed between 7 and 14 drinks per week, the adjusted HR for dementia was 0.63 among those without MCI and 0.93 among those with MCI, relative to light drinkers who consumed less than 1 drink per week.

Among adults with normal cognition at baseline, daily low-quantity drinking was associated with lower dementia risk, compared with infrequent higher-quantity drinking (HR, 0.45).
 

Trial excluded adults with excessive alcohol use

Limitations of the study include a lack of data about any changes in alcohol consumption over time. In addition, the original trial excluded people with a known history of excessive alcohol use. Furthermore, it is possible that the “long preclinical phase of dementia” and other health issues affect drinking behavior, the authors said. “At present, our findings cannot be directly translated into clinical recommendations,” the authors said. Nevertheless, the results “suggest that, while caring for older adults, physicians should carefully assess the full dimensions of drinking behavior and cognition when providing guidance to patients about alcohol consumption,” they said.

The study was supported by grants from the National Center for Complementary and Alternative Medicine; the National Institute of Neurological Disorders and Stroke; the Office of Dietary Supplements of the National Institute on Aging; the National Heart, Lung, and Blood Institute; the University of Pittsburgh Alzheimer’s Disease Research Center; the Roena Kulynych Center for Memory and Cognition Research; and Wake Forest University School of Medicine. In addition, the researchers used plasma samples from the National Cell Repository for Alzheimer’s Disease, which receives support from the National Institute on Aging. Dr. Koch had no conflicts of interest. Coauthors disclosed university and government grants and personal fees from pharmaceutical companies outside the study. One author was an employee of Genentech at the time of publication, but Genentech did not contribute to the study.

[email protected]

SOURCE: Koch M et al. JAMA Network Open. 2019 Sep 27. doi: 10.1001/jamanetworkopen.2019.10319.

Mild cognitive impairment (MCI) may influence the relationship between alcohol consumption and dementia risk, a study of more than 3,000 adults suggests. In addition, alcohol dose and the frequency of alcohol intake correlate with cognitive decline and the risk of dementia, according to the study, which was published in JAMA Network Open.

Thinkstockphotos.com

“The associations of self-reported alcohol consumption with dementia risk and cognitive decline were more consistently adverse among individuals with MCI than those with normal cognition,” reported Manja Koch, PhD, a researcher in the department of nutrition at Harvard T.H. Chan School of Public Health in Boston and colleagues. “This was particularly true for the subset of individuals [with MCI] who drank more than 14.0 servings per week, whose rate of cognitive decline and risk of dementia were the highest of any subgroup.”

Among older adults with normal cognition, the results generally were consistent with those of a recent meta-analysis that found a U-shaped relationship between drinking and dementia, the researchers said (Eur J Epidemiol. 2017 Jan;32[1]:31-42.).

“Our results did not show significant associations and clearly do not suffice to suggest a clinical benefit from even limited alcohol use,” said Dr. Koch and colleagues. “Nonetheless, our findings provide some reassurance that alcohol consumed within recommended limits was not associated with an increased risk of dementia among older adults with normal baseline cognition.”

GEMS data

To study whether alcohol consumption is associated with the risk of dementia and cognitive decline in older adults with and without MCI, the investigators analyzed data from the Ginkgo Evaluation of Memory Study (GEMS). GEMS was a randomized controlled trial conducted between 2000 and 2008 that found no overall association between ginkgo biloba and dementia prevention. During the trial, participants completed the Modified Mini-Mental State Examination, the Clinical Dementia Rating scale, and the cognitive portion of the Alzheimer’s Disease Assessment Scale.

In the present study, the investigators analyzed data from 3,021 participants aged 72 years and older who were free of dementia at baseline and had provided information about their alcohol intake. Their median age was 78 years, and 46.2% were female. Fifty-eight percent consumed alcohol, including 45% of the participants with MCI at baseline.

During follow-up, 512 cases of dementia occurred. Among the 473 participants with MCI at baseline, the adjusted hazard ratio (HR) for dementia was 1.72 for those who consumed more than 14 drinks per week, compared with light drinkers who consumed less than 1 drink per week. For participants who consumed between 7 and 14 drinks per week, the adjusted HR for dementia was 0.63 among those without MCI and 0.93 among those with MCI, relative to light drinkers who consumed less than 1 drink per week.

Among adults with normal cognition at baseline, daily low-quantity drinking was associated with lower dementia risk, compared with infrequent higher-quantity drinking (HR, 0.45).
 

Trial excluded adults with excessive alcohol use

Limitations of the study include a lack of data about any changes in alcohol consumption over time. In addition, the original trial excluded people with a known history of excessive alcohol use. Furthermore, it is possible that the “long preclinical phase of dementia” and other health issues affect drinking behavior, the authors said. “At present, our findings cannot be directly translated into clinical recommendations,” the authors said. Nevertheless, the results “suggest that, while caring for older adults, physicians should carefully assess the full dimensions of drinking behavior and cognition when providing guidance to patients about alcohol consumption,” they said.

The study was supported by grants from the National Center for Complementary and Alternative Medicine; the National Institute of Neurological Disorders and Stroke; the Office of Dietary Supplements of the National Institute on Aging; the National Heart, Lung, and Blood Institute; the University of Pittsburgh Alzheimer’s Disease Research Center; the Roena Kulynych Center for Memory and Cognition Research; and Wake Forest University School of Medicine. In addition, the researchers used plasma samples from the National Cell Repository for Alzheimer’s Disease, which receives support from the National Institute on Aging. Dr. Koch had no conflicts of interest. Coauthors disclosed university and government grants and personal fees from pharmaceutical companies outside the study. One author was an employee of Genentech at the time of publication, but Genentech did not contribute to the study.

[email protected]

SOURCE: Koch M et al. JAMA Network Open. 2019 Sep 27. doi: 10.1001/jamanetworkopen.2019.10319.

Migraines are associated with a significantly greater risk of Alzheimer’s disease and all forms of dementia except vascular dementia, according to research published online Sept. 4 in the International Journal of Geriatric Psychiatry.

In the Manitoba Study of Health and Aging, a population-based, prospective cohort study, 679 community-dwelling adults with a mean age of 75.9 years were followed for 5 years. Participants screened as cognitively intact at baseline had complete data on migraine history and all covariates at baseline and were assessed for cognitive outcomes 5 years later.

The study showed that a history of migraines was associated with a 2.97-fold greater likelihood of dementia, after adjustment for age, education, and a history of stroke, compared with individuals without a history of migraine. Individuals with Alzheimer’s disease were more than four times more likely to have a history of migraines (odds ratio 4.22).

However, researchers found no significant association between vascular dementia and a history of migraines, either before or after adjusting for confounders but particularly after incorporating a history of stroke into the model.

Lead investigator Suzanne L. Tyas, PhD, associate professor in the School of Public Health and Health Systems at the University of Waterloo, Ont., and coauthors suggested that the association between migraine and dementia was largely driven by the strong association between migraines and Alzheimer’s disease.

“This interpretation is supported by the weaker association for dementia than for Alzheimer’s disease, reflecting a dilution of the association with migraines across all types of dementia including vascular dementia, where a significant association was not found,” the researchers wrote.

The study population was 61.9% female, and no men reporting a history of migraine were diagnosed with dementia. While the study reflected a strong association between migraine and dementia in women, the researchers said they were unable to assess potential gender differences in this association.

Commenting on possible mechanisms behind the association, the authors wrote that there were overlaps underlying the biological mechanisms of migraine and dementia. Vascular risk factors such as diabetes, hypertension, heart attack, and stroke are associated with the development of dementia, and a relationship of these risk factors and migraine also has been seen.

“Many of the mechanisms involved in migraine neurophysiology, such as inflammation and reduced cerebral blood flow, are also underlying causes of dementia,” they wrote. “Repeated activation of these pathways in chronic migraineurs has been shown to cause permanent neurological and vascular damage.”

They also observed that the association could be influenced by genetic factors, as individuals with presenilin-1 mutations, which predispose them to Alzheimer’s disease, are more likely to experience migraines or recurrent headaches.

They suggested their findings could inform preventive strategies and treatments for Alzheimer’s disease, as well as interventions such as earlier screening for cognitive decline in individuals who experience migraines.

The study was funded by Manitoba Health and the National Health Research and Development Program of Health Canada. No conflicts of interest were declared.
 

SOURCE: Morton R et al. Int J Geriatr Psychiatry, 2019 Sep 4. doi: 10.1002/gps.5180.

Migraines are associated with a significantly greater risk of Alzheimer’s disease and all forms of dementia except vascular dementia, according to research published online Sept. 4 in the International Journal of Geriatric Psychiatry.

In the Manitoba Study of Health and Aging, a population-based, prospective cohort study, 679 community-dwelling adults with a mean age of 75.9 years were followed for 5 years. Participants screened as cognitively intact at baseline had complete data on migraine history and all covariates at baseline and were assessed for cognitive outcomes 5 years later.

The study showed that a history of migraines was associated with a 2.97-fold greater likelihood of dementia, after adjustment for age, education, and a history of stroke, compared with individuals without a history of migraine. Individuals with Alzheimer’s disease were more than four times more likely to have a history of migraines (odds ratio 4.22).

However, researchers found no significant association between vascular dementia and a history of migraines, either before or after adjusting for confounders but particularly after incorporating a history of stroke into the model.

Lead investigator Suzanne L. Tyas, PhD, associate professor in the School of Public Health and Health Systems at the University of Waterloo, Ont., and coauthors suggested that the association between migraine and dementia was largely driven by the strong association between migraines and Alzheimer’s disease.

“This interpretation is supported by the weaker association for dementia than for Alzheimer’s disease, reflecting a dilution of the association with migraines across all types of dementia including vascular dementia, where a significant association was not found,” the researchers wrote.

The study population was 61.9% female, and no men reporting a history of migraine were diagnosed with dementia. While the study reflected a strong association between migraine and dementia in women, the researchers said they were unable to assess potential gender differences in this association.

Commenting on possible mechanisms behind the association, the authors wrote that there were overlaps underlying the biological mechanisms of migraine and dementia. Vascular risk factors such as diabetes, hypertension, heart attack, and stroke are associated with the development of dementia, and a relationship of these risk factors and migraine also has been seen.

“Many of the mechanisms involved in migraine neurophysiology, such as inflammation and reduced cerebral blood flow, are also underlying causes of dementia,” they wrote. “Repeated activation of these pathways in chronic migraineurs has been shown to cause permanent neurological and vascular damage.”

They also observed that the association could be influenced by genetic factors, as individuals with presenilin-1 mutations, which predispose them to Alzheimer’s disease, are more likely to experience migraines or recurrent headaches.

They suggested their findings could inform preventive strategies and treatments for Alzheimer’s disease, as well as interventions such as earlier screening for cognitive decline in individuals who experience migraines.

The study was funded by Manitoba Health and the National Health Research and Development Program of Health Canada. No conflicts of interest were declared.
 

SOURCE: Morton R et al. Int J Geriatr Psychiatry, 2019 Sep 4. doi: 10.1002/gps.5180.

Migraines are associated with a significantly greater risk of Alzheimer’s disease and all forms of dementia except vascular dementia, according to research published online Sept. 4 in the International Journal of Geriatric Psychiatry.

In the Manitoba Study of Health and Aging, a population-based, prospective cohort study, 679 community-dwelling adults with a mean age of 75.9 years were followed for 5 years. Participants screened as cognitively intact at baseline had complete data on migraine history and all covariates at baseline and were assessed for cognitive outcomes 5 years later.

The study showed that a history of migraines was associated with a 2.97-fold greater likelihood of dementia, after adjustment for age, education, and a history of stroke, compared with individuals without a history of migraine. Individuals with Alzheimer’s disease were more than four times more likely to have a history of migraines (odds ratio 4.22).

However, researchers found no significant association between vascular dementia and a history of migraines, either before or after adjusting for confounders but particularly after incorporating a history of stroke into the model.

Lead investigator Suzanne L. Tyas, PhD, associate professor in the School of Public Health and Health Systems at the University of Waterloo, Ont., and coauthors suggested that the association between migraine and dementia was largely driven by the strong association between migraines and Alzheimer’s disease.

“This interpretation is supported by the weaker association for dementia than for Alzheimer’s disease, reflecting a dilution of the association with migraines across all types of dementia including vascular dementia, where a significant association was not found,” the researchers wrote.

The study population was 61.9% female, and no men reporting a history of migraine were diagnosed with dementia. While the study reflected a strong association between migraine and dementia in women, the researchers said they were unable to assess potential gender differences in this association.

Commenting on possible mechanisms behind the association, the authors wrote that there were overlaps underlying the biological mechanisms of migraine and dementia. Vascular risk factors such as diabetes, hypertension, heart attack, and stroke are associated with the development of dementia, and a relationship of these risk factors and migraine also has been seen.

“Many of the mechanisms involved in migraine neurophysiology, such as inflammation and reduced cerebral blood flow, are also underlying causes of dementia,” they wrote. “Repeated activation of these pathways in chronic migraineurs has been shown to cause permanent neurological and vascular damage.”

They also observed that the association could be influenced by genetic factors, as individuals with presenilin-1 mutations, which predispose them to Alzheimer’s disease, are more likely to experience migraines or recurrent headaches.

They suggested their findings could inform preventive strategies and treatments for Alzheimer’s disease, as well as interventions such as earlier screening for cognitive decline in individuals who experience migraines.

The study was funded by Manitoba Health and the National Health Research and Development Program of Health Canada. No conflicts of interest were declared.
 

SOURCE: Morton R et al. Int J Geriatr Psychiatry, 2019 Sep 4. doi: 10.1002/gps.5180.