Alzheimer's & Cognition

The history and findings in this case are suggestive of early-onset Alzheimer's disease (AD) with aphasia. 

AD is a neurodegenerative disorder characterized by cognitive and behavioral impairment that significantly interferes with a patient's social and occupational functioning. There is currently no cure for AD, which has a long preclinical period and a progressive course. Individuals with AD develop amyloid plaques in the hippocampus, a structure deep in the brain that helps to encode memories, and in other areas of the cerebral cortex that are involved in thinking and making decisions.

Patients with AD typically present with insidiously progressive memory loss; over the course of several years, other areas of cognition are impaired. Subsequent to memory loss, patients may also experience language disorders (eg, anomic aphasia or anomia) and impairment in visuospatial skills and executive functions. In many patients, slowly progressive behavioral changes are also observed.

AD is most prevalent in individuals older than 65 years; however, early‐onset AD (in individuals aged 60 years or older) can also occur. Early-onset AD shares the same essential neuropathological characteristics (ie, amyloid plaques and neurofibrillary tangles) as late-onset (65 years or older) AD, but it differs in several ways. For example, memory loss is an extremely common presenting symptom in late-onset AD, whereas nonamnestic presentation (ie, language, visuospatial, or executive impairment) is very rare, occurring in only about 5% of cases. Conversely, nonamnestic presentations may occur in 30%-40% of patients with early-onset AD. Frequent nonamnestic cognitive manifestations in patients with early-onset AD are those seen in mild to moderate AD, including visual agnosia (55.1%), aphasia (57.9%), and behavioral changes (61.7%). In addition, several studies have suggested that early-onset AD may have a more aggressive course than late-onset AD does, including faster cognitive and functional decline.

Presently, only symptomatic therapies are available for AD. The standard medical treatment for AD includes cholinesterase inhibitors and a partial N-methyl-D-aspartate antagonist. Newly approved antiamyloid therapies are also available for patients with mild cognitive impairment or mild dementia. These include aducanumab, a first-in-class amyloid beta–directed antibody that was approved in 2021, and lecanemab, another amyloid beta–directed antibody that was approved in 2023. Both aducanumab and lecanemab are recommended for the treatment of patients with mild cognitive impairment or mild dementia stage of disease, the population in which the safety and efficacy of these newer agents were demonstrated in clinical trials. 

Psychotropic agents may be used to treat the secondary symptoms of AD (eg, depression, agitation, aggression, hallucinations, delusions, sleep disorders), which can be problematic. Behavioral interventions ranging from patient-centered approaches to caregiver training may also be used to help manage cognitive and behavioral manifestations of AD, often in combination with pharmacologic interventions, such as anxiolytics for anxiety and agitation, neuroleptics for delusions or hallucinations, and antidepressants or mood stabilizers for mood disorders and specific manifestations (eg, episodes of anger or rage). Routine physical activity and exercise may affect AD progression and may possibly exert a protective effect on brain health. 

Jasvinder Chawla, MD, Professor of Neurology, Loyola University Medical Center, Maywood; Director, Clinical Neurophysiology Lab, Department of Neurology, Hines VA Hospital, Hines, IL.

Jasvinder Chawla, MD, has disclosed no relevant financial relationships.

Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.

The history and findings in this case are suggestive of early-onset Alzheimer's disease (AD) with aphasia. 

AD is a neurodegenerative disorder characterized by cognitive and behavioral impairment that significantly interferes with a patient's social and occupational functioning. There is currently no cure for AD, which has a long preclinical period and a progressive course. Individuals with AD develop amyloid plaques in the hippocampus, a structure deep in the brain that helps to encode memories, and in other areas of the cerebral cortex that are involved in thinking and making decisions.

Patients with AD typically present with insidiously progressive memory loss; over the course of several years, other areas of cognition are impaired. Subsequent to memory loss, patients may also experience language disorders (eg, anomic aphasia or anomia) and impairment in visuospatial skills and executive functions. In many patients, slowly progressive behavioral changes are also observed.

AD is most prevalent in individuals older than 65 years; however, early‐onset AD (in individuals aged 60 years or older) can also occur. Early-onset AD shares the same essential neuropathological characteristics (ie, amyloid plaques and neurofibrillary tangles) as late-onset (65 years or older) AD, but it differs in several ways. For example, memory loss is an extremely common presenting symptom in late-onset AD, whereas nonamnestic presentation (ie, language, visuospatial, or executive impairment) is very rare, occurring in only about 5% of cases. Conversely, nonamnestic presentations may occur in 30%-40% of patients with early-onset AD. Frequent nonamnestic cognitive manifestations in patients with early-onset AD are those seen in mild to moderate AD, including visual agnosia (55.1%), aphasia (57.9%), and behavioral changes (61.7%). In addition, several studies have suggested that early-onset AD may have a more aggressive course than late-onset AD does, including faster cognitive and functional decline.

Presently, only symptomatic therapies are available for AD. The standard medical treatment for AD includes cholinesterase inhibitors and a partial N-methyl-D-aspartate antagonist. Newly approved antiamyloid therapies are also available for patients with mild cognitive impairment or mild dementia. These include aducanumab, a first-in-class amyloid beta–directed antibody that was approved in 2021, and lecanemab, another amyloid beta–directed antibody that was approved in 2023. Both aducanumab and lecanemab are recommended for the treatment of patients with mild cognitive impairment or mild dementia stage of disease, the population in which the safety and efficacy of these newer agents were demonstrated in clinical trials. 

Psychotropic agents may be used to treat the secondary symptoms of AD (eg, depression, agitation, aggression, hallucinations, delusions, sleep disorders), which can be problematic. Behavioral interventions ranging from patient-centered approaches to caregiver training may also be used to help manage cognitive and behavioral manifestations of AD, often in combination with pharmacologic interventions, such as anxiolytics for anxiety and agitation, neuroleptics for delusions or hallucinations, and antidepressants or mood stabilizers for mood disorders and specific manifestations (eg, episodes of anger or rage). Routine physical activity and exercise may affect AD progression and may possibly exert a protective effect on brain health. 

Jasvinder Chawla, MD, Professor of Neurology, Loyola University Medical Center, Maywood; Director, Clinical Neurophysiology Lab, Department of Neurology, Hines VA Hospital, Hines, IL.

Jasvinder Chawla, MD, has disclosed no relevant financial relationships.

Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.

The history and findings in this case are suggestive of early-onset Alzheimer's disease (AD) with aphasia. 

AD is a neurodegenerative disorder characterized by cognitive and behavioral impairment that significantly interferes with a patient's social and occupational functioning. There is currently no cure for AD, which has a long preclinical period and a progressive course. Individuals with AD develop amyloid plaques in the hippocampus, a structure deep in the brain that helps to encode memories, and in other areas of the cerebral cortex that are involved in thinking and making decisions.

Patients with AD typically present with insidiously progressive memory loss; over the course of several years, other areas of cognition are impaired. Subsequent to memory loss, patients may also experience language disorders (eg, anomic aphasia or anomia) and impairment in visuospatial skills and executive functions. In many patients, slowly progressive behavioral changes are also observed.

AD is most prevalent in individuals older than 65 years; however, early‐onset AD (in individuals aged 60 years or older) can also occur. Early-onset AD shares the same essential neuropathological characteristics (ie, amyloid plaques and neurofibrillary tangles) as late-onset (65 years or older) AD, but it differs in several ways. For example, memory loss is an extremely common presenting symptom in late-onset AD, whereas nonamnestic presentation (ie, language, visuospatial, or executive impairment) is very rare, occurring in only about 5% of cases. Conversely, nonamnestic presentations may occur in 30%-40% of patients with early-onset AD. Frequent nonamnestic cognitive manifestations in patients with early-onset AD are those seen in mild to moderate AD, including visual agnosia (55.1%), aphasia (57.9%), and behavioral changes (61.7%). In addition, several studies have suggested that early-onset AD may have a more aggressive course than late-onset AD does, including faster cognitive and functional decline.

Presently, only symptomatic therapies are available for AD. The standard medical treatment for AD includes cholinesterase inhibitors and a partial N-methyl-D-aspartate antagonist. Newly approved antiamyloid therapies are also available for patients with mild cognitive impairment or mild dementia. These include aducanumab, a first-in-class amyloid beta–directed antibody that was approved in 2021, and lecanemab, another amyloid beta–directed antibody that was approved in 2023. Both aducanumab and lecanemab are recommended for the treatment of patients with mild cognitive impairment or mild dementia stage of disease, the population in which the safety and efficacy of these newer agents were demonstrated in clinical trials. 

Psychotropic agents may be used to treat the secondary symptoms of AD (eg, depression, agitation, aggression, hallucinations, delusions, sleep disorders), which can be problematic. Behavioral interventions ranging from patient-centered approaches to caregiver training may also be used to help manage cognitive and behavioral manifestations of AD, often in combination with pharmacologic interventions, such as anxiolytics for anxiety and agitation, neuroleptics for delusions or hallucinations, and antidepressants or mood stabilizers for mood disorders and specific manifestations (eg, episodes of anger or rage). Routine physical activity and exercise may affect AD progression and may possibly exert a protective effect on brain health. 

Jasvinder Chawla, MD, Professor of Neurology, Loyola University Medical Center, Maywood; Director, Clinical Neurophysiology Lab, Department of Neurology, Hines VA Hospital, Hines, IL.

Jasvinder Chawla, MD, has disclosed no relevant financial relationships.

Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.

There are millions of immature connections between the neurons in brains of adults that remain inactive until they’re recruited to help form new memories, according to neuroscientists from the Massachusetts Institute of Technology.

What to know:

• An estimated 30% of all synapses in the brain’s cortex are silent and become active to allow the adult brain to continually form new memories and leave existing conventional synapses unmodified.
• Silent synapses are looking for new connections, and when important new information is presented, connections between the relevant neurons are strengthened to allow the brain to remember new things.
• Using the silent synapses for the new memories does not overwrite the important memories stored in more mature synapses, which are harder to change.
• The brain’s neurons display a wide range of plasticity mechanisms that account for how brains can efficiently learn new things and retain them in long-term memory.
• Flexibility of synapses is critical for acquiring new information, and stability is required to retain important information, enabling one to more easily adjust and change behaviors and habits or incorporate new information.

This is a summary of the article, “Filopodia Are a Structural Substrate for Silent Synapses in Adult Neocortex,” published in Nature Nov. 30, 2022. The full article can be found at nature.com .

A version of this article first appeared on Medscape.com.

There are millions of immature connections between the neurons in brains of adults that remain inactive until they’re recruited to help form new memories, according to neuroscientists from the Massachusetts Institute of Technology.

What to know:

• An estimated 30% of all synapses in the brain’s cortex are silent and become active to allow the adult brain to continually form new memories and leave existing conventional synapses unmodified.
• Silent synapses are looking for new connections, and when important new information is presented, connections between the relevant neurons are strengthened to allow the brain to remember new things.
• Using the silent synapses for the new memories does not overwrite the important memories stored in more mature synapses, which are harder to change.
• The brain’s neurons display a wide range of plasticity mechanisms that account for how brains can efficiently learn new things and retain them in long-term memory.
• Flexibility of synapses is critical for acquiring new information, and stability is required to retain important information, enabling one to more easily adjust and change behaviors and habits or incorporate new information.

This is a summary of the article, “Filopodia Are a Structural Substrate for Silent Synapses in Adult Neocortex,” published in Nature Nov. 30, 2022. The full article can be found at nature.com .

A version of this article first appeared on Medscape.com.

There are millions of immature connections between the neurons in brains of adults that remain inactive until they’re recruited to help form new memories, according to neuroscientists from the Massachusetts Institute of Technology.

What to know:

• An estimated 30% of all synapses in the brain’s cortex are silent and become active to allow the adult brain to continually form new memories and leave existing conventional synapses unmodified.
• Silent synapses are looking for new connections, and when important new information is presented, connections between the relevant neurons are strengthened to allow the brain to remember new things.
• Using the silent synapses for the new memories does not overwrite the important memories stored in more mature synapses, which are harder to change.
• The brain’s neurons display a wide range of plasticity mechanisms that account for how brains can efficiently learn new things and retain them in long-term memory.
• Flexibility of synapses is critical for acquiring new information, and stability is required to retain important information, enabling one to more easily adjust and change behaviors and habits or incorporate new information.

This is a summary of the article, “Filopodia Are a Structural Substrate for Silent Synapses in Adult Neocortex,” published in Nature Nov. 30, 2022. The full article can be found at nature.com .

A version of this article first appeared on Medscape.com.

Treatment with the thiazolidinedione pioglitazone may offer the greatest protection against dementia for older adults with newly diagnosed type 2 diabetes mellitus (T2DM) who have a history of stroke or ischemic heart disease, new research suggests.

Overall, in a large cohort study from South Korea, patients who took pioglitazone were 16% less likely to develop dementia over an average of 10 years than peers who did not take the drug.

However, the dementia risk reduction was 54% among those with ischemic heart disease and 43% among those with a history of stroke.

“Our study was to see the association between pioglitazone use and incidence of dementia, not how (with what mechanisms) this drug can suppress dementia pathology,” coinvestigator Eosu Kim, MD, PhD, Yonsei University, Seoul, South Korea, said in an interview.

However, “as we found this drug is more effective in diabetic patients who have blood circulation problems in the heart or brain than in those without such problems, we speculate that pioglitazone’s antidementia action may be related to improving blood vessel’s health,” Dr. Kim said.

This finding suggests that pioglitazone could be used as a personalized treatment approach for dementia prevention in this subgroup of patients with diabetes, the researchers noted.

The results were published online in Neurology.
 

Dose-response relationship

Risk for dementia is doubled in adults with T2DM, the investigators wrote. Prior studies have suggested that pioglitazone may protect against dementia, as well as a first or recurrent stroke, in patients with T2DM.

This led Dr. Kim and colleagues to examine the effects of pioglitazone on dementia risk overall and in relation to stroke and ischemic heart disease.

Using the national Korean health database, the researchers identified 91,218 adults aged 50 and older with new-onset T2DM who did not have dementia. A total of 3,467 were treated with pioglitazone.

Pioglitazone exposure was defined as a total cumulative daily dose of 90 or more calculated from all dispensations during 4 years after T2DM diagnosis, with outcomes assessed after this period.

Over an average of 10 years, 8.3% of pioglitazone users developed dementia, compared with 10.0% of nonusers.

There was a statistically significant 16% lower risk for developing all-cause dementia among pioglitazone users than among nonusers (adjusted hazard ratio, 0.84; 95% confidence interval, 0.75-0.95).

A dose-response relationship was evident; pioglitazone users who received the highest cumulative daily dose were at lower risk for dementia (aHR, 0.72; 95% CI, 0.55-0.94).
 

Several limitations

The reduced risk for dementia was more pronounced among patients who used pioglitazone for 4 years in comparison with patients who did not use the drug (aHR, 0.63; 95% CI, 0.44-0.90).

The apparent protective effect of pioglitazone with regard to dementia was greater among those with a history of ischemic heart disease (aHR, 0.46; 95% CI, 0.24-0.90) or stroke (aHR, 0.57; 95% CI, 0.38-0.86) before diabetes diagnosis.

The incidence of stroke was also reduced with pioglitazone use (aHR, 0.81; 95% CI, 0.66-1.0).

“These results provide valuable information on who could potentially benefit from pioglitazone use for prevention of dementia,” Dr. Kim said in a news release.

However, “the risk and benefit balance of long-term use of this drug to prevent dementia should be prospectively assessed,” he said in an interview.

The researchers cautioned that the study was observational; hence, the reported associations cannot address causal relationships. Also, because of the use of claims data, drug compliance could not be guaranteed, and exposure may have been overestimated.

There is also the potential for selection bias, and no information on apolipoprotein E was available, they noted.
 

More data needed

In an accompanying editorial, Colleen J. Maxwell, PhD, University of Waterloo (Ont.), and colleagues wrote that the results “not only support previous studies showing the potential cognitive benefit of pioglitazone but also extend our understanding of this benefit through the mediating effect of reducing ischemic stroke.”

However, because of their associated risks, which include fractures, weight gain, heart failure, and bladder cancer, thiazolidinediones are not currently favored in diabetes management guidelines – and their use has significantly declined since the mid to late 2000s, the editorialists noted.

They agreed that it will be important to reassess the risk-benefit profile of pioglitazone in T2DM as additional findings emerge.

They also noted that sodium-glucose cotransporter-2 inhibitors, which have significant cardiovascular and renal benefits and minimal side effects, may also lower the risk for dementia.

“As both pioglitazone and SGLT-2 inhibitors are second-line options for physicians, the current decision would easily be in favor of SGLT-2 inhibitors given their safety profile,” Dr. Maxwell and colleagues wrote.

For now, pioglitazone “should not be used to prevent dementia in patients with T2DM,” they concluded.

The study was supported by grants from the National Research Foundation of Korea funded by the Korean government and the Ministry of Health and Welfare. The investigators and editorialists report no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Treatment with the thiazolidinedione pioglitazone may offer the greatest protection against dementia for older adults with newly diagnosed type 2 diabetes mellitus (T2DM) who have a history of stroke or ischemic heart disease, new research suggests.

Overall, in a large cohort study from South Korea, patients who took pioglitazone were 16% less likely to develop dementia over an average of 10 years than peers who did not take the drug.

However, the dementia risk reduction was 54% among those with ischemic heart disease and 43% among those with a history of stroke.

“Our study was to see the association between pioglitazone use and incidence of dementia, not how (with what mechanisms) this drug can suppress dementia pathology,” coinvestigator Eosu Kim, MD, PhD, Yonsei University, Seoul, South Korea, said in an interview.

However, “as we found this drug is more effective in diabetic patients who have blood circulation problems in the heart or brain than in those without such problems, we speculate that pioglitazone’s antidementia action may be related to improving blood vessel’s health,” Dr. Kim said.

This finding suggests that pioglitazone could be used as a personalized treatment approach for dementia prevention in this subgroup of patients with diabetes, the researchers noted.

The results were published online in Neurology.
 

Dose-response relationship

Risk for dementia is doubled in adults with T2DM, the investigators wrote. Prior studies have suggested that pioglitazone may protect against dementia, as well as a first or recurrent stroke, in patients with T2DM.

This led Dr. Kim and colleagues to examine the effects of pioglitazone on dementia risk overall and in relation to stroke and ischemic heart disease.

Using the national Korean health database, the researchers identified 91,218 adults aged 50 and older with new-onset T2DM who did not have dementia. A total of 3,467 were treated with pioglitazone.

Pioglitazone exposure was defined as a total cumulative daily dose of 90 or more calculated from all dispensations during 4 years after T2DM diagnosis, with outcomes assessed after this period.

Over an average of 10 years, 8.3% of pioglitazone users developed dementia, compared with 10.0% of nonusers.

There was a statistically significant 16% lower risk for developing all-cause dementia among pioglitazone users than among nonusers (adjusted hazard ratio, 0.84; 95% confidence interval, 0.75-0.95).

A dose-response relationship was evident; pioglitazone users who received the highest cumulative daily dose were at lower risk for dementia (aHR, 0.72; 95% CI, 0.55-0.94).
 

Several limitations

The reduced risk for dementia was more pronounced among patients who used pioglitazone for 4 years in comparison with patients who did not use the drug (aHR, 0.63; 95% CI, 0.44-0.90).

The apparent protective effect of pioglitazone with regard to dementia was greater among those with a history of ischemic heart disease (aHR, 0.46; 95% CI, 0.24-0.90) or stroke (aHR, 0.57; 95% CI, 0.38-0.86) before diabetes diagnosis.

The incidence of stroke was also reduced with pioglitazone use (aHR, 0.81; 95% CI, 0.66-1.0).

“These results provide valuable information on who could potentially benefit from pioglitazone use for prevention of dementia,” Dr. Kim said in a news release.

However, “the risk and benefit balance of long-term use of this drug to prevent dementia should be prospectively assessed,” he said in an interview.

The researchers cautioned that the study was observational; hence, the reported associations cannot address causal relationships. Also, because of the use of claims data, drug compliance could not be guaranteed, and exposure may have been overestimated.

There is also the potential for selection bias, and no information on apolipoprotein E was available, they noted.
 

More data needed

In an accompanying editorial, Colleen J. Maxwell, PhD, University of Waterloo (Ont.), and colleagues wrote that the results “not only support previous studies showing the potential cognitive benefit of pioglitazone but also extend our understanding of this benefit through the mediating effect of reducing ischemic stroke.”

However, because of their associated risks, which include fractures, weight gain, heart failure, and bladder cancer, thiazolidinediones are not currently favored in diabetes management guidelines – and their use has significantly declined since the mid to late 2000s, the editorialists noted.

They agreed that it will be important to reassess the risk-benefit profile of pioglitazone in T2DM as additional findings emerge.

They also noted that sodium-glucose cotransporter-2 inhibitors, which have significant cardiovascular and renal benefits and minimal side effects, may also lower the risk for dementia.

“As both pioglitazone and SGLT-2 inhibitors are second-line options for physicians, the current decision would easily be in favor of SGLT-2 inhibitors given their safety profile,” Dr. Maxwell and colleagues wrote.

For now, pioglitazone “should not be used to prevent dementia in patients with T2DM,” they concluded.

The study was supported by grants from the National Research Foundation of Korea funded by the Korean government and the Ministry of Health and Welfare. The investigators and editorialists report no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Treatment with the thiazolidinedione pioglitazone may offer the greatest protection against dementia for older adults with newly diagnosed type 2 diabetes mellitus (T2DM) who have a history of stroke or ischemic heart disease, new research suggests.

Overall, in a large cohort study from South Korea, patients who took pioglitazone were 16% less likely to develop dementia over an average of 10 years than peers who did not take the drug.

However, the dementia risk reduction was 54% among those with ischemic heart disease and 43% among those with a history of stroke.

“Our study was to see the association between pioglitazone use and incidence of dementia, not how (with what mechanisms) this drug can suppress dementia pathology,” coinvestigator Eosu Kim, MD, PhD, Yonsei University, Seoul, South Korea, said in an interview.

However, “as we found this drug is more effective in diabetic patients who have blood circulation problems in the heart or brain than in those without such problems, we speculate that pioglitazone’s antidementia action may be related to improving blood vessel’s health,” Dr. Kim said.

This finding suggests that pioglitazone could be used as a personalized treatment approach for dementia prevention in this subgroup of patients with diabetes, the researchers noted.

The results were published online in Neurology.
 

Dose-response relationship

Risk for dementia is doubled in adults with T2DM, the investigators wrote. Prior studies have suggested that pioglitazone may protect against dementia, as well as a first or recurrent stroke, in patients with T2DM.

This led Dr. Kim and colleagues to examine the effects of pioglitazone on dementia risk overall and in relation to stroke and ischemic heart disease.

Using the national Korean health database, the researchers identified 91,218 adults aged 50 and older with new-onset T2DM who did not have dementia. A total of 3,467 were treated with pioglitazone.

Pioglitazone exposure was defined as a total cumulative daily dose of 90 or more calculated from all dispensations during 4 years after T2DM diagnosis, with outcomes assessed after this period.

Over an average of 10 years, 8.3% of pioglitazone users developed dementia, compared with 10.0% of nonusers.

There was a statistically significant 16% lower risk for developing all-cause dementia among pioglitazone users than among nonusers (adjusted hazard ratio, 0.84; 95% confidence interval, 0.75-0.95).

A dose-response relationship was evident; pioglitazone users who received the highest cumulative daily dose were at lower risk for dementia (aHR, 0.72; 95% CI, 0.55-0.94).
 

Several limitations

The reduced risk for dementia was more pronounced among patients who used pioglitazone for 4 years in comparison with patients who did not use the drug (aHR, 0.63; 95% CI, 0.44-0.90).

The apparent protective effect of pioglitazone with regard to dementia was greater among those with a history of ischemic heart disease (aHR, 0.46; 95% CI, 0.24-0.90) or stroke (aHR, 0.57; 95% CI, 0.38-0.86) before diabetes diagnosis.

The incidence of stroke was also reduced with pioglitazone use (aHR, 0.81; 95% CI, 0.66-1.0).

“These results provide valuable information on who could potentially benefit from pioglitazone use for prevention of dementia,” Dr. Kim said in a news release.

However, “the risk and benefit balance of long-term use of this drug to prevent dementia should be prospectively assessed,” he said in an interview.

The researchers cautioned that the study was observational; hence, the reported associations cannot address causal relationships. Also, because of the use of claims data, drug compliance could not be guaranteed, and exposure may have been overestimated.

There is also the potential for selection bias, and no information on apolipoprotein E was available, they noted.
 

More data needed

In an accompanying editorial, Colleen J. Maxwell, PhD, University of Waterloo (Ont.), and colleagues wrote that the results “not only support previous studies showing the potential cognitive benefit of pioglitazone but also extend our understanding of this benefit through the mediating effect of reducing ischemic stroke.”

However, because of their associated risks, which include fractures, weight gain, heart failure, and bladder cancer, thiazolidinediones are not currently favored in diabetes management guidelines – and their use has significantly declined since the mid to late 2000s, the editorialists noted.

They agreed that it will be important to reassess the risk-benefit profile of pioglitazone in T2DM as additional findings emerge.

They also noted that sodium-glucose cotransporter-2 inhibitors, which have significant cardiovascular and renal benefits and minimal side effects, may also lower the risk for dementia.

“As both pioglitazone and SGLT-2 inhibitors are second-line options for physicians, the current decision would easily be in favor of SGLT-2 inhibitors given their safety profile,” Dr. Maxwell and colleagues wrote.

For now, pioglitazone “should not be used to prevent dementia in patients with T2DM,” they concluded.

The study was supported by grants from the National Research Foundation of Korea funded by the Korean government and the Ministry of Health and Welfare. The investigators and editorialists report no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Slowing progression of, rather than stopping, Alzheimer’s disease (AD) has measurable benefits for patients and families and may be a more realistic goal for clinical AD drug trials, a new report suggests.

The report is a yearlong undertaking by an expert work group convened by the Alzheimer’s Association and was prompted, in part, by the fallout from the U.S. Food and Drug Administration’s controversial decision to grant aducanumab (Aduhelm) accelerated approval, which came over the objection of an advisory panel that found the drug was ineffective.

The report’s authors call for a “reframing” of how researchers define “clinically meaningful” in randomized controlled trials (RCTs), noting that it’s time to adjust expectations of outcomes from relatively short clinical trials.

“Without lowering the bar, are we expecting too much from a clinical trial by expecting that unless the disease is halted in its tracks and there’s no progression, we failed at treatment?” the report’s lead author and group leader Ronald C. Petersen, MD, PhD, lead author, chair of the work group, and professor of neurology at the Mayo Clinic, Rochester, Minn., told this news organization.

Interpretations of clinical meaningfulness are used in the drug approval process and in decisions about whether an insurer will cover the cost of treatment, the authors note.

While the report doesn’t provide a consensus definition of clinically meaningful benefit, it does offer a starting point for a conversation about how the phrase should be defined in the context of RCTs for disease-modifying therapies (DMTs) in AD, Dr. Petersen said.

“What we tried to do was to put it into some kind of perspective and at least have people reflect on this: If you’re going to design the perfect drug trial in Alzheimer’s disease, what would it be? We wanted to get people to think about it without digging in their heels for or against,” he added.

The report was published online  in Alzheimer’s and Dementia: The Journal of the Alzheimer’s Association.
 

A proactive measure

The expert group began its work in January 2022, less than a year after the FDA approved aducanumab. Since the panel began its work, the FDA has approved a second AD drug, lecanemab (Leqembi), and denied accelerated approval of a third medication, donanemab.

“At the time we started this group, we had one approved treatment, and we just knew that there were others on the way, and we needed to be prepared to have this conversation and be more proactive than reactive,” Christopher Weber, PhD, director of global science initiatives for the Alzheimer’s Association and co-author of the report, said in an interview.

The work group suggests that simply slowing disease progression might be a desired goal for drug trials, especially early on, before cognition and memory are affected.

They also note that a benefit identified during an 18-month clinical trial may ultimately lead to even more meaningful changes over coming years, well beyond the trial’s end.

In addition, the report authors call for the development of better research tools to more accurately assess meaningful change. The Clinical Dementia Rating (CDR) scale is currently the key instrument used as a primary outcome measure in RCTs. However, the report’s authors note that it may not be adequate to measure meaningful change in early-stage disease.

“Developing better tools certainly should be on the radar screen for all of us, because I think we can do better,” Dr. Petersen said. “The CDR, as good as it is and as long as it’s been used in the field, is a pretty blunt instrument, and it’s the result of subjective ratings.”
 

‘Quality of mind’

Jason Karlawish, MD, professor of medicine, medical ethics, health policy, and neurology at the University of Pennsylvania, Philadelphia, said measuring the actual impact of a drug on a patient’s disease and quality of life has been a hot topic in the AD field for some time, but settling on a definition of “clinically meaningful” that everyone agrees upon will be a challenge.

“I think the idea of ‘clinically meaningful’ is truly a socially constructed idea,” said Dr. Karlawish, co-director of Penn’s Memory Center, who did not work on the report.

“You can come up with objective measures of cognition, but a measure to call something ‘clinically meaningful’ ultimately requires some sort of negotiated social order among clinicians and patients and others who have immediate interest in the health and well-being of the patient.”

Dr. Karlawish added that he’s interested in the conversations the report might prompt and the challenges it could highlight, especially when it comes to how meaningful clinical benefit can be measured, regardless of how it’s defined.

“Hidden in this conversation about clinically meaningful treatments in Alzheimer’s disease is, frankly, not quality of life, but quality of mind,” said Dr. Karlawish. “No measure captures acceptably the very thing that everyone actually cares a lot about and why we view this disease as so dreadful, which is damage to our mind.”
 

More evidence needed

The development of such tools will take time. What does that mean for drugs already in the pipeline? Members of the work group argue that those trials must move forward at the same time new tools are being created.

“We need to continue to refine, develop better instruments, [and] develop tools that are going to assess the disease in its more subtle features early on, even in the so-called ‘pre-symptomatic’ stage of the disease,” said lead author Dr. Petersen. “We shouldn’t wait for the development of that before intervening if we have a drug that seems to work.”

However, not everyone who agrees with the premise of the report agrees with this position, including Joel S. Perlmutter, MD, professor of neurology, Washington University School of Medicine, St. Louis, who also commented on the report.

As reported by this news organization, Dr. Perlmutter was one of three physicians who resigned from the FDA advisory panel that voted against approving aducanumab after the agency moved forward anyway.

“We have to be careful not to recommend DMTs that we hope will help without strong evidence, especially when potential side effects are not trivial,” Dr. Perlmutter said. “We have to have evidence before making these recommendations so we don’t end up harming people more than helping them.”

The report received no specific funding. Dr. Petersen received consulting fees from Roche, Nestle, Merck, Biogen, Eisai, and Genentech. Full disclosures are included in the original article. Dr. Perlmutter and Dr. Karlawish report no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Slowing progression of, rather than stopping, Alzheimer’s disease (AD) has measurable benefits for patients and families and may be a more realistic goal for clinical AD drug trials, a new report suggests.

The report is a yearlong undertaking by an expert work group convened by the Alzheimer’s Association and was prompted, in part, by the fallout from the U.S. Food and Drug Administration’s controversial decision to grant aducanumab (Aduhelm) accelerated approval, which came over the objection of an advisory panel that found the drug was ineffective.

The report’s authors call for a “reframing” of how researchers define “clinically meaningful” in randomized controlled trials (RCTs), noting that it’s time to adjust expectations of outcomes from relatively short clinical trials.

“Without lowering the bar, are we expecting too much from a clinical trial by expecting that unless the disease is halted in its tracks and there’s no progression, we failed at treatment?” the report’s lead author and group leader Ronald C. Petersen, MD, PhD, lead author, chair of the work group, and professor of neurology at the Mayo Clinic, Rochester, Minn., told this news organization.

Interpretations of clinical meaningfulness are used in the drug approval process and in decisions about whether an insurer will cover the cost of treatment, the authors note.

While the report doesn’t provide a consensus definition of clinically meaningful benefit, it does offer a starting point for a conversation about how the phrase should be defined in the context of RCTs for disease-modifying therapies (DMTs) in AD, Dr. Petersen said.

“What we tried to do was to put it into some kind of perspective and at least have people reflect on this: If you’re going to design the perfect drug trial in Alzheimer’s disease, what would it be? We wanted to get people to think about it without digging in their heels for or against,” he added.

The report was published online  in Alzheimer’s and Dementia: The Journal of the Alzheimer’s Association.
 

A proactive measure

The expert group began its work in January 2022, less than a year after the FDA approved aducanumab. Since the panel began its work, the FDA has approved a second AD drug, lecanemab (Leqembi), and denied accelerated approval of a third medication, donanemab.

“At the time we started this group, we had one approved treatment, and we just knew that there were others on the way, and we needed to be prepared to have this conversation and be more proactive than reactive,” Christopher Weber, PhD, director of global science initiatives for the Alzheimer’s Association and co-author of the report, said in an interview.

The work group suggests that simply slowing disease progression might be a desired goal for drug trials, especially early on, before cognition and memory are affected.

They also note that a benefit identified during an 18-month clinical trial may ultimately lead to even more meaningful changes over coming years, well beyond the trial’s end.

In addition, the report authors call for the development of better research tools to more accurately assess meaningful change. The Clinical Dementia Rating (CDR) scale is currently the key instrument used as a primary outcome measure in RCTs. However, the report’s authors note that it may not be adequate to measure meaningful change in early-stage disease.

“Developing better tools certainly should be on the radar screen for all of us, because I think we can do better,” Dr. Petersen said. “The CDR, as good as it is and as long as it’s been used in the field, is a pretty blunt instrument, and it’s the result of subjective ratings.”
 

‘Quality of mind’

Jason Karlawish, MD, professor of medicine, medical ethics, health policy, and neurology at the University of Pennsylvania, Philadelphia, said measuring the actual impact of a drug on a patient’s disease and quality of life has been a hot topic in the AD field for some time, but settling on a definition of “clinically meaningful” that everyone agrees upon will be a challenge.

“I think the idea of ‘clinically meaningful’ is truly a socially constructed idea,” said Dr. Karlawish, co-director of Penn’s Memory Center, who did not work on the report.

“You can come up with objective measures of cognition, but a measure to call something ‘clinically meaningful’ ultimately requires some sort of negotiated social order among clinicians and patients and others who have immediate interest in the health and well-being of the patient.”

Dr. Karlawish added that he’s interested in the conversations the report might prompt and the challenges it could highlight, especially when it comes to how meaningful clinical benefit can be measured, regardless of how it’s defined.

“Hidden in this conversation about clinically meaningful treatments in Alzheimer’s disease is, frankly, not quality of life, but quality of mind,” said Dr. Karlawish. “No measure captures acceptably the very thing that everyone actually cares a lot about and why we view this disease as so dreadful, which is damage to our mind.”
 

More evidence needed

The development of such tools will take time. What does that mean for drugs already in the pipeline? Members of the work group argue that those trials must move forward at the same time new tools are being created.

“We need to continue to refine, develop better instruments, [and] develop tools that are going to assess the disease in its more subtle features early on, even in the so-called ‘pre-symptomatic’ stage of the disease,” said lead author Dr. Petersen. “We shouldn’t wait for the development of that before intervening if we have a drug that seems to work.”

However, not everyone who agrees with the premise of the report agrees with this position, including Joel S. Perlmutter, MD, professor of neurology, Washington University School of Medicine, St. Louis, who also commented on the report.

As reported by this news organization, Dr. Perlmutter was one of three physicians who resigned from the FDA advisory panel that voted against approving aducanumab after the agency moved forward anyway.

“We have to be careful not to recommend DMTs that we hope will help without strong evidence, especially when potential side effects are not trivial,” Dr. Perlmutter said. “We have to have evidence before making these recommendations so we don’t end up harming people more than helping them.”

The report received no specific funding. Dr. Petersen received consulting fees from Roche, Nestle, Merck, Biogen, Eisai, and Genentech. Full disclosures are included in the original article. Dr. Perlmutter and Dr. Karlawish report no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Slowing progression of, rather than stopping, Alzheimer’s disease (AD) has measurable benefits for patients and families and may be a more realistic goal for clinical AD drug trials, a new report suggests.

The report is a yearlong undertaking by an expert work group convened by the Alzheimer’s Association and was prompted, in part, by the fallout from the U.S. Food and Drug Administration’s controversial decision to grant aducanumab (Aduhelm) accelerated approval, which came over the objection of an advisory panel that found the drug was ineffective.

The report’s authors call for a “reframing” of how researchers define “clinically meaningful” in randomized controlled trials (RCTs), noting that it’s time to adjust expectations of outcomes from relatively short clinical trials.

“Without lowering the bar, are we expecting too much from a clinical trial by expecting that unless the disease is halted in its tracks and there’s no progression, we failed at treatment?” the report’s lead author and group leader Ronald C. Petersen, MD, PhD, lead author, chair of the work group, and professor of neurology at the Mayo Clinic, Rochester, Minn., told this news organization.

Interpretations of clinical meaningfulness are used in the drug approval process and in decisions about whether an insurer will cover the cost of treatment, the authors note.

While the report doesn’t provide a consensus definition of clinically meaningful benefit, it does offer a starting point for a conversation about how the phrase should be defined in the context of RCTs for disease-modifying therapies (DMTs) in AD, Dr. Petersen said.

“What we tried to do was to put it into some kind of perspective and at least have people reflect on this: If you’re going to design the perfect drug trial in Alzheimer’s disease, what would it be? We wanted to get people to think about it without digging in their heels for or against,” he added.

The report was published online  in Alzheimer’s and Dementia: The Journal of the Alzheimer’s Association.
 

A proactive measure

The expert group began its work in January 2022, less than a year after the FDA approved aducanumab. Since the panel began its work, the FDA has approved a second AD drug, lecanemab (Leqembi), and denied accelerated approval of a third medication, donanemab.

“At the time we started this group, we had one approved treatment, and we just knew that there were others on the way, and we needed to be prepared to have this conversation and be more proactive than reactive,” Christopher Weber, PhD, director of global science initiatives for the Alzheimer’s Association and co-author of the report, said in an interview.

The work group suggests that simply slowing disease progression might be a desired goal for drug trials, especially early on, before cognition and memory are affected.

They also note that a benefit identified during an 18-month clinical trial may ultimately lead to even more meaningful changes over coming years, well beyond the trial’s end.

In addition, the report authors call for the development of better research tools to more accurately assess meaningful change. The Clinical Dementia Rating (CDR) scale is currently the key instrument used as a primary outcome measure in RCTs. However, the report’s authors note that it may not be adequate to measure meaningful change in early-stage disease.

“Developing better tools certainly should be on the radar screen for all of us, because I think we can do better,” Dr. Petersen said. “The CDR, as good as it is and as long as it’s been used in the field, is a pretty blunt instrument, and it’s the result of subjective ratings.”
 

‘Quality of mind’

Jason Karlawish, MD, professor of medicine, medical ethics, health policy, and neurology at the University of Pennsylvania, Philadelphia, said measuring the actual impact of a drug on a patient’s disease and quality of life has been a hot topic in the AD field for some time, but settling on a definition of “clinically meaningful” that everyone agrees upon will be a challenge.

“I think the idea of ‘clinically meaningful’ is truly a socially constructed idea,” said Dr. Karlawish, co-director of Penn’s Memory Center, who did not work on the report.

“You can come up with objective measures of cognition, but a measure to call something ‘clinically meaningful’ ultimately requires some sort of negotiated social order among clinicians and patients and others who have immediate interest in the health and well-being of the patient.”

Dr. Karlawish added that he’s interested in the conversations the report might prompt and the challenges it could highlight, especially when it comes to how meaningful clinical benefit can be measured, regardless of how it’s defined.

“Hidden in this conversation about clinically meaningful treatments in Alzheimer’s disease is, frankly, not quality of life, but quality of mind,” said Dr. Karlawish. “No measure captures acceptably the very thing that everyone actually cares a lot about and why we view this disease as so dreadful, which is damage to our mind.”
 

More evidence needed

The development of such tools will take time. What does that mean for drugs already in the pipeline? Members of the work group argue that those trials must move forward at the same time new tools are being created.

“We need to continue to refine, develop better instruments, [and] develop tools that are going to assess the disease in its more subtle features early on, even in the so-called ‘pre-symptomatic’ stage of the disease,” said lead author Dr. Petersen. “We shouldn’t wait for the development of that before intervening if we have a drug that seems to work.”

However, not everyone who agrees with the premise of the report agrees with this position, including Joel S. Perlmutter, MD, professor of neurology, Washington University School of Medicine, St. Louis, who also commented on the report.

As reported by this news organization, Dr. Perlmutter was one of three physicians who resigned from the FDA advisory panel that voted against approving aducanumab after the agency moved forward anyway.

“We have to be careful not to recommend DMTs that we hope will help without strong evidence, especially when potential side effects are not trivial,” Dr. Perlmutter said. “We have to have evidence before making these recommendations so we don’t end up harming people more than helping them.”

The report received no specific funding. Dr. Petersen received consulting fees from Roche, Nestle, Merck, Biogen, Eisai, and Genentech. Full disclosures are included in the original article. Dr. Perlmutter and Dr. Karlawish report no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

This transcript has been edited for clarity.

Dear colleagues, I am Christoph Diener from the medical faculty of the University of Duisburg-Essen in Germany. Today, I would like to discuss what happened in neurology in the past month.
 

Treatment of tension-type headache

I would like to start with headache. You are all aware that we have several new studies regarding the prevention of migraine, but very few studies involving nondrug treatments for tension-type headache.

A working group in Göttingen, Germany, conducted a study in people with frequent episodic and chronic tension-type headache. The first of the four randomized groups received traditional Chinese acupuncture for 3 months. The second group received physical therapy and exercise for 1 hour per week for 12 weeks. The third group received a combination of acupuncture and exercise. The last was a control group that received only standard care.

The outcome parameters of tension-type headache were evaluated after 6 months and again after 12 months. Previously, these same researchers published that the intensity but not the frequency of tension-type headache was reduced by active therapy.

In Cephalalgia, they published the outcome for the endpoints of depression, anxiety, and quality of life. Acupuncture, exercise, and the combination of the two improved depression, anxiety, and quality of life. This shows that nonmedical treatment is effective in people with frequent episodic and chronic tension-type headache.
 

Headache after COVID-19

The next study was published in Headache and discusses headache after COVID-19. In this review of published studies, more than 50% of people with COVID-19 develop headache. It is more frequent in young patients and people with preexisting primary headaches, such as migraine and tension-type headache. Prognosis is usually good, but some patients develop new, daily persistent headache, which is a major problem because treatment is unclear. We desperately need studies investigating how to treat this new, daily persistent headache after COVID-19.

SSRIs during COVID-19 infection

The next study also focuses on COVID-19. We have conflicting results from several studies suggesting that selective serotonin reuptake inhibitors might be effective in people with mild COVID-19 infection. This hypothesis was tested in a study in Brazil and was published in JAMA, The study included 1,288 outpatients with mild COVID-19 who either received 50 mg of fluvoxamine twice daily for 10 days or placebo. There was no benefit of the treatment for any outcome.

Preventing dementia with antihypertensive treatment

The next study was published in the European Heart Journal and addresses the question of whether effective antihypertensive treatment in elderly persons can prevent dementia. This is a meta-analysis of five placebo-controlled trials with more than 28,000 patients. The meta-analysis clearly shows that treating hypertension in elderly patients does prevent dementia. The benefit is higher if the blood pressure is lowered by a larger amount which also stays true for elderly patients. There is no negative impact of lowering blood pressure in this population.

Antiplatelet therapy

The next study was published in Stroke and reexamines whether resumption of antiplatelet therapy should be early or late in people who had an intracerebral hemorrhage while on antiplatelet therapy. In the Taiwanese Health Registry, this was studied in 1,584 patients. The researchers divided participants into groups based on whether antiplatelet therapy was resumed within 30 days or after 30 days. In 1 year, the rate of recurrent intracerebral hemorrhage was 3.2%. There was no difference whether antiplatelet therapy was resumed early or late.

Regular exercise in Parkinson’s disease

The final study is a review of nonmedical therapy. This meta-analysis of 19 randomized trials looked at the benefit of regular exercise in patients with Parkinson’s disease and depression. The analysis clearly showed that rigorous and moderate exercise improved depression in patients with Parkinson’s disease. This is very important because exercise improves not only the symptoms of Parkinson’s disease but also comorbid depression while presenting no serious adverse events or side effects.

Dr. Diener is a professor in the department of neurology at Stroke Center–Headache Center, University Duisburg-Essen, Germany. He disclosed ties with Abbott, Addex Pharma, Alder, Allergan, Almirall, Amgen, Autonomic Technology, AstraZeneca, Bayer Vital, Berlin Chemie, Bristol-Myers Squibb, Boehringer Ingelheim, Chordate, CoAxia, Corimmun, Covidien, Coherex, CoLucid, Daiichi Sankyo, D-Pharm, Electrocore, Fresenius, GlaxoSmithKline, Grunenthal, Janssen-Cilag, Labrys Biologics Lilly, La Roche, Lundbeck, 3M Medica, MSD, Medtronic, Menarini, MindFrame, Minster, Neuroscore, Neurobiological Technologies, Novartis, Novo Nordisk, Johnson & Johnson, Knoll, Paion, Parke-Davis, Pierre Fabre, Pfizer Inc, Schaper and Brummer, Sanofi-Aventis, Schering-Plough, Servier, Solvay, St. Jude, Talecris, Thrombogenics, WebMD Global, Weber and Weber, Wyeth, and Yamanouchi. Dr. Diener has served as editor of Aktuelle Neurologie, Arzneimitteltherapie, Kopfschmerz News, Stroke News, and the Treatment Guidelines of the German Neurological Society; as co-editor of Cephalalgia; and on the editorial board of The Lancet Neurology, Stroke, European Neurology, and Cerebrovascular Disorders. The department of neurology in Essen is supported by the German Research Council, the German Ministry of Education and Research, European Union, National Institutes of Health, Bertelsmann Foundation, and Heinz Nixdorf Foundation. Dr. Diener has no ownership interest and does not own stocks in any pharmaceutical company. A version of this article originally appeared on Medscape.com.

This transcript has been edited for clarity.

Dear colleagues, I am Christoph Diener from the medical faculty of the University of Duisburg-Essen in Germany. Today, I would like to discuss what happened in neurology in the past month.
 

Treatment of tension-type headache

I would like to start with headache. You are all aware that we have several new studies regarding the prevention of migraine, but very few studies involving nondrug treatments for tension-type headache.

A working group in Göttingen, Germany, conducted a study in people with frequent episodic and chronic tension-type headache. The first of the four randomized groups received traditional Chinese acupuncture for 3 months. The second group received physical therapy and exercise for 1 hour per week for 12 weeks. The third group received a combination of acupuncture and exercise. The last was a control group that received only standard care.

The outcome parameters of tension-type headache were evaluated after 6 months and again after 12 months. Previously, these same researchers published that the intensity but not the frequency of tension-type headache was reduced by active therapy.

In Cephalalgia, they published the outcome for the endpoints of depression, anxiety, and quality of life. Acupuncture, exercise, and the combination of the two improved depression, anxiety, and quality of life. This shows that nonmedical treatment is effective in people with frequent episodic and chronic tension-type headache.
 

Headache after COVID-19

The next study was published in Headache and discusses headache after COVID-19. In this review of published studies, more than 50% of people with COVID-19 develop headache. It is more frequent in young patients and people with preexisting primary headaches, such as migraine and tension-type headache. Prognosis is usually good, but some patients develop new, daily persistent headache, which is a major problem because treatment is unclear. We desperately need studies investigating how to treat this new, daily persistent headache after COVID-19.

SSRIs during COVID-19 infection

The next study also focuses on COVID-19. We have conflicting results from several studies suggesting that selective serotonin reuptake inhibitors might be effective in people with mild COVID-19 infection. This hypothesis was tested in a study in Brazil and was published in JAMA, The study included 1,288 outpatients with mild COVID-19 who either received 50 mg of fluvoxamine twice daily for 10 days or placebo. There was no benefit of the treatment for any outcome.

Preventing dementia with antihypertensive treatment

The next study was published in the European Heart Journal and addresses the question of whether effective antihypertensive treatment in elderly persons can prevent dementia. This is a meta-analysis of five placebo-controlled trials with more than 28,000 patients. The meta-analysis clearly shows that treating hypertension in elderly patients does prevent dementia. The benefit is higher if the blood pressure is lowered by a larger amount which also stays true for elderly patients. There is no negative impact of lowering blood pressure in this population.

Antiplatelet therapy

The next study was published in Stroke and reexamines whether resumption of antiplatelet therapy should be early or late in people who had an intracerebral hemorrhage while on antiplatelet therapy. In the Taiwanese Health Registry, this was studied in 1,584 patients. The researchers divided participants into groups based on whether antiplatelet therapy was resumed within 30 days or after 30 days. In 1 year, the rate of recurrent intracerebral hemorrhage was 3.2%. There was no difference whether antiplatelet therapy was resumed early or late.

Regular exercise in Parkinson’s disease

The final study is a review of nonmedical therapy. This meta-analysis of 19 randomized trials looked at the benefit of regular exercise in patients with Parkinson’s disease and depression. The analysis clearly showed that rigorous and moderate exercise improved depression in patients with Parkinson’s disease. This is very important because exercise improves not only the symptoms of Parkinson’s disease but also comorbid depression while presenting no serious adverse events or side effects.

Dr. Diener is a professor in the department of neurology at Stroke Center–Headache Center, University Duisburg-Essen, Germany. He disclosed ties with Abbott, Addex Pharma, Alder, Allergan, Almirall, Amgen, Autonomic Technology, AstraZeneca, Bayer Vital, Berlin Chemie, Bristol-Myers Squibb, Boehringer Ingelheim, Chordate, CoAxia, Corimmun, Covidien, Coherex, CoLucid, Daiichi Sankyo, D-Pharm, Electrocore, Fresenius, GlaxoSmithKline, Grunenthal, Janssen-Cilag, Labrys Biologics Lilly, La Roche, Lundbeck, 3M Medica, MSD, Medtronic, Menarini, MindFrame, Minster, Neuroscore, Neurobiological Technologies, Novartis, Novo Nordisk, Johnson & Johnson, Knoll, Paion, Parke-Davis, Pierre Fabre, Pfizer Inc, Schaper and Brummer, Sanofi-Aventis, Schering-Plough, Servier, Solvay, St. Jude, Talecris, Thrombogenics, WebMD Global, Weber and Weber, Wyeth, and Yamanouchi. Dr. Diener has served as editor of Aktuelle Neurologie, Arzneimitteltherapie, Kopfschmerz News, Stroke News, and the Treatment Guidelines of the German Neurological Society; as co-editor of Cephalalgia; and on the editorial board of The Lancet Neurology, Stroke, European Neurology, and Cerebrovascular Disorders. The department of neurology in Essen is supported by the German Research Council, the German Ministry of Education and Research, European Union, National Institutes of Health, Bertelsmann Foundation, and Heinz Nixdorf Foundation. Dr. Diener has no ownership interest and does not own stocks in any pharmaceutical company. A version of this article originally appeared on Medscape.com.

This transcript has been edited for clarity.

Dear colleagues, I am Christoph Diener from the medical faculty of the University of Duisburg-Essen in Germany. Today, I would like to discuss what happened in neurology in the past month.
 

Treatment of tension-type headache

I would like to start with headache. You are all aware that we have several new studies regarding the prevention of migraine, but very few studies involving nondrug treatments for tension-type headache.

A working group in Göttingen, Germany, conducted a study in people with frequent episodic and chronic tension-type headache. The first of the four randomized groups received traditional Chinese acupuncture for 3 months. The second group received physical therapy and exercise for 1 hour per week for 12 weeks. The third group received a combination of acupuncture and exercise. The last was a control group that received only standard care.

The outcome parameters of tension-type headache were evaluated after 6 months and again after 12 months. Previously, these same researchers published that the intensity but not the frequency of tension-type headache was reduced by active therapy.

In Cephalalgia, they published the outcome for the endpoints of depression, anxiety, and quality of life. Acupuncture, exercise, and the combination of the two improved depression, anxiety, and quality of life. This shows that nonmedical treatment is effective in people with frequent episodic and chronic tension-type headache.
 

Headache after COVID-19

The next study was published in Headache and discusses headache after COVID-19. In this review of published studies, more than 50% of people with COVID-19 develop headache. It is more frequent in young patients and people with preexisting primary headaches, such as migraine and tension-type headache. Prognosis is usually good, but some patients develop new, daily persistent headache, which is a major problem because treatment is unclear. We desperately need studies investigating how to treat this new, daily persistent headache after COVID-19.

SSRIs during COVID-19 infection

The next study also focuses on COVID-19. We have conflicting results from several studies suggesting that selective serotonin reuptake inhibitors might be effective in people with mild COVID-19 infection. This hypothesis was tested in a study in Brazil and was published in JAMA, The study included 1,288 outpatients with mild COVID-19 who either received 50 mg of fluvoxamine twice daily for 10 days or placebo. There was no benefit of the treatment for any outcome.

Preventing dementia with antihypertensive treatment

The next study was published in the European Heart Journal and addresses the question of whether effective antihypertensive treatment in elderly persons can prevent dementia. This is a meta-analysis of five placebo-controlled trials with more than 28,000 patients. The meta-analysis clearly shows that treating hypertension in elderly patients does prevent dementia. The benefit is higher if the blood pressure is lowered by a larger amount which also stays true for elderly patients. There is no negative impact of lowering blood pressure in this population.

Antiplatelet therapy

The next study was published in Stroke and reexamines whether resumption of antiplatelet therapy should be early or late in people who had an intracerebral hemorrhage while on antiplatelet therapy. In the Taiwanese Health Registry, this was studied in 1,584 patients. The researchers divided participants into groups based on whether antiplatelet therapy was resumed within 30 days or after 30 days. In 1 year, the rate of recurrent intracerebral hemorrhage was 3.2%. There was no difference whether antiplatelet therapy was resumed early or late.

Regular exercise in Parkinson’s disease

The final study is a review of nonmedical therapy. This meta-analysis of 19 randomized trials looked at the benefit of regular exercise in patients with Parkinson’s disease and depression. The analysis clearly showed that rigorous and moderate exercise improved depression in patients with Parkinson’s disease. This is very important because exercise improves not only the symptoms of Parkinson’s disease but also comorbid depression while presenting no serious adverse events or side effects.

Dr. Diener is a professor in the department of neurology at Stroke Center–Headache Center, University Duisburg-Essen, Germany. He disclosed ties with Abbott, Addex Pharma, Alder, Allergan, Almirall, Amgen, Autonomic Technology, AstraZeneca, Bayer Vital, Berlin Chemie, Bristol-Myers Squibb, Boehringer Ingelheim, Chordate, CoAxia, Corimmun, Covidien, Coherex, CoLucid, Daiichi Sankyo, D-Pharm, Electrocore, Fresenius, GlaxoSmithKline, Grunenthal, Janssen-Cilag, Labrys Biologics Lilly, La Roche, Lundbeck, 3M Medica, MSD, Medtronic, Menarini, MindFrame, Minster, Neuroscore, Neurobiological Technologies, Novartis, Novo Nordisk, Johnson & Johnson, Knoll, Paion, Parke-Davis, Pierre Fabre, Pfizer Inc, Schaper and Brummer, Sanofi-Aventis, Schering-Plough, Servier, Solvay, St. Jude, Talecris, Thrombogenics, WebMD Global, Weber and Weber, Wyeth, and Yamanouchi. Dr. Diener has served as editor of Aktuelle Neurologie, Arzneimitteltherapie, Kopfschmerz News, Stroke News, and the Treatment Guidelines of the German Neurological Society; as co-editor of Cephalalgia; and on the editorial board of The Lancet Neurology, Stroke, European Neurology, and Cerebrovascular Disorders. The department of neurology in Essen is supported by the German Research Council, the German Ministry of Education and Research, European Union, National Institutes of Health, Bertelsmann Foundation, and Heinz Nixdorf Foundation. Dr. Diener has no ownership interest and does not own stocks in any pharmaceutical company. A version of this article originally appeared on Medscape.com.

A combination of two drugs has shown promising results, including a reduction in cognitive impairment in patients who have had a lacunar stroke, and is seen as a new therapeutic approach for patients with cerebral small-vessel disease. The drugs – isosorbide mononitrate and cilostazol – stabilize endothelial function, which is a new therapeutic target for patients with small-vessel disease stroke.

The phase 2 LACI-2 study, evaluating these drugs individually and in combination in patients with lacunar stroke, showed promising trends toward reductions in recurrent stroke, cognitive impairment, and dependency, some of which became significant when the drugs were given together. There was also some suggestion of positive impacts on mood and quality of life.

“Isosorbide mononitrate was associated with a reduction in recurrent stroke, a tendency toward a reduction in dependency and a reduction in cognitive impairment, and cilostazol also seemed to reduce dependency,” study investigator Joanna M. Wardlaw, MD, professor of applied neuroimaging at Edinburgh University, reported.

“When used together, they seemed to have more benefits than either drug on its own. So this is good preliminary evidence that the drugs are working together in a positive way,” she said. But she cautioned that these potential benefits will need to be confirmed in a larger phase 3 trial.

The LACI-2 study was presented at the International Stroke Conference by Dr. Wardlaw and coinvestigator Philip Bath, DSc, professor of medicine at the University of Nottingham (England).

They both highlighted the effect seen on cognitive impairment at the conference presented by the American Stroke Association, a division of the American Heart Association.

“We saw a significant reduction in the number of patients with cognitive impairment with the two drugs together in this phase 2 study,” Dr. Wardlaw said. “This is very encouraging since no study has previously found any medications that positively affect cognitive impairment in small-vessel disease strokes. We cautiously hope that these medications may have wider implications for other types of small-vessel disease as well.”

Dr. Bath added: “The results on cognitive impairment are particularly important. Many patients rate cognitive impairment as one of the most dreaded outcomes of a stroke even if they also have quite significant physical disability. People simply don’t want to lose their memory and thinking ability.”

“The results of LACI-2 also raise interesting questions about whether these drugs would be beneficial for other types of small-vessel disease which do not present as stroke, but maybe may manifest as headaches or memory impairment,” he noted.
 

‘Very intriguing results’

Outside experts were enthusiastic about these preliminary results. In an ISC highlights presentation, program chair Tudor Jovin, MD, Cooper Neurological Institute, Cherry Hill, N.J., said: “It is refreshing to finally see some positive signals in studies in small-vessel stroke. This is an area where we haven’t had answers for a long time.”

He described the reduction in cognitive impairment seen in the study as “very intriguing and very important.”

“I think we have underestimated the burden that cognitive impairment has in stroke, and the burden in general in society of vascular cognitive impairment. This is a very promising approach that definitely deserves to be investigated more thoroughly in a larger trial.”

Commenting on the study findings, Mitchell Elkind, MD, professor of neurology and epidemiology at Columbia University Irving Medical Center, New York, said this study “provides evidence that points us in at least two important directions.”

“First, it suggests that endothelial dysfunction, or problems with the lining of the blood vessels, may be an important contributor to small-vessel disease and the cognitive decline that often accompanies it. This is a new mechanism of action and different from blood clotting, blood pressure, and other conventional targets of treatment,” Dr. Elkind said.

“Second, and more generally, it suggests that stroke trials, particularly in the subtype of small-vessel disease, can and should explore not only the incidence of recurrent acute events but also the steady decline that occurs after stroke. Poststroke cognitive decline is a relatively new area of stroke research.”

Dr. Wardlaw noted that lacunar stroke is a common type of ischemic stroke, but it has been rather neglected in terms of research. It is assumed to be caused by atherosclerosis of the small vessel but there is now mounting evidence suggesting that it is a result of problems in the endothelium of the small vessels.  

“We looked for potential available drugs that targeted endothelial dysfunction. Both the drugs we tested are already widely used – isosorbide mononitrate for the treatment of coronary artery disease and angina, and cilostazol, mainly in Asia, for stroke prevention,” she said.  

LACI-2 was primarily a feasibility study looking at whether it was possible to recruit enough patients who had had a lacunar stroke and would take the drugs, individually or in combination, for up to a year. Outcomes were investigated on an exploratory basis. The study enrolled 363 patients who had experienced lacunar stroke from 26 stroke centers throughout the United Kingdom. They were randomly assigned to one of four treatment groups for 1 year:

• 40-60 mg/day of oral isosorbide mononitrate alone.
• 200 mg/day of oral cilostazol alone.
• Both medications.
• Neither medication.

Patients completed phone surveys at 6 and 12 months to assess health status, including recurrent stroke, myocardial infarction, cognitive tests, symptoms, quality of life surveys, and they also had brain imaging at 12 months.

Results showed 98% of patients were still taking their study medication at 1 year, and the drugs appeared to be safe on top of usual care with few deaths or hemorrhages in the study.

The composite outcome including recurrent stroke, MI, cognitive impairment, dependency (modified Rankin score > 2) and death was reduced by 20% in the isosorbide mononitrate–alone group (adjusted hazard ratio, 0.80; 95% confidence interval, 0.59-1.09).

The composite endpoint was reduced by 23% in the cilostazol group (aHR, 0.77; 95% CI, 0.57-1.05) and by 42% in the combination group (aHR, 0.58, 95% CI, 0.36-0.92) compared with those taking neither drug.

Isosorbide mononitrate alone showed trends toward a reduction in recurrent stroke, cognitive impairment, and dependency, whereas cilostazol alone reduced dependency with a trend toward a reduction in cognitive impairment. When used together, the drugs showed large reductions in cognitive impairment (aHR, 0.44; 95% CI, 0.19-0.99) and dependency (aHR ,0.14; 95% CI, 0.03-0.59).

During the highlights session, Dr. Jovin commented: “It is obvious that the investigators have put a lot of thought into the design of this trial. Presumably because of the composite score they were able to increase the power. We are used to trials which require thousands of patients, but here we are able to see significant results, although exploratory, with just a few hundred patients.”

Dr. Bath stressed that this was only a phase 2 study. “We now need to see if we can confirm these results in a larger phase 3 study.” That study, LACI-3, is planned to start later this year. He also suggested that it would be interesting to investigate whether these drugs would work in other types of ischemic stroke such as those caused by large-artery disease or cardioembolic strokes, as well as other forms of small-vessel disease such as patients with vascular cognitive impairment.

“There are many areas to investigate in future. It might be that in a few years’ time these drugs may be standard of care across many different forms of small-vessel disease,” he said.

Dr. Wardlaw noted that lacunar strokes are generally quite mild strokes, which could be one of the reasons why they have not been the target of much research to date. But Dr. Bath added: “While they may be labeled as a mild stroke on the NIHSS scale, patients can still be quite badly affected. About half of patients with a lacunar stroke develop cognitive impairment and eventually dementia – that is certainly not mild.”

The study was funded primarily by the British Heart Foundation, with support from the UK Alzheimer’s Society, the UK Dementia Research Institute, the Stroke Association, the Fondation Leducq, NHS Research Scotland, and the UK National Institutes of Health Research Clinical Research Networks. Dr. Bath is an adviser to CoMind, DiaMedica, Phagenesis, and Roche. Dr. Wardlaw reports no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A combination of two drugs has shown promising results, including a reduction in cognitive impairment in patients who have had a lacunar stroke, and is seen as a new therapeutic approach for patients with cerebral small-vessel disease. The drugs – isosorbide mononitrate and cilostazol – stabilize endothelial function, which is a new therapeutic target for patients with small-vessel disease stroke.

The phase 2 LACI-2 study, evaluating these drugs individually and in combination in patients with lacunar stroke, showed promising trends toward reductions in recurrent stroke, cognitive impairment, and dependency, some of which became significant when the drugs were given together. There was also some suggestion of positive impacts on mood and quality of life.

“Isosorbide mononitrate was associated with a reduction in recurrent stroke, a tendency toward a reduction in dependency and a reduction in cognitive impairment, and cilostazol also seemed to reduce dependency,” study investigator Joanna M. Wardlaw, MD, professor of applied neuroimaging at Edinburgh University, reported.

“When used together, they seemed to have more benefits than either drug on its own. So this is good preliminary evidence that the drugs are working together in a positive way,” she said. But she cautioned that these potential benefits will need to be confirmed in a larger phase 3 trial.

The LACI-2 study was presented at the International Stroke Conference by Dr. Wardlaw and coinvestigator Philip Bath, DSc, professor of medicine at the University of Nottingham (England).

They both highlighted the effect seen on cognitive impairment at the conference presented by the American Stroke Association, a division of the American Heart Association.

“We saw a significant reduction in the number of patients with cognitive impairment with the two drugs together in this phase 2 study,” Dr. Wardlaw said. “This is very encouraging since no study has previously found any medications that positively affect cognitive impairment in small-vessel disease strokes. We cautiously hope that these medications may have wider implications for other types of small-vessel disease as well.”

Dr. Bath added: “The results on cognitive impairment are particularly important. Many patients rate cognitive impairment as one of the most dreaded outcomes of a stroke even if they also have quite significant physical disability. People simply don’t want to lose their memory and thinking ability.”

“The results of LACI-2 also raise interesting questions about whether these drugs would be beneficial for other types of small-vessel disease which do not present as stroke, but maybe may manifest as headaches or memory impairment,” he noted.
 

‘Very intriguing results’

Outside experts were enthusiastic about these preliminary results. In an ISC highlights presentation, program chair Tudor Jovin, MD, Cooper Neurological Institute, Cherry Hill, N.J., said: “It is refreshing to finally see some positive signals in studies in small-vessel stroke. This is an area where we haven’t had answers for a long time.”

He described the reduction in cognitive impairment seen in the study as “very intriguing and very important.”

“I think we have underestimated the burden that cognitive impairment has in stroke, and the burden in general in society of vascular cognitive impairment. This is a very promising approach that definitely deserves to be investigated more thoroughly in a larger trial.”

Commenting on the study findings, Mitchell Elkind, MD, professor of neurology and epidemiology at Columbia University Irving Medical Center, New York, said this study “provides evidence that points us in at least two important directions.”

“First, it suggests that endothelial dysfunction, or problems with the lining of the blood vessels, may be an important contributor to small-vessel disease and the cognitive decline that often accompanies it. This is a new mechanism of action and different from blood clotting, blood pressure, and other conventional targets of treatment,” Dr. Elkind said.

“Second, and more generally, it suggests that stroke trials, particularly in the subtype of small-vessel disease, can and should explore not only the incidence of recurrent acute events but also the steady decline that occurs after stroke. Poststroke cognitive decline is a relatively new area of stroke research.”

Dr. Wardlaw noted that lacunar stroke is a common type of ischemic stroke, but it has been rather neglected in terms of research. It is assumed to be caused by atherosclerosis of the small vessel but there is now mounting evidence suggesting that it is a result of problems in the endothelium of the small vessels.  

“We looked for potential available drugs that targeted endothelial dysfunction. Both the drugs we tested are already widely used – isosorbide mononitrate for the treatment of coronary artery disease and angina, and cilostazol, mainly in Asia, for stroke prevention,” she said.  

LACI-2 was primarily a feasibility study looking at whether it was possible to recruit enough patients who had had a lacunar stroke and would take the drugs, individually or in combination, for up to a year. Outcomes were investigated on an exploratory basis. The study enrolled 363 patients who had experienced lacunar stroke from 26 stroke centers throughout the United Kingdom. They were randomly assigned to one of four treatment groups for 1 year:

• 40-60 mg/day of oral isosorbide mononitrate alone.
• 200 mg/day of oral cilostazol alone.
• Both medications.
• Neither medication.

Patients completed phone surveys at 6 and 12 months to assess health status, including recurrent stroke, myocardial infarction, cognitive tests, symptoms, quality of life surveys, and they also had brain imaging at 12 months.

Results showed 98% of patients were still taking their study medication at 1 year, and the drugs appeared to be safe on top of usual care with few deaths or hemorrhages in the study.

The composite outcome including recurrent stroke, MI, cognitive impairment, dependency (modified Rankin score > 2) and death was reduced by 20% in the isosorbide mononitrate–alone group (adjusted hazard ratio, 0.80; 95% confidence interval, 0.59-1.09).

The composite endpoint was reduced by 23% in the cilostazol group (aHR, 0.77; 95% CI, 0.57-1.05) and by 42% in the combination group (aHR, 0.58, 95% CI, 0.36-0.92) compared with those taking neither drug.

Isosorbide mononitrate alone showed trends toward a reduction in recurrent stroke, cognitive impairment, and dependency, whereas cilostazol alone reduced dependency with a trend toward a reduction in cognitive impairment. When used together, the drugs showed large reductions in cognitive impairment (aHR, 0.44; 95% CI, 0.19-0.99) and dependency (aHR ,0.14; 95% CI, 0.03-0.59).

During the highlights session, Dr. Jovin commented: “It is obvious that the investigators have put a lot of thought into the design of this trial. Presumably because of the composite score they were able to increase the power. We are used to trials which require thousands of patients, but here we are able to see significant results, although exploratory, with just a few hundred patients.”

Dr. Bath stressed that this was only a phase 2 study. “We now need to see if we can confirm these results in a larger phase 3 study.” That study, LACI-3, is planned to start later this year. He also suggested that it would be interesting to investigate whether these drugs would work in other types of ischemic stroke such as those caused by large-artery disease or cardioembolic strokes, as well as other forms of small-vessel disease such as patients with vascular cognitive impairment.

“There are many areas to investigate in future. It might be that in a few years’ time these drugs may be standard of care across many different forms of small-vessel disease,” he said.

Dr. Wardlaw noted that lacunar strokes are generally quite mild strokes, which could be one of the reasons why they have not been the target of much research to date. But Dr. Bath added: “While they may be labeled as a mild stroke on the NIHSS scale, patients can still be quite badly affected. About half of patients with a lacunar stroke develop cognitive impairment and eventually dementia – that is certainly not mild.”

The study was funded primarily by the British Heart Foundation, with support from the UK Alzheimer’s Society, the UK Dementia Research Institute, the Stroke Association, the Fondation Leducq, NHS Research Scotland, and the UK National Institutes of Health Research Clinical Research Networks. Dr. Bath is an adviser to CoMind, DiaMedica, Phagenesis, and Roche. Dr. Wardlaw reports no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A combination of two drugs has shown promising results, including a reduction in cognitive impairment in patients who have had a lacunar stroke, and is seen as a new therapeutic approach for patients with cerebral small-vessel disease. The drugs – isosorbide mononitrate and cilostazol – stabilize endothelial function, which is a new therapeutic target for patients with small-vessel disease stroke.

The phase 2 LACI-2 study, evaluating these drugs individually and in combination in patients with lacunar stroke, showed promising trends toward reductions in recurrent stroke, cognitive impairment, and dependency, some of which became significant when the drugs were given together. There was also some suggestion of positive impacts on mood and quality of life.

“Isosorbide mononitrate was associated with a reduction in recurrent stroke, a tendency toward a reduction in dependency and a reduction in cognitive impairment, and cilostazol also seemed to reduce dependency,” study investigator Joanna M. Wardlaw, MD, professor of applied neuroimaging at Edinburgh University, reported.

“When used together, they seemed to have more benefits than either drug on its own. So this is good preliminary evidence that the drugs are working together in a positive way,” she said. But she cautioned that these potential benefits will need to be confirmed in a larger phase 3 trial.

The LACI-2 study was presented at the International Stroke Conference by Dr. Wardlaw and coinvestigator Philip Bath, DSc, professor of medicine at the University of Nottingham (England).

They both highlighted the effect seen on cognitive impairment at the conference presented by the American Stroke Association, a division of the American Heart Association.

“We saw a significant reduction in the number of patients with cognitive impairment with the two drugs together in this phase 2 study,” Dr. Wardlaw said. “This is very encouraging since no study has previously found any medications that positively affect cognitive impairment in small-vessel disease strokes. We cautiously hope that these medications may have wider implications for other types of small-vessel disease as well.”

Dr. Bath added: “The results on cognitive impairment are particularly important. Many patients rate cognitive impairment as one of the most dreaded outcomes of a stroke even if they also have quite significant physical disability. People simply don’t want to lose their memory and thinking ability.”

“The results of LACI-2 also raise interesting questions about whether these drugs would be beneficial for other types of small-vessel disease which do not present as stroke, but maybe may manifest as headaches or memory impairment,” he noted.
 

‘Very intriguing results’

Outside experts were enthusiastic about these preliminary results. In an ISC highlights presentation, program chair Tudor Jovin, MD, Cooper Neurological Institute, Cherry Hill, N.J., said: “It is refreshing to finally see some positive signals in studies in small-vessel stroke. This is an area where we haven’t had answers for a long time.”

He described the reduction in cognitive impairment seen in the study as “very intriguing and very important.”

“I think we have underestimated the burden that cognitive impairment has in stroke, and the burden in general in society of vascular cognitive impairment. This is a very promising approach that definitely deserves to be investigated more thoroughly in a larger trial.”

Commenting on the study findings, Mitchell Elkind, MD, professor of neurology and epidemiology at Columbia University Irving Medical Center, New York, said this study “provides evidence that points us in at least two important directions.”

“First, it suggests that endothelial dysfunction, or problems with the lining of the blood vessels, may be an important contributor to small-vessel disease and the cognitive decline that often accompanies it. This is a new mechanism of action and different from blood clotting, blood pressure, and other conventional targets of treatment,” Dr. Elkind said.

“Second, and more generally, it suggests that stroke trials, particularly in the subtype of small-vessel disease, can and should explore not only the incidence of recurrent acute events but also the steady decline that occurs after stroke. Poststroke cognitive decline is a relatively new area of stroke research.”

Dr. Wardlaw noted that lacunar stroke is a common type of ischemic stroke, but it has been rather neglected in terms of research. It is assumed to be caused by atherosclerosis of the small vessel but there is now mounting evidence suggesting that it is a result of problems in the endothelium of the small vessels.  

“We looked for potential available drugs that targeted endothelial dysfunction. Both the drugs we tested are already widely used – isosorbide mononitrate for the treatment of coronary artery disease and angina, and cilostazol, mainly in Asia, for stroke prevention,” she said.  

LACI-2 was primarily a feasibility study looking at whether it was possible to recruit enough patients who had had a lacunar stroke and would take the drugs, individually or in combination, for up to a year. Outcomes were investigated on an exploratory basis. The study enrolled 363 patients who had experienced lacunar stroke from 26 stroke centers throughout the United Kingdom. They were randomly assigned to one of four treatment groups for 1 year:

• 40-60 mg/day of oral isosorbide mononitrate alone.
• 200 mg/day of oral cilostazol alone.
• Both medications.
• Neither medication.

Patients completed phone surveys at 6 and 12 months to assess health status, including recurrent stroke, myocardial infarction, cognitive tests, symptoms, quality of life surveys, and they also had brain imaging at 12 months.

Results showed 98% of patients were still taking their study medication at 1 year, and the drugs appeared to be safe on top of usual care with few deaths or hemorrhages in the study.

The composite outcome including recurrent stroke, MI, cognitive impairment, dependency (modified Rankin score > 2) and death was reduced by 20% in the isosorbide mononitrate–alone group (adjusted hazard ratio, 0.80; 95% confidence interval, 0.59-1.09).

The composite endpoint was reduced by 23% in the cilostazol group (aHR, 0.77; 95% CI, 0.57-1.05) and by 42% in the combination group (aHR, 0.58, 95% CI, 0.36-0.92) compared with those taking neither drug.

Isosorbide mononitrate alone showed trends toward a reduction in recurrent stroke, cognitive impairment, and dependency, whereas cilostazol alone reduced dependency with a trend toward a reduction in cognitive impairment. When used together, the drugs showed large reductions in cognitive impairment (aHR, 0.44; 95% CI, 0.19-0.99) and dependency (aHR ,0.14; 95% CI, 0.03-0.59).

During the highlights session, Dr. Jovin commented: “It is obvious that the investigators have put a lot of thought into the design of this trial. Presumably because of the composite score they were able to increase the power. We are used to trials which require thousands of patients, but here we are able to see significant results, although exploratory, with just a few hundred patients.”

Dr. Bath stressed that this was only a phase 2 study. “We now need to see if we can confirm these results in a larger phase 3 study.” That study, LACI-3, is planned to start later this year. He also suggested that it would be interesting to investigate whether these drugs would work in other types of ischemic stroke such as those caused by large-artery disease or cardioembolic strokes, as well as other forms of small-vessel disease such as patients with vascular cognitive impairment.

“There are many areas to investigate in future. It might be that in a few years’ time these drugs may be standard of care across many different forms of small-vessel disease,” he said.

Dr. Wardlaw noted that lacunar strokes are generally quite mild strokes, which could be one of the reasons why they have not been the target of much research to date. But Dr. Bath added: “While they may be labeled as a mild stroke on the NIHSS scale, patients can still be quite badly affected. About half of patients with a lacunar stroke develop cognitive impairment and eventually dementia – that is certainly not mild.”

The study was funded primarily by the British Heart Foundation, with support from the UK Alzheimer’s Society, the UK Dementia Research Institute, the Stroke Association, the Fondation Leducq, NHS Research Scotland, and the UK National Institutes of Health Research Clinical Research Networks. Dr. Bath is an adviser to CoMind, DiaMedica, Phagenesis, and Roche. Dr. Wardlaw reports no relevant financial relationships.

A version of this article first appeared on Medscape.com.

We’re gonna need a bigger meth lab

In case you’ve been living under a rock for the past 15 years, the TV show “Breaking Bad” details the spiraling rise and downfall of a high school chemistry teacher who, after developing a case of terminal lung cancer, starts producing methamphetamine to provide for his family in response to the steep cost of treatment for his cancer.

TheaDesign/Thinkstock

Meanwhile, here in 2023 in the real world, we have Paul Davis, a retired physician in Ohio, who’s being forced to choose between an expensive cancer treatment and bankrupting his family, since Medicare’s decided it doesn’t want to cover the cost. Hey, we’ve seen this one before!

A bit of backstory: In November 2019, Dr. Davis was diagnosed with uveal melanoma, a very rare type of cancer that affects eye tissue. The news got worse in 2022 when the cancer spread to his liver, a move which typically proves fatal within a year. However, in a stroke of great news, the Food and Drug Administration approved the drug Kimmtrak earlier that year, which could be used to treat his cancer. Not cure, of course, but it would give him more time.

His initial treatments with the drug went fine and were covered, but when he transferred his care from a hospital in Columbus to one closer to home, big problem. Medicare decided it didn’t like that hospital and abruptly cut off coverage, denying the local hospital’s claims. That leaves Dr. Davis on the hook for his cancer treatment, and it’s what you might call expensive. Expensive to the tune of $50,000.

A week.

Apparently the coding the local hospital submitted was wrong, indicating that Dr. Davis was receiving Kimmtrak for a type of cancer that the FDA hadn’t approved the drug for. So until the government bureaucracy works itself out, his treatment is on hold, leaving all his faith in Medicare working quickly to rectify its mistake. If it can rectify its mistake. We’re not hopeful.

And in case you were wondering, if Dr. Davis wanted to go full Walter White, the average street price of meth is about $20-$60 per gram, so to pay for his treatment, he’d need to make at least a kilogram of meth every week. That’s, uh, quite a lot of illegal drug, or what we here at the LOTME office would call a fun Saturday night.
 

When you give a mouse a movie

Researchers have been successfully testing Alzheimer drugs on mice for years, but none of the drugs has proved successful in humans. Recent work, however, might have found the missing link, and it’s a combination no one ever thought of before: mice and movies.

procesocreativo/PxHere

Turns out that Orson Welles’ 1958 film noir classic “Touch of Evil” tapped a part of the mouse brain that has been overlooked: the hippocampus, which is crucial for learning and memory. Previous researchers thought it was just used as a kind of GPS system, but that’s only partially true.

Not only did the mice choose to pay attention to the movie clip, but the hippocampus responded to the visual stimuli only when the rodents saw the scenes from the clip later in the order that they were presented and not in a scrambled order. These findings represent a “major paradigm shift” in studying mouse recall, Mayank Mehta, PhD, of the University of California, Los Angeles, said in a statement from the school.

This breakthrough could run parallel to Alzheimer’s patients struggling with similar defects. “Selective and episodic activation of the mouse hippocampus using a human movie opens up the possibility of directly testing human episodic memory disorders and therapies using mouse neurons, a major step forward,” said coauthor Chinmay Purandare, PhD, who is now at the University of California, San Francisco.

Who would have thought that a classic film would help advance Alzheimer research?
 

A less human way to study mosquitoes

We here at LOTME have a history with mosquitoes. We know they don’t like us, and they know that we don’t like them. Trust us, they know. So when humans gain a little ground in the war against the buzzy little bloodsuckers, we want to share the joy.

Wesson Group/Tulane University

To know the enemy, scientists have to study the enemy, but there is a problem. “Many mosquito experiments still rely on human volunteers and animal subjects,” bioengineering graduate student Kevin Janson, said in a statement from Rice University. Most people don’t like being bitten by mosquitoes, so that kind of testing can be expensive.

Is there a way to automate the collection and processing of mosquito behavior data using inexpensive cameras and machine-learning software? We’re glad you asked, because Mr. Janson and the research team, which includes bioengineers from Rice and tropical medicine experts from Tulane University, have managed to eliminate the need for live volunteers by using patches of synthetic skin made with a 3D printer.

“Each patch of gelatin-like hydrogel comes complete with tiny passageways that can be filled with flowing blood” from a chicken, sheep, or cow, they explained, and proof-of-concept testing showed that mosquitoes would feed on hydrogels without any repellent and stay away from those treated with a repellent.

To conduct the feeding tests, the blood-infused hydrogels are placed in a clear plastic box that is surrounded by cameras.

A bunch of mosquitoes are then tossed in the box and the cameras record all their insect activities: how often they land at each location, how long they stay, whether or not they bite, how long they feed, etc. Humans don’t have to watch and don’t have to be food sources.

Humans don’t have to be food sources, and we just pictured the future of mosquito control. Imagine a dozen Arnold Schwarzenegger–style Terminators, covered in 3D-printed skin, walking through your neighborhood in the summer while wearing sweat-soaked, brightly colored clothing. The mosquitoes wouldn’t be able to stay away, but guess what? They’re feeding off robots with nonhuman skin and nonhuman blood, so we win. It’s good to have a cerebral cortex.
 

Getting medieval on brain surgery

Let’s get one thing clear: The so-called “Dark Ages” were not nearly as dark as they’re made out to be. For one thing, there’s a world beyond Western Europe. The Roman Empire didn’t collapse everywhere. But even in Western Europe, the centuries between the fall of Rome and the Renaissance were hardly lacking in cultural development.

Gleb Lucky/Unsplash

That said, we wouldn’t want to be in the position of the seventh-century noblewoman whose remains were recently uncovered in a Byzantine fortress in central Italy with multiple cross-shaped incisions in her skull. Yes, this unfortunate woman underwent at least two brain surgeries.

Then again, maybe not. Nothing like it had been discovered at the site, and while the markings – signs of a procedure called trepanation – can be surgical in nature, there are other explanations. For example, the Avar people practiced ritual trepanation during the same time period, but they were hundreds of miles away in the Carpathian mountains, and there was no evidence to support that a different form of ritualistic trepanation ever took place in Byzantine-era Italy.

The investigators then moved on to a form of judicial punishment called decalvatio, which involves mutilation by scalping. Look, the Dark Ages weren’t dark, but no one said they were fun. Anyway, this was discarded, since decalvatio was only meted out to soldiers who deserted the battlefield.

That brings us back to surgery. While one of the trepanations was fully engraved into her skull, indicating that the woman died soon after the surgery, she also bore indications of a healed trepanation. A 50% success rate isn’t terrible for our medieval surgeon. Sure, the Incas managed 80%, but even during the Civil War brain surgery only had a 50% success rate. And that’s the end of the story, nothing more to say about our medieval Italian woman.

Nope. Nothing at all.

Fine. While a surgical procedure was deemed most likely, the study investigators found no direct evidence of a medical condition. No trauma, no tumor, nothing. Just a couple of suggestions of “a systemic pathological condition,” they said. Okay, we swear, it really wasn’t that bad in the Middle [Editor’s note: Approximately 5,000 more words on medieval culture not included. This is a medical column, thank you very much.]

We’re gonna need a bigger meth lab

In case you’ve been living under a rock for the past 15 years, the TV show “Breaking Bad” details the spiraling rise and downfall of a high school chemistry teacher who, after developing a case of terminal lung cancer, starts producing methamphetamine to provide for his family in response to the steep cost of treatment for his cancer.

TheaDesign/Thinkstock

Meanwhile, here in 2023 in the real world, we have Paul Davis, a retired physician in Ohio, who’s being forced to choose between an expensive cancer treatment and bankrupting his family, since Medicare’s decided it doesn’t want to cover the cost. Hey, we’ve seen this one before!

A bit of backstory: In November 2019, Dr. Davis was diagnosed with uveal melanoma, a very rare type of cancer that affects eye tissue. The news got worse in 2022 when the cancer spread to his liver, a move which typically proves fatal within a year. However, in a stroke of great news, the Food and Drug Administration approved the drug Kimmtrak earlier that year, which could be used to treat his cancer. Not cure, of course, but it would give him more time.

His initial treatments with the drug went fine and were covered, but when he transferred his care from a hospital in Columbus to one closer to home, big problem. Medicare decided it didn’t like that hospital and abruptly cut off coverage, denying the local hospital’s claims. That leaves Dr. Davis on the hook for his cancer treatment, and it’s what you might call expensive. Expensive to the tune of $50,000.

A week.

Apparently the coding the local hospital submitted was wrong, indicating that Dr. Davis was receiving Kimmtrak for a type of cancer that the FDA hadn’t approved the drug for. So until the government bureaucracy works itself out, his treatment is on hold, leaving all his faith in Medicare working quickly to rectify its mistake. If it can rectify its mistake. We’re not hopeful.

And in case you were wondering, if Dr. Davis wanted to go full Walter White, the average street price of meth is about $20-$60 per gram, so to pay for his treatment, he’d need to make at least a kilogram of meth every week. That’s, uh, quite a lot of illegal drug, or what we here at the LOTME office would call a fun Saturday night.
 

When you give a mouse a movie

Researchers have been successfully testing Alzheimer drugs on mice for years, but none of the drugs has proved successful in humans. Recent work, however, might have found the missing link, and it’s a combination no one ever thought of before: mice and movies.

procesocreativo/PxHere

Turns out that Orson Welles’ 1958 film noir classic “Touch of Evil” tapped a part of the mouse brain that has been overlooked: the hippocampus, which is crucial for learning and memory. Previous researchers thought it was just used as a kind of GPS system, but that’s only partially true.

Not only did the mice choose to pay attention to the movie clip, but the hippocampus responded to the visual stimuli only when the rodents saw the scenes from the clip later in the order that they were presented and not in a scrambled order. These findings represent a “major paradigm shift” in studying mouse recall, Mayank Mehta, PhD, of the University of California, Los Angeles, said in a statement from the school.

This breakthrough could run parallel to Alzheimer’s patients struggling with similar defects. “Selective and episodic activation of the mouse hippocampus using a human movie opens up the possibility of directly testing human episodic memory disorders and therapies using mouse neurons, a major step forward,” said coauthor Chinmay Purandare, PhD, who is now at the University of California, San Francisco.

Who would have thought that a classic film would help advance Alzheimer research?
 

A less human way to study mosquitoes

We here at LOTME have a history with mosquitoes. We know they don’t like us, and they know that we don’t like them. Trust us, they know. So when humans gain a little ground in the war against the buzzy little bloodsuckers, we want to share the joy.

Wesson Group/Tulane University

To know the enemy, scientists have to study the enemy, but there is a problem. “Many mosquito experiments still rely on human volunteers and animal subjects,” bioengineering graduate student Kevin Janson, said in a statement from Rice University. Most people don’t like being bitten by mosquitoes, so that kind of testing can be expensive.

Is there a way to automate the collection and processing of mosquito behavior data using inexpensive cameras and machine-learning software? We’re glad you asked, because Mr. Janson and the research team, which includes bioengineers from Rice and tropical medicine experts from Tulane University, have managed to eliminate the need for live volunteers by using patches of synthetic skin made with a 3D printer.

“Each patch of gelatin-like hydrogel comes complete with tiny passageways that can be filled with flowing blood” from a chicken, sheep, or cow, they explained, and proof-of-concept testing showed that mosquitoes would feed on hydrogels without any repellent and stay away from those treated with a repellent.

To conduct the feeding tests, the blood-infused hydrogels are placed in a clear plastic box that is surrounded by cameras.

A bunch of mosquitoes are then tossed in the box and the cameras record all their insect activities: how often they land at each location, how long they stay, whether or not they bite, how long they feed, etc. Humans don’t have to watch and don’t have to be food sources.

Humans don’t have to be food sources, and we just pictured the future of mosquito control. Imagine a dozen Arnold Schwarzenegger–style Terminators, covered in 3D-printed skin, walking through your neighborhood in the summer while wearing sweat-soaked, brightly colored clothing. The mosquitoes wouldn’t be able to stay away, but guess what? They’re feeding off robots with nonhuman skin and nonhuman blood, so we win. It’s good to have a cerebral cortex.
 

Getting medieval on brain surgery

Let’s get one thing clear: The so-called “Dark Ages” were not nearly as dark as they’re made out to be. For one thing, there’s a world beyond Western Europe. The Roman Empire didn’t collapse everywhere. But even in Western Europe, the centuries between the fall of Rome and the Renaissance were hardly lacking in cultural development.

Gleb Lucky/Unsplash

That said, we wouldn’t want to be in the position of the seventh-century noblewoman whose remains were recently uncovered in a Byzantine fortress in central Italy with multiple cross-shaped incisions in her skull. Yes, this unfortunate woman underwent at least two brain surgeries.

Then again, maybe not. Nothing like it had been discovered at the site, and while the markings – signs of a procedure called trepanation – can be surgical in nature, there are other explanations. For example, the Avar people practiced ritual trepanation during the same time period, but they were hundreds of miles away in the Carpathian mountains, and there was no evidence to support that a different form of ritualistic trepanation ever took place in Byzantine-era Italy.

The investigators then moved on to a form of judicial punishment called decalvatio, which involves mutilation by scalping. Look, the Dark Ages weren’t dark, but no one said they were fun. Anyway, this was discarded, since decalvatio was only meted out to soldiers who deserted the battlefield.

That brings us back to surgery. While one of the trepanations was fully engraved into her skull, indicating that the woman died soon after the surgery, she also bore indications of a healed trepanation. A 50% success rate isn’t terrible for our medieval surgeon. Sure, the Incas managed 80%, but even during the Civil War brain surgery only had a 50% success rate. And that’s the end of the story, nothing more to say about our medieval Italian woman.

Nope. Nothing at all.

Fine. While a surgical procedure was deemed most likely, the study investigators found no direct evidence of a medical condition. No trauma, no tumor, nothing. Just a couple of suggestions of “a systemic pathological condition,” they said. Okay, we swear, it really wasn’t that bad in the Middle [Editor’s note: Approximately 5,000 more words on medieval culture not included. This is a medical column, thank you very much.]

We’re gonna need a bigger meth lab

In case you’ve been living under a rock for the past 15 years, the TV show “Breaking Bad” details the spiraling rise and downfall of a high school chemistry teacher who, after developing a case of terminal lung cancer, starts producing methamphetamine to provide for his family in response to the steep cost of treatment for his cancer.

TheaDesign/Thinkstock

Meanwhile, here in 2023 in the real world, we have Paul Davis, a retired physician in Ohio, who’s being forced to choose between an expensive cancer treatment and bankrupting his family, since Medicare’s decided it doesn’t want to cover the cost. Hey, we’ve seen this one before!

A bit of backstory: In November 2019, Dr. Davis was diagnosed with uveal melanoma, a very rare type of cancer that affects eye tissue. The news got worse in 2022 when the cancer spread to his liver, a move which typically proves fatal within a year. However, in a stroke of great news, the Food and Drug Administration approved the drug Kimmtrak earlier that year, which could be used to treat his cancer. Not cure, of course, but it would give him more time.

His initial treatments with the drug went fine and were covered, but when he transferred his care from a hospital in Columbus to one closer to home, big problem. Medicare decided it didn’t like that hospital and abruptly cut off coverage, denying the local hospital’s claims. That leaves Dr. Davis on the hook for his cancer treatment, and it’s what you might call expensive. Expensive to the tune of $50,000.

A week.

Apparently the coding the local hospital submitted was wrong, indicating that Dr. Davis was receiving Kimmtrak for a type of cancer that the FDA hadn’t approved the drug for. So until the government bureaucracy works itself out, his treatment is on hold, leaving all his faith in Medicare working quickly to rectify its mistake. If it can rectify its mistake. We’re not hopeful.

And in case you were wondering, if Dr. Davis wanted to go full Walter White, the average street price of meth is about $20-$60 per gram, so to pay for his treatment, he’d need to make at least a kilogram of meth every week. That’s, uh, quite a lot of illegal drug, or what we here at the LOTME office would call a fun Saturday night.
 

When you give a mouse a movie

Researchers have been successfully testing Alzheimer drugs on mice for years, but none of the drugs has proved successful in humans. Recent work, however, might have found the missing link, and it’s a combination no one ever thought of before: mice and movies.

procesocreativo/PxHere

Turns out that Orson Welles’ 1958 film noir classic “Touch of Evil” tapped a part of the mouse brain that has been overlooked: the hippocampus, which is crucial for learning and memory. Previous researchers thought it was just used as a kind of GPS system, but that’s only partially true.

Not only did the mice choose to pay attention to the movie clip, but the hippocampus responded to the visual stimuli only when the rodents saw the scenes from the clip later in the order that they were presented and not in a scrambled order. These findings represent a “major paradigm shift” in studying mouse recall, Mayank Mehta, PhD, of the University of California, Los Angeles, said in a statement from the school.

This breakthrough could run parallel to Alzheimer’s patients struggling with similar defects. “Selective and episodic activation of the mouse hippocampus using a human movie opens up the possibility of directly testing human episodic memory disorders and therapies using mouse neurons, a major step forward,” said coauthor Chinmay Purandare, PhD, who is now at the University of California, San Francisco.

Who would have thought that a classic film would help advance Alzheimer research?
 

A less human way to study mosquitoes

We here at LOTME have a history with mosquitoes. We know they don’t like us, and they know that we don’t like them. Trust us, they know. So when humans gain a little ground in the war against the buzzy little bloodsuckers, we want to share the joy.

Wesson Group/Tulane University

To know the enemy, scientists have to study the enemy, but there is a problem. “Many mosquito experiments still rely on human volunteers and animal subjects,” bioengineering graduate student Kevin Janson, said in a statement from Rice University. Most people don’t like being bitten by mosquitoes, so that kind of testing can be expensive.

Is there a way to automate the collection and processing of mosquito behavior data using inexpensive cameras and machine-learning software? We’re glad you asked, because Mr. Janson and the research team, which includes bioengineers from Rice and tropical medicine experts from Tulane University, have managed to eliminate the need for live volunteers by using patches of synthetic skin made with a 3D printer.

“Each patch of gelatin-like hydrogel comes complete with tiny passageways that can be filled with flowing blood” from a chicken, sheep, or cow, they explained, and proof-of-concept testing showed that mosquitoes would feed on hydrogels without any repellent and stay away from those treated with a repellent.

To conduct the feeding tests, the blood-infused hydrogels are placed in a clear plastic box that is surrounded by cameras.

A bunch of mosquitoes are then tossed in the box and the cameras record all their insect activities: how often they land at each location, how long they stay, whether or not they bite, how long they feed, etc. Humans don’t have to watch and don’t have to be food sources.

Humans don’t have to be food sources, and we just pictured the future of mosquito control. Imagine a dozen Arnold Schwarzenegger–style Terminators, covered in 3D-printed skin, walking through your neighborhood in the summer while wearing sweat-soaked, brightly colored clothing. The mosquitoes wouldn’t be able to stay away, but guess what? They’re feeding off robots with nonhuman skin and nonhuman blood, so we win. It’s good to have a cerebral cortex.
 

Getting medieval on brain surgery

Let’s get one thing clear: The so-called “Dark Ages” were not nearly as dark as they’re made out to be. For one thing, there’s a world beyond Western Europe. The Roman Empire didn’t collapse everywhere. But even in Western Europe, the centuries between the fall of Rome and the Renaissance were hardly lacking in cultural development.

Gleb Lucky/Unsplash

That said, we wouldn’t want to be in the position of the seventh-century noblewoman whose remains were recently uncovered in a Byzantine fortress in central Italy with multiple cross-shaped incisions in her skull. Yes, this unfortunate woman underwent at least two brain surgeries.

Then again, maybe not. Nothing like it had been discovered at the site, and while the markings – signs of a procedure called trepanation – can be surgical in nature, there are other explanations. For example, the Avar people practiced ritual trepanation during the same time period, but they were hundreds of miles away in the Carpathian mountains, and there was no evidence to support that a different form of ritualistic trepanation ever took place in Byzantine-era Italy.

The investigators then moved on to a form of judicial punishment called decalvatio, which involves mutilation by scalping. Look, the Dark Ages weren’t dark, but no one said they were fun. Anyway, this was discarded, since decalvatio was only meted out to soldiers who deserted the battlefield.

That brings us back to surgery. While one of the trepanations was fully engraved into her skull, indicating that the woman died soon after the surgery, she also bore indications of a healed trepanation. A 50% success rate isn’t terrible for our medieval surgeon. Sure, the Incas managed 80%, but even during the Civil War brain surgery only had a 50% success rate. And that’s the end of the story, nothing more to say about our medieval Italian woman.

Nope. Nothing at all.

Fine. While a surgical procedure was deemed most likely, the study investigators found no direct evidence of a medical condition. No trauma, no tumor, nothing. Just a couple of suggestions of “a systemic pathological condition,” they said. Okay, we swear, it really wasn’t that bad in the Middle [Editor’s note: Approximately 5,000 more words on medieval culture not included. This is a medical column, thank you very much.]

Dementia frequently coexists with hepatic encephalopathy (HE) in patients with cirrhosis but doesn’t correlate with other decompensating events, according to a new study involving U.S. veterans.

The overlap between dementia and HE was also independent of alcohol use, brain injury, age, and other metabolic risk factors.

“The aging of patients with cirrhosis leads us to encounter several individuals who may be prone to both of these diseases,” senior author Jasmohan Bajaj, MD, a professor of gastroenterology, hepatology, and nutrition at Virginia Commonwealth University Medical Center and GI section of the Central Virginia Veterans Healthcare System in Richmond, said in an interview.

“Given the epidemic of metabolic syndrome and alcohol, consider excluding cirrhosis in your patient [for] whom the presumptive diagnosis is dementia, since they could have concomitant HE,” he said.

“On the flip side, in those with HE who have predominant long-term memory issues and persistent cognitive changes, consider consulting a neuropsychiatrist or neurologist to ensure there is a resolution of the underlying disease process,” Dr. Bajaj added.

The study was published online in The American Journal of Gastroenterology.
 

Analyzing associations

HE is a common decompensating event in patients with cirrhosis. Because of the aging population of patients with cirrhosis, however, it’s important to differentiate HE from nonhepatic etiologies of cognitive impairment, such as dementia, the authors note.

Using data from the VA Corporate Data Warehouse, Dr. Bajaj and colleagues identified veterans with cirrhosis who received VA care between October 2019 and September 2021 and compared baseline characteristics between the cohorts based on the presence or absence of dementia. The research team then evaluated factors associated with having a diagnosis of dementia, adjusting for demographics, comorbid illnesses, cirrhosis etiology, and cirrhosis complications.

Investigators identified 71,522 veterans with diagnostic codes for cirrhosis who were engaged in VA care in 2019. They were mostly men (96.2%) and had a median age of 66. The most common etiologies of cirrhosis were alcohol and hepatitis C, followed by nonalcoholic steatohepatitis (NASH). The group also included veterans with predominantly compensated cirrhosis and a median MELD-Na score of 9. The MELD-Na score gauges the severity of chronic liver disease using values such as serum bilirubin, serum creatinine, and the international normalized ratio for prothrombin time and sodium to predict survival.

Among those with cirrhosis, 5,647 (7.9%) also had dementia diagnosis codes. This rate is higher than the prevalence of dementia in the general population and equivalent to the rate of dementia in veterans without cirrhosis who are older than 65, the authors note.

In general, veterans with dementia tended to be older, to be White, to live in an urban area, and to have higher MELD-Na scores, and they were more frequently diagnosed with alcohol-related cirrhosis, alcohol and tobacco use disorder, diabetes, chronic kidney disease, chronic heart failure, brain trauma, and cerebrovascular disease.

In a multivariable analysis, the presence of any decompensating event was significantly associated with dementia. In subsequent analyses of individual decompensating events, however, the strongest association was with HE, while ascites or variceal bleeding did not add to the risk.

When HE was defined as patients who filled prescriptions for lactulose or rifaximin, the frequency of patients with HE decreased from 13.7% to 10.9%. In an analysis with HE as the decompensating event, the association between HE and dementia remained significant compared to when HE was defined by diagnostic codes alone.

“We were surprised by the high proportion of patients with dementia who also had cirrhosis, and given the genuine difficulty that clinicians have with defining HE vs. dementia, we were not very surprised at that overlap,” Dr. Bajaj said.

“We were also surprised at the specificity of this overlap only with HE and not with other decompensating events, which was also independent of head injury, alcohol use, and PTSD,” he added.
 

Additional research needed

Future research should look at the characteristics of HE, including the number of episodes or breakthrough episodes, and should focus on objective biomarkers to differentiate dementia and HE, the study authors write.

“The distinction and study of potential overlapping features among HE and dementia is important because HE is often treatable with medications and reverses after liver transplant, while this does not occur with dementia,” they add.

Dr. Bajaj and colleagues call for a greater awareness of disease processes and complications in older patients with cirrhosis, particularly since diagnostic imprecision can lead to patient and family confusion, distrust, and ineffective treatment.

The study will help physicians better understand the important overlap between dementia and HE, said Eric Orman, MD, an associate professor of medicine at Indiana University, Indianapolis.

Dr. Orman, who wasn’t involved with this study, has researched recent trends in the characteristics and outcomes of patients with newly diagnosed cirrhosis and has found that the proportion of older adults has increased, as well as those with alcoholic cirrhosis and NASH, which has implications for future patient care.

“It is important to recognize that both dementia and HE can occur either separately or concurrently in individuals with cirrhosis,” Dr. Orman told this news organization. “When seeing patients with cognitive impairment, having a high index of suspicion for both conditions is critical to ensure appropriate diagnosis and treatment.”

The study’s findings “represent the tip of the iceberg,” Neal Parikh, MD, an assistant professor of neurology and neuroscience at Weill Cornell Medicine in New York, said in an interview. “There is a tremendous amount left to be discovered regarding the role of the liver in brain health.”

Dr. Parikh, who wasn’t associated with this study, has researched the impact of chronic liver conditions on cognitive impairment and dementia. He is working on a project that addresses HE in detail.

“There is growing recognition of a so-called ‘liver-brain axis,’ with several researchers, including my group, showing that a range of chronic liver conditions may detrimentally impact cognitive function and increase the risk of dementia,” he said. “Studying the specific contributions of cirrhosis is critical for understanding the role of hepatic encephalopathy in age-related cognitive decline.”

The study received no financial support. The authors reported no potential competing interests.

A version of this article first appeared on Medscape.com.

Dementia frequently coexists with hepatic encephalopathy (HE) in patients with cirrhosis but doesn’t correlate with other decompensating events, according to a new study involving U.S. veterans.

The overlap between dementia and HE was also independent of alcohol use, brain injury, age, and other metabolic risk factors.

“The aging of patients with cirrhosis leads us to encounter several individuals who may be prone to both of these diseases,” senior author Jasmohan Bajaj, MD, a professor of gastroenterology, hepatology, and nutrition at Virginia Commonwealth University Medical Center and GI section of the Central Virginia Veterans Healthcare System in Richmond, said in an interview.

“Given the epidemic of metabolic syndrome and alcohol, consider excluding cirrhosis in your patient [for] whom the presumptive diagnosis is dementia, since they could have concomitant HE,” he said.

“On the flip side, in those with HE who have predominant long-term memory issues and persistent cognitive changes, consider consulting a neuropsychiatrist or neurologist to ensure there is a resolution of the underlying disease process,” Dr. Bajaj added.

The study was published online in The American Journal of Gastroenterology.
 

Analyzing associations

HE is a common decompensating event in patients with cirrhosis. Because of the aging population of patients with cirrhosis, however, it’s important to differentiate HE from nonhepatic etiologies of cognitive impairment, such as dementia, the authors note.

Using data from the VA Corporate Data Warehouse, Dr. Bajaj and colleagues identified veterans with cirrhosis who received VA care between October 2019 and September 2021 and compared baseline characteristics between the cohorts based on the presence or absence of dementia. The research team then evaluated factors associated with having a diagnosis of dementia, adjusting for demographics, comorbid illnesses, cirrhosis etiology, and cirrhosis complications.

Investigators identified 71,522 veterans with diagnostic codes for cirrhosis who were engaged in VA care in 2019. They were mostly men (96.2%) and had a median age of 66. The most common etiologies of cirrhosis were alcohol and hepatitis C, followed by nonalcoholic steatohepatitis (NASH). The group also included veterans with predominantly compensated cirrhosis and a median MELD-Na score of 9. The MELD-Na score gauges the severity of chronic liver disease using values such as serum bilirubin, serum creatinine, and the international normalized ratio for prothrombin time and sodium to predict survival.

Among those with cirrhosis, 5,647 (7.9%) also had dementia diagnosis codes. This rate is higher than the prevalence of dementia in the general population and equivalent to the rate of dementia in veterans without cirrhosis who are older than 65, the authors note.

In general, veterans with dementia tended to be older, to be White, to live in an urban area, and to have higher MELD-Na scores, and they were more frequently diagnosed with alcohol-related cirrhosis, alcohol and tobacco use disorder, diabetes, chronic kidney disease, chronic heart failure, brain trauma, and cerebrovascular disease.

In a multivariable analysis, the presence of any decompensating event was significantly associated with dementia. In subsequent analyses of individual decompensating events, however, the strongest association was with HE, while ascites or variceal bleeding did not add to the risk.

When HE was defined as patients who filled prescriptions for lactulose or rifaximin, the frequency of patients with HE decreased from 13.7% to 10.9%. In an analysis with HE as the decompensating event, the association between HE and dementia remained significant compared to when HE was defined by diagnostic codes alone.

“We were surprised by the high proportion of patients with dementia who also had cirrhosis, and given the genuine difficulty that clinicians have with defining HE vs. dementia, we were not very surprised at that overlap,” Dr. Bajaj said.

“We were also surprised at the specificity of this overlap only with HE and not with other decompensating events, which was also independent of head injury, alcohol use, and PTSD,” he added.
 

Additional research needed

Future research should look at the characteristics of HE, including the number of episodes or breakthrough episodes, and should focus on objective biomarkers to differentiate dementia and HE, the study authors write.

“The distinction and study of potential overlapping features among HE and dementia is important because HE is often treatable with medications and reverses after liver transplant, while this does not occur with dementia,” they add.

Dr. Bajaj and colleagues call for a greater awareness of disease processes and complications in older patients with cirrhosis, particularly since diagnostic imprecision can lead to patient and family confusion, distrust, and ineffective treatment.

The study will help physicians better understand the important overlap between dementia and HE, said Eric Orman, MD, an associate professor of medicine at Indiana University, Indianapolis.

Dr. Orman, who wasn’t involved with this study, has researched recent trends in the characteristics and outcomes of patients with newly diagnosed cirrhosis and has found that the proportion of older adults has increased, as well as those with alcoholic cirrhosis and NASH, which has implications for future patient care.

“It is important to recognize that both dementia and HE can occur either separately or concurrently in individuals with cirrhosis,” Dr. Orman told this news organization. “When seeing patients with cognitive impairment, having a high index of suspicion for both conditions is critical to ensure appropriate diagnosis and treatment.”

The study’s findings “represent the tip of the iceberg,” Neal Parikh, MD, an assistant professor of neurology and neuroscience at Weill Cornell Medicine in New York, said in an interview. “There is a tremendous amount left to be discovered regarding the role of the liver in brain health.”

Dr. Parikh, who wasn’t associated with this study, has researched the impact of chronic liver conditions on cognitive impairment and dementia. He is working on a project that addresses HE in detail.

“There is growing recognition of a so-called ‘liver-brain axis,’ with several researchers, including my group, showing that a range of chronic liver conditions may detrimentally impact cognitive function and increase the risk of dementia,” he said. “Studying the specific contributions of cirrhosis is critical for understanding the role of hepatic encephalopathy in age-related cognitive decline.”

The study received no financial support. The authors reported no potential competing interests.

A version of this article first appeared on Medscape.com.

Dementia frequently coexists with hepatic encephalopathy (HE) in patients with cirrhosis but doesn’t correlate with other decompensating events, according to a new study involving U.S. veterans.

The overlap between dementia and HE was also independent of alcohol use, brain injury, age, and other metabolic risk factors.

“The aging of patients with cirrhosis leads us to encounter several individuals who may be prone to both of these diseases,” senior author Jasmohan Bajaj, MD, a professor of gastroenterology, hepatology, and nutrition at Virginia Commonwealth University Medical Center and GI section of the Central Virginia Veterans Healthcare System in Richmond, said in an interview.

“Given the epidemic of metabolic syndrome and alcohol, consider excluding cirrhosis in your patient [for] whom the presumptive diagnosis is dementia, since they could have concomitant HE,” he said.

“On the flip side, in those with HE who have predominant long-term memory issues and persistent cognitive changes, consider consulting a neuropsychiatrist or neurologist to ensure there is a resolution of the underlying disease process,” Dr. Bajaj added.

The study was published online in The American Journal of Gastroenterology.
 

Analyzing associations

HE is a common decompensating event in patients with cirrhosis. Because of the aging population of patients with cirrhosis, however, it’s important to differentiate HE from nonhepatic etiologies of cognitive impairment, such as dementia, the authors note.

Using data from the VA Corporate Data Warehouse, Dr. Bajaj and colleagues identified veterans with cirrhosis who received VA care between October 2019 and September 2021 and compared baseline characteristics between the cohorts based on the presence or absence of dementia. The research team then evaluated factors associated with having a diagnosis of dementia, adjusting for demographics, comorbid illnesses, cirrhosis etiology, and cirrhosis complications.

Investigators identified 71,522 veterans with diagnostic codes for cirrhosis who were engaged in VA care in 2019. They were mostly men (96.2%) and had a median age of 66. The most common etiologies of cirrhosis were alcohol and hepatitis C, followed by nonalcoholic steatohepatitis (NASH). The group also included veterans with predominantly compensated cirrhosis and a median MELD-Na score of 9. The MELD-Na score gauges the severity of chronic liver disease using values such as serum bilirubin, serum creatinine, and the international normalized ratio for prothrombin time and sodium to predict survival.

Among those with cirrhosis, 5,647 (7.9%) also had dementia diagnosis codes. This rate is higher than the prevalence of dementia in the general population and equivalent to the rate of dementia in veterans without cirrhosis who are older than 65, the authors note.

In general, veterans with dementia tended to be older, to be White, to live in an urban area, and to have higher MELD-Na scores, and they were more frequently diagnosed with alcohol-related cirrhosis, alcohol and tobacco use disorder, diabetes, chronic kidney disease, chronic heart failure, brain trauma, and cerebrovascular disease.

In a multivariable analysis, the presence of any decompensating event was significantly associated with dementia. In subsequent analyses of individual decompensating events, however, the strongest association was with HE, while ascites or variceal bleeding did not add to the risk.

When HE was defined as patients who filled prescriptions for lactulose or rifaximin, the frequency of patients with HE decreased from 13.7% to 10.9%. In an analysis with HE as the decompensating event, the association between HE and dementia remained significant compared to when HE was defined by diagnostic codes alone.

“We were surprised by the high proportion of patients with dementia who also had cirrhosis, and given the genuine difficulty that clinicians have with defining HE vs. dementia, we were not very surprised at that overlap,” Dr. Bajaj said.

“We were also surprised at the specificity of this overlap only with HE and not with other decompensating events, which was also independent of head injury, alcohol use, and PTSD,” he added.
 

Additional research needed

Future research should look at the characteristics of HE, including the number of episodes or breakthrough episodes, and should focus on objective biomarkers to differentiate dementia and HE, the study authors write.

“The distinction and study of potential overlapping features among HE and dementia is important because HE is often treatable with medications and reverses after liver transplant, while this does not occur with dementia,” they add.

Dr. Bajaj and colleagues call for a greater awareness of disease processes and complications in older patients with cirrhosis, particularly since diagnostic imprecision can lead to patient and family confusion, distrust, and ineffective treatment.

The study will help physicians better understand the important overlap between dementia and HE, said Eric Orman, MD, an associate professor of medicine at Indiana University, Indianapolis.

Dr. Orman, who wasn’t involved with this study, has researched recent trends in the characteristics and outcomes of patients with newly diagnosed cirrhosis and has found that the proportion of older adults has increased, as well as those with alcoholic cirrhosis and NASH, which has implications for future patient care.

“It is important to recognize that both dementia and HE can occur either separately or concurrently in individuals with cirrhosis,” Dr. Orman told this news organization. “When seeing patients with cognitive impairment, having a high index of suspicion for both conditions is critical to ensure appropriate diagnosis and treatment.”

The study’s findings “represent the tip of the iceberg,” Neal Parikh, MD, an assistant professor of neurology and neuroscience at Weill Cornell Medicine in New York, said in an interview. “There is a tremendous amount left to be discovered regarding the role of the liver in brain health.”

Dr. Parikh, who wasn’t associated with this study, has researched the impact of chronic liver conditions on cognitive impairment and dementia. He is working on a project that addresses HE in detail.

“There is growing recognition of a so-called ‘liver-brain axis,’ with several researchers, including my group, showing that a range of chronic liver conditions may detrimentally impact cognitive function and increase the risk of dementia,” he said. “Studying the specific contributions of cirrhosis is critical for understanding the role of hepatic encephalopathy in age-related cognitive decline.”

The study received no financial support. The authors reported no potential competing interests.

A version of this article first appeared on Medscape.com.