Alzheimer's & Cognition

Unexpected results from a phase 3 trial exploring the effect of multivitamins and cognition have now been published.

Findings from a phase 3 study show daily multivitamin use, but not cocoa, is linked to a significantly slower rate of age-related cognitive decline.

Originally presented last November at the 14th Clinical Trials on Alzheimer’s Disease (CTAD) conference, this is the first large-scale, long-term randomized controlled trial to examine the effects of cocoa extract and multivitamins on global cognition. The trial’s primary focus was on cocoa extract, which earlier studies suggest may preserve cognitive function. Analyzing the effect of multivitamins was a secondary outcome.

Showing vitamins, but not cocoa, were beneficial is the exact opposite of what researchers expected. Still, the results offer an interesting new direction for future study, lead investigator Laura D. Baker, PhD, professor of gerontology and geriatric medicine at Wake Forest University, Winston-Salem, N.C., said in an interview.

“This study made us take notice of a pathway for possible cognitive protection,” Dr. Baker said. “Without this study, we would never have looked down that road.”

The full results were published online in Alzheimer’s and Dementia.
 

Unexpected effect

The COSMOS-Mind study is a substudy to a larger parent trial called COSMOS. It investigated the effects of cocoa extract and a standard multivitamin-mineral on cardiovascular and cancer outcomes in more than 21,000 older participants.

In COSMOS-Mind, researchers tested whether daily intake of cocoa extract vs. placebo and a multivitamin-mineral vs. placebo improved cognition in older adults.

More than 2,200 participants aged 65 and older were enrolled and followed for 3 years. They completed tests over the telephone at baseline and annually to evaluate memory and other cognitive abilities.

Results showed cocoa extract had no effect on global cognition compared with placebo (mean z-score, 0.03; P = .28). Daily multivitamin use, however, did show significant benefits on global cognition vs. placebo (mean z, 0.07, P = .007).

The beneficial effect was most pronounced in participants with a history of cardiovascular disease (no history 0.06 vs. history 0.14; P = .01).

Researchers found similar protective effects for memory and executive function. 

Dr. Baker suggested one possible explanation for the positive effects of multivitamins may be the boost in micronutrients and essential minerals they provided.

“With nutrient-deficient diets plus a high prevalence of cardiovascular disease, diabetes, and other medical comorbidities that we know impact the bioavailability of these nutrients, we are possibly dealing with older adults who are at below optimum in terms of their essential micronutrients and minerals,” she said.

“Even suboptimum levels of micronutrients and essential minerals can have significant consequences for brain health,” she added.
 

More research needed

Intriguing as the results may be, more work is needed before the findings could affect nutritional guidance, according to Maria C. Carrillo, PhD, chief science officer for the Alzheimer’s Association.

“While the Alzheimer’s Association is encouraged by these results, we are not ready to recommend widespread use of a multivitamin supplement to reduce risk of cognitive decline in older adults,” Dr. Carrillo said in a statement.

“For now, and until there is more data, people should talk with their health care providers about the benefits and risks of all dietary supplements, including multivitamins,” she added.

Dr. Baker agreed, noting that the study was not designed to measure multivitamin use as a primary outcome. In addition, nearly 90% of the participants were non-Hispanic White, which is not representative of the overall population demographics.

The investigators are now designing another, larger trial that would include a more diverse participant pool. It will be aimed specifically at learning more about how and why multivitamins seem to offer a protective effect on cognition, Dr. Baker noted.

The study was funded by the National Institute on Aging of the National Institutes of Health. Dr. Baker and Dr. Carrillo report no relevant financial relationships.

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

Unexpected results from a phase 3 trial exploring the effect of multivitamins and cognition have now been published.

Findings from a phase 3 study show daily multivitamin use, but not cocoa, is linked to a significantly slower rate of age-related cognitive decline.

Originally presented last November at the 14th Clinical Trials on Alzheimer’s Disease (CTAD) conference, this is the first large-scale, long-term randomized controlled trial to examine the effects of cocoa extract and multivitamins on global cognition. The trial’s primary focus was on cocoa extract, which earlier studies suggest may preserve cognitive function. Analyzing the effect of multivitamins was a secondary outcome.

Showing vitamins, but not cocoa, were beneficial is the exact opposite of what researchers expected. Still, the results offer an interesting new direction for future study, lead investigator Laura D. Baker, PhD, professor of gerontology and geriatric medicine at Wake Forest University, Winston-Salem, N.C., said in an interview.

“This study made us take notice of a pathway for possible cognitive protection,” Dr. Baker said. “Without this study, we would never have looked down that road.”

The full results were published online in Alzheimer’s and Dementia.
 

Unexpected effect

The COSMOS-Mind study is a substudy to a larger parent trial called COSMOS. It investigated the effects of cocoa extract and a standard multivitamin-mineral on cardiovascular and cancer outcomes in more than 21,000 older participants.

In COSMOS-Mind, researchers tested whether daily intake of cocoa extract vs. placebo and a multivitamin-mineral vs. placebo improved cognition in older adults.

More than 2,200 participants aged 65 and older were enrolled and followed for 3 years. They completed tests over the telephone at baseline and annually to evaluate memory and other cognitive abilities.

Results showed cocoa extract had no effect on global cognition compared with placebo (mean z-score, 0.03; P = .28). Daily multivitamin use, however, did show significant benefits on global cognition vs. placebo (mean z, 0.07, P = .007).

The beneficial effect was most pronounced in participants with a history of cardiovascular disease (no history 0.06 vs. history 0.14; P = .01).

Researchers found similar protective effects for memory and executive function. 

Dr. Baker suggested one possible explanation for the positive effects of multivitamins may be the boost in micronutrients and essential minerals they provided.

“With nutrient-deficient diets plus a high prevalence of cardiovascular disease, diabetes, and other medical comorbidities that we know impact the bioavailability of these nutrients, we are possibly dealing with older adults who are at below optimum in terms of their essential micronutrients and minerals,” she said.

“Even suboptimum levels of micronutrients and essential minerals can have significant consequences for brain health,” she added.
 

More research needed

Intriguing as the results may be, more work is needed before the findings could affect nutritional guidance, according to Maria C. Carrillo, PhD, chief science officer for the Alzheimer’s Association.

“While the Alzheimer’s Association is encouraged by these results, we are not ready to recommend widespread use of a multivitamin supplement to reduce risk of cognitive decline in older adults,” Dr. Carrillo said in a statement.

“For now, and until there is more data, people should talk with their health care providers about the benefits and risks of all dietary supplements, including multivitamins,” she added.

Dr. Baker agreed, noting that the study was not designed to measure multivitamin use as a primary outcome. In addition, nearly 90% of the participants were non-Hispanic White, which is not representative of the overall population demographics.

The investigators are now designing another, larger trial that would include a more diverse participant pool. It will be aimed specifically at learning more about how and why multivitamins seem to offer a protective effect on cognition, Dr. Baker noted.

The study was funded by the National Institute on Aging of the National Institutes of Health. Dr. Baker and Dr. Carrillo report no relevant financial relationships.

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

Unexpected results from a phase 3 trial exploring the effect of multivitamins and cognition have now been published.

Findings from a phase 3 study show daily multivitamin use, but not cocoa, is linked to a significantly slower rate of age-related cognitive decline.

Originally presented last November at the 14th Clinical Trials on Alzheimer’s Disease (CTAD) conference, this is the first large-scale, long-term randomized controlled trial to examine the effects of cocoa extract and multivitamins on global cognition. The trial’s primary focus was on cocoa extract, which earlier studies suggest may preserve cognitive function. Analyzing the effect of multivitamins was a secondary outcome.

Showing vitamins, but not cocoa, were beneficial is the exact opposite of what researchers expected. Still, the results offer an interesting new direction for future study, lead investigator Laura D. Baker, PhD, professor of gerontology and geriatric medicine at Wake Forest University, Winston-Salem, N.C., said in an interview.

“This study made us take notice of a pathway for possible cognitive protection,” Dr. Baker said. “Without this study, we would never have looked down that road.”

The full results were published online in Alzheimer’s and Dementia.
 

Unexpected effect

The COSMOS-Mind study is a substudy to a larger parent trial called COSMOS. It investigated the effects of cocoa extract and a standard multivitamin-mineral on cardiovascular and cancer outcomes in more than 21,000 older participants.

In COSMOS-Mind, researchers tested whether daily intake of cocoa extract vs. placebo and a multivitamin-mineral vs. placebo improved cognition in older adults.

More than 2,200 participants aged 65 and older were enrolled and followed for 3 years. They completed tests over the telephone at baseline and annually to evaluate memory and other cognitive abilities.

Results showed cocoa extract had no effect on global cognition compared with placebo (mean z-score, 0.03; P = .28). Daily multivitamin use, however, did show significant benefits on global cognition vs. placebo (mean z, 0.07, P = .007).

The beneficial effect was most pronounced in participants with a history of cardiovascular disease (no history 0.06 vs. history 0.14; P = .01).

Researchers found similar protective effects for memory and executive function. 

Dr. Baker suggested one possible explanation for the positive effects of multivitamins may be the boost in micronutrients and essential minerals they provided.

“With nutrient-deficient diets plus a high prevalence of cardiovascular disease, diabetes, and other medical comorbidities that we know impact the bioavailability of these nutrients, we are possibly dealing with older adults who are at below optimum in terms of their essential micronutrients and minerals,” she said.

“Even suboptimum levels of micronutrients and essential minerals can have significant consequences for brain health,” she added.
 

More research needed

Intriguing as the results may be, more work is needed before the findings could affect nutritional guidance, according to Maria C. Carrillo, PhD, chief science officer for the Alzheimer’s Association.

“While the Alzheimer’s Association is encouraged by these results, we are not ready to recommend widespread use of a multivitamin supplement to reduce risk of cognitive decline in older adults,” Dr. Carrillo said in a statement.

“For now, and until there is more data, people should talk with their health care providers about the benefits and risks of all dietary supplements, including multivitamins,” she added.

Dr. Baker agreed, noting that the study was not designed to measure multivitamin use as a primary outcome. In addition, nearly 90% of the participants were non-Hispanic White, which is not representative of the overall population demographics.

The investigators are now designing another, larger trial that would include a more diverse participant pool. It will be aimed specifically at learning more about how and why multivitamins seem to offer a protective effect on cognition, Dr. Baker noted.

The study was funded by the National Institute on Aging of the National Institutes of Health. Dr. Baker and Dr. Carrillo report no relevant financial relationships.

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

BARCELONA – Treatment of patients with chronic heart failure with sacubitril/valsartan (Entresto), a mainstay agent for people with this disorder, produced no hint of incremental adverse cognitive effects during 3 years of treatment in a prospective, controlled, multicenter study with nearly 600 patients, although some experts note that possible adverse cognitive effects of sacubitril were not an issue for many heart failure clinicians, even before the study ran.

The potential for an adverse effect of sacubitril on cognition had arisen as a hypothetical concern because sacubitril inhibits the human enzyme neprilysin. This activity results in beneficial effects for patients with heart failure by increasing levels of several endogenous vasoactive peptides. But neprilysin also degrades amyloid beta peptides and so inhibition of this enzyme could possibly result in accumulation of amyloid peptides in the brain with potential neurotoxic effects, which raised concern among some cardiologists and patients that sacubitril/valsartan could hasten cognitive decline.

Catherine Hackett/MDedge News

Results from the new study, PERSPECTIVE, showed “no evidence that neprilysin inhibition increased the risk of cognitive impairment due to the accumulation of beta amyloid” in patients with heart failure with either mid-range or preserved ejection fraction,” John McMurray, MD, said at the annual congress of the European Society of Cardiology.

Dr. McMurray, professor of medical cardiology at the University of Glasgow, highlighted that the study enrolled only patients with heart failure with a left ventricular ejection fraction of greater than 40% because the study designers considered it “unethical” to withhold treatment with sacubitril/valsartan from patients with an ejection fraction of 40% or less (heart failure with reduced ejection fraction, HFrEF), whereas “no mandate” exists in current treatment guidelines for using sacubitril/valsartan in patients with heart failure and higher ejection fractions. He added that he could see no reason why the results seen in patients with higher ejection fractions would not also apply to those with HFrEF.
 

Reassuring results, but cost still a drag on uptake

“This was a well-designed trial” with results that are “very reassuring” for a lack of harm from sacubitril/valsartan, commented Biykem Bozkurt, MD, PhD, the study’s designated discussant and professor of medicine at Baylor College of Medicine, Houston. The findings “solidify the lack of risk and are very exciting for the heart failure community because the question has bothered a large number of people, especially older patients” with heart failure.

Catherine Hackett/MDedge News

Following these results, “hopefully more patients with heart failure will receive” sacubitril/valsartan, agreed Dr. McMurray, but he added the caveat that the relatively high cost of the agent (which has a U.S. list price of roughly $6,000/year) has been the primary barrier to wider uptake of the drug for patients with heart failure. Treatment with sacubitril/valsartan is recommended in several society guidelines as a core intervention for patients with HFrEF and as a treatment option for patients with heart failure and higher ejection fractions.

“Cost remains the single biggest deterrent for use” of sacubitril/valsartan, agreed Dipti N. Itchhaporia, MD, director of disease management at the Hoag Heart and Vascular Institute in Newport Beach, Calif. “Concerns about cognitive impairment has not been why people have not been using sacubitril/valsartan,” Dr. Itchhaporia commented in an interview.

PERSPECTIVE enrolled patients with heart failure with an ejection fraction greater than 40% and at least 60 years old at any of 137 sites in 20 countries, with about a third of enrolled patients coming from U.S. centers. The study, which ran enrollment during January 2017–May 2019, excluded people with clinically discernible cognitive impairment at the time of entry.

Researchers randomized patients to either a standard regimen of sacubitril/valsartan (295) or valsartan (297) on top of their background treatment, with most patients also receiving a beta-blocker, a diuretic, and a statin. The enrolled patients averaged about 72 years of age, and more than one-third were at least 75 years old.

The study’s primary endpoint was the performance of these patients in seven different tests of cognitive function using a proprietary metric, the CogState Global Cognitive Composite Score, measured at baseline and then every 6 months during follow-up designed to run for 3 years on treatment (the researchers collected data for at least 30 months of follow-up from 71%-73% of enrolled patients). Average changes in these scores over time tracked nearly the same in both treatment arms and met the study’s prespecified criteria for noninferiority of the sacubitril valsartan treatment, Dr. McMurray reported. The results also showed that roughly 60% of patients in both arms had “some degree of cognitive impairment” during follow-up.

A secondary outcome measure used PET imaging to quantify cerebral accumulation of beta amyloid, and again the results met the study’s prespecified threshold for noninferiority for the patients treated with sacubitril/valsartan, said Dr. McMurray.

Another concern raised by some experts was the relatively brief follow-up of 3 years, and the complexity of heart failure patients who could face several other causes of cognitive decline. The findings “help reassure, but 3 years is not long enough, and I’m not sure the study eliminated all the other possible variables,” commented Dr. Itchhaporia.

But Dr. McMurray contended that 3 years represents robust follow-up in patients with heart failure who notoriously have limited life expectancy following their diagnosis. “Three years is a long time for patients with heart failure.”

The findings also raise the prospect of developing sacubitril/valsartan as an antihypertensive treatment, an indication that has been avoided until now because of the uncertain cognitive effects of the agent and the need for prolonged use when the treated disorder is hypertension instead of heart failure.

PERSPECTIVE was funded by Novartis, the company that markets sacubitril/valsartan (Entresto). Dr. McMurray has received consulting and lecture fees from Novartis and he and his institution have received research funding from Novartis. Dr. Bozkurt has been a consultant to numerous companies but has no relationship with Novartis. Dr. Itchhaporia had no disclosures.

BARCELONA – Treatment of patients with chronic heart failure with sacubitril/valsartan (Entresto), a mainstay agent for people with this disorder, produced no hint of incremental adverse cognitive effects during 3 years of treatment in a prospective, controlled, multicenter study with nearly 600 patients, although some experts note that possible adverse cognitive effects of sacubitril were not an issue for many heart failure clinicians, even before the study ran.

The potential for an adverse effect of sacubitril on cognition had arisen as a hypothetical concern because sacubitril inhibits the human enzyme neprilysin. This activity results in beneficial effects for patients with heart failure by increasing levels of several endogenous vasoactive peptides. But neprilysin also degrades amyloid beta peptides and so inhibition of this enzyme could possibly result in accumulation of amyloid peptides in the brain with potential neurotoxic effects, which raised concern among some cardiologists and patients that sacubitril/valsartan could hasten cognitive decline.

Catherine Hackett/MDedge News

Results from the new study, PERSPECTIVE, showed “no evidence that neprilysin inhibition increased the risk of cognitive impairment due to the accumulation of beta amyloid” in patients with heart failure with either mid-range or preserved ejection fraction,” John McMurray, MD, said at the annual congress of the European Society of Cardiology.

Dr. McMurray, professor of medical cardiology at the University of Glasgow, highlighted that the study enrolled only patients with heart failure with a left ventricular ejection fraction of greater than 40% because the study designers considered it “unethical” to withhold treatment with sacubitril/valsartan from patients with an ejection fraction of 40% or less (heart failure with reduced ejection fraction, HFrEF), whereas “no mandate” exists in current treatment guidelines for using sacubitril/valsartan in patients with heart failure and higher ejection fractions. He added that he could see no reason why the results seen in patients with higher ejection fractions would not also apply to those with HFrEF.
 

Reassuring results, but cost still a drag on uptake

“This was a well-designed trial” with results that are “very reassuring” for a lack of harm from sacubitril/valsartan, commented Biykem Bozkurt, MD, PhD, the study’s designated discussant and professor of medicine at Baylor College of Medicine, Houston. The findings “solidify the lack of risk and are very exciting for the heart failure community because the question has bothered a large number of people, especially older patients” with heart failure.

Catherine Hackett/MDedge News

Following these results, “hopefully more patients with heart failure will receive” sacubitril/valsartan, agreed Dr. McMurray, but he added the caveat that the relatively high cost of the agent (which has a U.S. list price of roughly $6,000/year) has been the primary barrier to wider uptake of the drug for patients with heart failure. Treatment with sacubitril/valsartan is recommended in several society guidelines as a core intervention for patients with HFrEF and as a treatment option for patients with heart failure and higher ejection fractions.

“Cost remains the single biggest deterrent for use” of sacubitril/valsartan, agreed Dipti N. Itchhaporia, MD, director of disease management at the Hoag Heart and Vascular Institute in Newport Beach, Calif. “Concerns about cognitive impairment has not been why people have not been using sacubitril/valsartan,” Dr. Itchhaporia commented in an interview.

PERSPECTIVE enrolled patients with heart failure with an ejection fraction greater than 40% and at least 60 years old at any of 137 sites in 20 countries, with about a third of enrolled patients coming from U.S. centers. The study, which ran enrollment during January 2017–May 2019, excluded people with clinically discernible cognitive impairment at the time of entry.

Researchers randomized patients to either a standard regimen of sacubitril/valsartan (295) or valsartan (297) on top of their background treatment, with most patients also receiving a beta-blocker, a diuretic, and a statin. The enrolled patients averaged about 72 years of age, and more than one-third were at least 75 years old.

The study’s primary endpoint was the performance of these patients in seven different tests of cognitive function using a proprietary metric, the CogState Global Cognitive Composite Score, measured at baseline and then every 6 months during follow-up designed to run for 3 years on treatment (the researchers collected data for at least 30 months of follow-up from 71%-73% of enrolled patients). Average changes in these scores over time tracked nearly the same in both treatment arms and met the study’s prespecified criteria for noninferiority of the sacubitril valsartan treatment, Dr. McMurray reported. The results also showed that roughly 60% of patients in both arms had “some degree of cognitive impairment” during follow-up.

A secondary outcome measure used PET imaging to quantify cerebral accumulation of beta amyloid, and again the results met the study’s prespecified threshold for noninferiority for the patients treated with sacubitril/valsartan, said Dr. McMurray.

Another concern raised by some experts was the relatively brief follow-up of 3 years, and the complexity of heart failure patients who could face several other causes of cognitive decline. The findings “help reassure, but 3 years is not long enough, and I’m not sure the study eliminated all the other possible variables,” commented Dr. Itchhaporia.

But Dr. McMurray contended that 3 years represents robust follow-up in patients with heart failure who notoriously have limited life expectancy following their diagnosis. “Three years is a long time for patients with heart failure.”

The findings also raise the prospect of developing sacubitril/valsartan as an antihypertensive treatment, an indication that has been avoided until now because of the uncertain cognitive effects of the agent and the need for prolonged use when the treated disorder is hypertension instead of heart failure.

PERSPECTIVE was funded by Novartis, the company that markets sacubitril/valsartan (Entresto). Dr. McMurray has received consulting and lecture fees from Novartis and he and his institution have received research funding from Novartis. Dr. Bozkurt has been a consultant to numerous companies but has no relationship with Novartis. Dr. Itchhaporia had no disclosures.

BARCELONA – Treatment of patients with chronic heart failure with sacubitril/valsartan (Entresto), a mainstay agent for people with this disorder, produced no hint of incremental adverse cognitive effects during 3 years of treatment in a prospective, controlled, multicenter study with nearly 600 patients, although some experts note that possible adverse cognitive effects of sacubitril were not an issue for many heart failure clinicians, even before the study ran.

The potential for an adverse effect of sacubitril on cognition had arisen as a hypothetical concern because sacubitril inhibits the human enzyme neprilysin. This activity results in beneficial effects for patients with heart failure by increasing levels of several endogenous vasoactive peptides. But neprilysin also degrades amyloid beta peptides and so inhibition of this enzyme could possibly result in accumulation of amyloid peptides in the brain with potential neurotoxic effects, which raised concern among some cardiologists and patients that sacubitril/valsartan could hasten cognitive decline.

Catherine Hackett/MDedge News

Results from the new study, PERSPECTIVE, showed “no evidence that neprilysin inhibition increased the risk of cognitive impairment due to the accumulation of beta amyloid” in patients with heart failure with either mid-range or preserved ejection fraction,” John McMurray, MD, said at the annual congress of the European Society of Cardiology.

Dr. McMurray, professor of medical cardiology at the University of Glasgow, highlighted that the study enrolled only patients with heart failure with a left ventricular ejection fraction of greater than 40% because the study designers considered it “unethical” to withhold treatment with sacubitril/valsartan from patients with an ejection fraction of 40% or less (heart failure with reduced ejection fraction, HFrEF), whereas “no mandate” exists in current treatment guidelines for using sacubitril/valsartan in patients with heart failure and higher ejection fractions. He added that he could see no reason why the results seen in patients with higher ejection fractions would not also apply to those with HFrEF.
 

Reassuring results, but cost still a drag on uptake

“This was a well-designed trial” with results that are “very reassuring” for a lack of harm from sacubitril/valsartan, commented Biykem Bozkurt, MD, PhD, the study’s designated discussant and professor of medicine at Baylor College of Medicine, Houston. The findings “solidify the lack of risk and are very exciting for the heart failure community because the question has bothered a large number of people, especially older patients” with heart failure.

Catherine Hackett/MDedge News

Following these results, “hopefully more patients with heart failure will receive” sacubitril/valsartan, agreed Dr. McMurray, but he added the caveat that the relatively high cost of the agent (which has a U.S. list price of roughly $6,000/year) has been the primary barrier to wider uptake of the drug for patients with heart failure. Treatment with sacubitril/valsartan is recommended in several society guidelines as a core intervention for patients with HFrEF and as a treatment option for patients with heart failure and higher ejection fractions.

“Cost remains the single biggest deterrent for use” of sacubitril/valsartan, agreed Dipti N. Itchhaporia, MD, director of disease management at the Hoag Heart and Vascular Institute in Newport Beach, Calif. “Concerns about cognitive impairment has not been why people have not been using sacubitril/valsartan,” Dr. Itchhaporia commented in an interview.

PERSPECTIVE enrolled patients with heart failure with an ejection fraction greater than 40% and at least 60 years old at any of 137 sites in 20 countries, with about a third of enrolled patients coming from U.S. centers. The study, which ran enrollment during January 2017–May 2019, excluded people with clinically discernible cognitive impairment at the time of entry.

Researchers randomized patients to either a standard regimen of sacubitril/valsartan (295) or valsartan (297) on top of their background treatment, with most patients also receiving a beta-blocker, a diuretic, and a statin. The enrolled patients averaged about 72 years of age, and more than one-third were at least 75 years old.

The study’s primary endpoint was the performance of these patients in seven different tests of cognitive function using a proprietary metric, the CogState Global Cognitive Composite Score, measured at baseline and then every 6 months during follow-up designed to run for 3 years on treatment (the researchers collected data for at least 30 months of follow-up from 71%-73% of enrolled patients). Average changes in these scores over time tracked nearly the same in both treatment arms and met the study’s prespecified criteria for noninferiority of the sacubitril valsartan treatment, Dr. McMurray reported. The results also showed that roughly 60% of patients in both arms had “some degree of cognitive impairment” during follow-up.

A secondary outcome measure used PET imaging to quantify cerebral accumulation of beta amyloid, and again the results met the study’s prespecified threshold for noninferiority for the patients treated with sacubitril/valsartan, said Dr. McMurray.

Another concern raised by some experts was the relatively brief follow-up of 3 years, and the complexity of heart failure patients who could face several other causes of cognitive decline. The findings “help reassure, but 3 years is not long enough, and I’m not sure the study eliminated all the other possible variables,” commented Dr. Itchhaporia.

But Dr. McMurray contended that 3 years represents robust follow-up in patients with heart failure who notoriously have limited life expectancy following their diagnosis. “Three years is a long time for patients with heart failure.”

The findings also raise the prospect of developing sacubitril/valsartan as an antihypertensive treatment, an indication that has been avoided until now because of the uncertain cognitive effects of the agent and the need for prolonged use when the treated disorder is hypertension instead of heart failure.

PERSPECTIVE was funded by Novartis, the company that markets sacubitril/valsartan (Entresto). Dr. McMurray has received consulting and lecture fees from Novartis and he and his institution have received research funding from Novartis. Dr. Bozkurt has been a consultant to numerous companies but has no relationship with Novartis. Dr. Itchhaporia had no disclosures.

Watching TV may increase your risk of dementia, while using a computer may lower it, new research suggests.

The relationship to dementia with these activities remained strong no matter how much physical activity a person did, the authors wrote in Proceedings of the National Academy of Sciences.

Both watching TV and using a computer have been linked to increased risk of chronic disease and mortality, while exercise and physical activity (PA) have shown benefit in reducing cognitive decline, structural brain atrophy, and dementia risk in older adults, the authors wrote.

The authors said they wanted to try to understand the effects of watching TV and using computers on dementia risk, because people in the United States and Europe have been engaging in both of these activities more often.

They concluded that it’s not the sitting part of sedentary behavior (SB) that potentially has the effect on dementia but what people are doing while sitting.

Some of the results were surprising, lead author David Raichlen, PhD, professor of Human and Evolutionary Biology at University of Southern California, Los Angeles, said in an interview.

Previous literature on sedentary behaviors have documented their negative effects on a wide range of health outcomes, rather than finding positive associations, he explained.
 

More than 140,000 included in study

The researchers conducted their prospective cohort study using data from the United Kingdom Biobank. After excluding people younger than 60, those with prevalent dementia at the start of follow-up, and those without complete data, 146,651 participants were included.

The participants were followed from their baseline visit until they received a dementia diagnosis, died, were lost to follow-up, or were last admitted to the hospital.

TV-watching time was linked with an increased risk of incident dementia (HR [95% confidence interval] = 1.31 [1.23-1.40]), and computer use was linked with a reduced risk of incident dementia HR [95% CI] = 0.80 [0.76-0.85]).

TV’s link with higher dementia risk increased in those who had the highest use, compared with those who had the lowest use (HR [95% CI] = 1.28 [1.18-1.39].

Similarly, the link with risk reduction for dementia with computer use increased with more use.

Both medium and high computer time were associated with reduced risk of incident dementia (HR [95% CI] = 0.70 [0.64-0.76] and HR [95% CI] = 0.76 [0.70-0.83] respectively).

Dr. Raichlen pointed out that the high use of TV in this study was 4 or more hours a day and computer use – which included leisure use, not work use – had benefits on dementia risk after just half an hour.

These results remained significant after researchers adjusted for demographic, health, and lifestyle variables, including time spent on physical activity, sleeping, obesity, alcohol consumption, smoking status, diet scores, education level, body mass index, and employment type.
 

Physical is still better than sedentary activity

One potential reason for the different effects on dementia risk in the two activities studied, the authors write, is that sitting down to watch TV is associated with “uniquely low levels of muscle activity and energy expenditure, compared with sitting to use a computer.”

Andrew Budson, MD, chief of Cognitive & Behavioral Neurology and Associate Chief of Staff for Education for the VA Boston Healthcare System, Mass., who was not part of the study, said he thinks a more likely explanation for the study findings lies in the active versus passive tasks required in the two kinds of viewing that the authors reference.

“When we’re doing cognitive activity involving using the computer, we’re using large parts of our cortex to carry out that activity, whereas when we’re watching TV, there are probably relatively small amounts of our brain that are actually active,” Dr. Budson, author of Seven Steps to Managing Your Memory, explained in an interview.

“This is one of the first times I’ve been convinced that even when the computer activity isn’t completely new and novel, it may be beneficial,” Dr. Budson said.

It would be much better to do physical activity, but if the choice is sedentary activity, active cognitive activities, such as computer use, are better than TV watching, he continued.

The results of the current study are consistent with previous work showing that the type of sedentary behavior matters, according to the authors.

“Several studies have shown that TV time is associated with mortality and poor cardiometabolic biomarkers, whereas computer time is not,” they wrote.

A limitation of the study is that sedentary behaviors were self-reported via questionnaires, and there may be errors in recall.

“The use of objective methods for measuring both SB and PA are needed in future studies,” they write.

The authors receive support from the National Institutes of Health, the State of Arizona, the Arizona Department of Health Services, and the McKnight Brain Research Foundation. Neither the authors nor Dr. Budson declared relevant financial relationships.

Watching TV may increase your risk of dementia, while using a computer may lower it, new research suggests.

The relationship to dementia with these activities remained strong no matter how much physical activity a person did, the authors wrote in Proceedings of the National Academy of Sciences.

Both watching TV and using a computer have been linked to increased risk of chronic disease and mortality, while exercise and physical activity (PA) have shown benefit in reducing cognitive decline, structural brain atrophy, and dementia risk in older adults, the authors wrote.

The authors said they wanted to try to understand the effects of watching TV and using computers on dementia risk, because people in the United States and Europe have been engaging in both of these activities more often.

They concluded that it’s not the sitting part of sedentary behavior (SB) that potentially has the effect on dementia but what people are doing while sitting.

Some of the results were surprising, lead author David Raichlen, PhD, professor of Human and Evolutionary Biology at University of Southern California, Los Angeles, said in an interview.

Previous literature on sedentary behaviors have documented their negative effects on a wide range of health outcomes, rather than finding positive associations, he explained.
 

More than 140,000 included in study

The researchers conducted their prospective cohort study using data from the United Kingdom Biobank. After excluding people younger than 60, those with prevalent dementia at the start of follow-up, and those without complete data, 146,651 participants were included.

The participants were followed from their baseline visit until they received a dementia diagnosis, died, were lost to follow-up, or were last admitted to the hospital.

TV-watching time was linked with an increased risk of incident dementia (HR [95% confidence interval] = 1.31 [1.23-1.40]), and computer use was linked with a reduced risk of incident dementia HR [95% CI] = 0.80 [0.76-0.85]).

TV’s link with higher dementia risk increased in those who had the highest use, compared with those who had the lowest use (HR [95% CI] = 1.28 [1.18-1.39].

Similarly, the link with risk reduction for dementia with computer use increased with more use.

Both medium and high computer time were associated with reduced risk of incident dementia (HR [95% CI] = 0.70 [0.64-0.76] and HR [95% CI] = 0.76 [0.70-0.83] respectively).

Dr. Raichlen pointed out that the high use of TV in this study was 4 or more hours a day and computer use – which included leisure use, not work use – had benefits on dementia risk after just half an hour.

These results remained significant after researchers adjusted for demographic, health, and lifestyle variables, including time spent on physical activity, sleeping, obesity, alcohol consumption, smoking status, diet scores, education level, body mass index, and employment type.
 

Physical is still better than sedentary activity

One potential reason for the different effects on dementia risk in the two activities studied, the authors write, is that sitting down to watch TV is associated with “uniquely low levels of muscle activity and energy expenditure, compared with sitting to use a computer.”

Andrew Budson, MD, chief of Cognitive & Behavioral Neurology and Associate Chief of Staff for Education for the VA Boston Healthcare System, Mass., who was not part of the study, said he thinks a more likely explanation for the study findings lies in the active versus passive tasks required in the two kinds of viewing that the authors reference.

“When we’re doing cognitive activity involving using the computer, we’re using large parts of our cortex to carry out that activity, whereas when we’re watching TV, there are probably relatively small amounts of our brain that are actually active,” Dr. Budson, author of Seven Steps to Managing Your Memory, explained in an interview.

“This is one of the first times I’ve been convinced that even when the computer activity isn’t completely new and novel, it may be beneficial,” Dr. Budson said.

It would be much better to do physical activity, but if the choice is sedentary activity, active cognitive activities, such as computer use, are better than TV watching, he continued.

The results of the current study are consistent with previous work showing that the type of sedentary behavior matters, according to the authors.

“Several studies have shown that TV time is associated with mortality and poor cardiometabolic biomarkers, whereas computer time is not,” they wrote.

A limitation of the study is that sedentary behaviors were self-reported via questionnaires, and there may be errors in recall.

“The use of objective methods for measuring both SB and PA are needed in future studies,” they write.

The authors receive support from the National Institutes of Health, the State of Arizona, the Arizona Department of Health Services, and the McKnight Brain Research Foundation. Neither the authors nor Dr. Budson declared relevant financial relationships.

Watching TV may increase your risk of dementia, while using a computer may lower it, new research suggests.

The relationship to dementia with these activities remained strong no matter how much physical activity a person did, the authors wrote in Proceedings of the National Academy of Sciences.

Both watching TV and using a computer have been linked to increased risk of chronic disease and mortality, while exercise and physical activity (PA) have shown benefit in reducing cognitive decline, structural brain atrophy, and dementia risk in older adults, the authors wrote.

The authors said they wanted to try to understand the effects of watching TV and using computers on dementia risk, because people in the United States and Europe have been engaging in both of these activities more often.

They concluded that it’s not the sitting part of sedentary behavior (SB) that potentially has the effect on dementia but what people are doing while sitting.

Some of the results were surprising, lead author David Raichlen, PhD, professor of Human and Evolutionary Biology at University of Southern California, Los Angeles, said in an interview.

Previous literature on sedentary behaviors have documented their negative effects on a wide range of health outcomes, rather than finding positive associations, he explained.
 

More than 140,000 included in study

The researchers conducted their prospective cohort study using data from the United Kingdom Biobank. After excluding people younger than 60, those with prevalent dementia at the start of follow-up, and those without complete data, 146,651 participants were included.

The participants were followed from their baseline visit until they received a dementia diagnosis, died, were lost to follow-up, or were last admitted to the hospital.

TV-watching time was linked with an increased risk of incident dementia (HR [95% confidence interval] = 1.31 [1.23-1.40]), and computer use was linked with a reduced risk of incident dementia HR [95% CI] = 0.80 [0.76-0.85]).

TV’s link with higher dementia risk increased in those who had the highest use, compared with those who had the lowest use (HR [95% CI] = 1.28 [1.18-1.39].

Similarly, the link with risk reduction for dementia with computer use increased with more use.

Both medium and high computer time were associated with reduced risk of incident dementia (HR [95% CI] = 0.70 [0.64-0.76] and HR [95% CI] = 0.76 [0.70-0.83] respectively).

Dr. Raichlen pointed out that the high use of TV in this study was 4 or more hours a day and computer use – which included leisure use, not work use – had benefits on dementia risk after just half an hour.

These results remained significant after researchers adjusted for demographic, health, and lifestyle variables, including time spent on physical activity, sleeping, obesity, alcohol consumption, smoking status, diet scores, education level, body mass index, and employment type.
 

Physical is still better than sedentary activity

One potential reason for the different effects on dementia risk in the two activities studied, the authors write, is that sitting down to watch TV is associated with “uniquely low levels of muscle activity and energy expenditure, compared with sitting to use a computer.”

Andrew Budson, MD, chief of Cognitive & Behavioral Neurology and Associate Chief of Staff for Education for the VA Boston Healthcare System, Mass., who was not part of the study, said he thinks a more likely explanation for the study findings lies in the active versus passive tasks required in the two kinds of viewing that the authors reference.

“When we’re doing cognitive activity involving using the computer, we’re using large parts of our cortex to carry out that activity, whereas when we’re watching TV, there are probably relatively small amounts of our brain that are actually active,” Dr. Budson, author of Seven Steps to Managing Your Memory, explained in an interview.

“This is one of the first times I’ve been convinced that even when the computer activity isn’t completely new and novel, it may be beneficial,” Dr. Budson said.

It would be much better to do physical activity, but if the choice is sedentary activity, active cognitive activities, such as computer use, are better than TV watching, he continued.

The results of the current study are consistent with previous work showing that the type of sedentary behavior matters, according to the authors.

“Several studies have shown that TV time is associated with mortality and poor cardiometabolic biomarkers, whereas computer time is not,” they wrote.

A limitation of the study is that sedentary behaviors were self-reported via questionnaires, and there may be errors in recall.

“The use of objective methods for measuring both SB and PA are needed in future studies,” they write.

The authors receive support from the National Institutes of Health, the State of Arizona, the Arizona Department of Health Services, and the McKnight Brain Research Foundation. Neither the authors nor Dr. Budson declared relevant financial relationships.

Older adults with atrial cardiopathy may have up to 35% higher risk for dementia even before symptoms develop, new research suggests.

“We cautiously suggest that an understanding of this relationship might provide a basis for new interventional strategies to help thwart the development of dementia,” the authors write.

The research, led by Michelle C. Johansen, MD, department of neurology, Johns Hopkins University, Baltimore, was published online in the Journal of the American Heart Association.

Atrial cardiopathy, characterized by abnormal size and function of the left atrium, has been associated with an increased risk of stroke and atrial fibrillation (AFib), and because both stroke and AFib are associated with an increased dementia risk, the authors write, it was important to investigate whether atrial cardiopathy is linked to dementia.

If that’s the case, they reasoned, the next question was whether that link is independent of AFib and stroke, and their new research suggests that it is.

For this analysis, the researchers conducted a prospective cohort analysis of participants in the Atherosclerosis Risk in Communities (ARIC) study who were attending visit 5 (2011-2013). During their fifth, sixth, and seventh clinical visits, the ARIC participants were evaluated for cognitive decline indicating dementia.

They studied a diverse population of 5,078 older adults living in four U.S. communities: Washington County, Md.; Forsyth County, N.C.; the northwestern suburbs of Minneapolis; and Jackson, Miss.

Just more than a third (34%) had atrial cardiopathy (average age, 75 years; 59% female; 21% Black) and 763 participants developed dementia.

Investigators found that atrial cardiopathy was significantly associated with dementia (adjusted hazard ratio, 1.35 [95% confidence interval, 1.16-1.58]).

They considered ARIC participants to have atrial cardiopathy if they had at least one of the following: P-wave terminal force greater than 5,000 mV·ms in ECG lead V1; NTproBNP greater than 250 pg/mL; or left atrial volume index greater than or equal to 34 mL/m² by transthoracic echocardiography.

The risk of dementia was even stronger when the researchers defined cardiopathy by at least two biomarkers instead of one (aHR, 1.54 [95% CI, 1.25-1.89]).

The authors point out, however, that this study is observational and cannot make a causal link.

Clifford Kavinsky, MD, PhD, head of the Comprehensive Stroke and Cardiology Clinic at Rush University Medical Center, Chicago, told this news organization that much more research would need to be done to show convincingly that atrial cardiopathy causes dementia.

He called the findings “provocative in trying to understand in a general sense how cardiac dysfunction leads to dementia.”

“We all know heart failure leads to dementia, but now we see there may be a relationship with just dysfunction of the upper chambers,” he said.
 

Unresolved questions

But it still not clear is what is mediating the connection, who is at risk, and how the increased risk can be prevented, he said.

He said he also wonders whether the results eliminated all patients with atrial fibrillation, a point the authors acknowledge as well.

Researchers list in the limitations that “asymptomatic AFib or silent cerebral infarction may have been missed by the ARIC adjudication process.”

There is broad understanding that preventing heart disease is important for a wide array of reasons, Dr. Kavinsky noted, and one of the reasons is cognitive deterioration.

He said this study helps identify that “even dysfunction of the upper chambers of the heart contributes to the evolution of dementia.”

The study amplifies the need to shift to prevention with heart disease in general, and more specifically in atrial dysfunction, Dr. Kavinsky said, noting a lot of atrial dysfunction is mediated by underlying hypertension and coronary disease.

Researchers evaluated cognitive decline in all participants with a comprehensive array of neuropsychological tests and interviewed some of the patients.

“A diagnosis of dementia was generated based on testing results by a computer diagnostic algorithm and then decided upon by an expert based on the Diagnostic and Statistical Manual of Mental Disorders and the criteria outlined by the National Institutes of Health and the National Institutes of Health,” they write.

Dr. Johansen reported funding from National Institute of Neurological Disorders and Stroke. Study coauthor disclosures are listed in the paper. Dr. Kavinsky has disclosed no relevant financial relationships.

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

Older adults with atrial cardiopathy may have up to 35% higher risk for dementia even before symptoms develop, new research suggests.

“We cautiously suggest that an understanding of this relationship might provide a basis for new interventional strategies to help thwart the development of dementia,” the authors write.

The research, led by Michelle C. Johansen, MD, department of neurology, Johns Hopkins University, Baltimore, was published online in the Journal of the American Heart Association.

Atrial cardiopathy, characterized by abnormal size and function of the left atrium, has been associated with an increased risk of stroke and atrial fibrillation (AFib), and because both stroke and AFib are associated with an increased dementia risk, the authors write, it was important to investigate whether atrial cardiopathy is linked to dementia.

If that’s the case, they reasoned, the next question was whether that link is independent of AFib and stroke, and their new research suggests that it is.

For this analysis, the researchers conducted a prospective cohort analysis of participants in the Atherosclerosis Risk in Communities (ARIC) study who were attending visit 5 (2011-2013). During their fifth, sixth, and seventh clinical visits, the ARIC participants were evaluated for cognitive decline indicating dementia.

They studied a diverse population of 5,078 older adults living in four U.S. communities: Washington County, Md.; Forsyth County, N.C.; the northwestern suburbs of Minneapolis; and Jackson, Miss.

Just more than a third (34%) had atrial cardiopathy (average age, 75 years; 59% female; 21% Black) and 763 participants developed dementia.

Investigators found that atrial cardiopathy was significantly associated with dementia (adjusted hazard ratio, 1.35 [95% confidence interval, 1.16-1.58]).

They considered ARIC participants to have atrial cardiopathy if they had at least one of the following: P-wave terminal force greater than 5,000 mV·ms in ECG lead V1; NTproBNP greater than 250 pg/mL; or left atrial volume index greater than or equal to 34 mL/m² by transthoracic echocardiography.

The risk of dementia was even stronger when the researchers defined cardiopathy by at least two biomarkers instead of one (aHR, 1.54 [95% CI, 1.25-1.89]).

The authors point out, however, that this study is observational and cannot make a causal link.

Clifford Kavinsky, MD, PhD, head of the Comprehensive Stroke and Cardiology Clinic at Rush University Medical Center, Chicago, told this news organization that much more research would need to be done to show convincingly that atrial cardiopathy causes dementia.

He called the findings “provocative in trying to understand in a general sense how cardiac dysfunction leads to dementia.”

“We all know heart failure leads to dementia, but now we see there may be a relationship with just dysfunction of the upper chambers,” he said.
 

Unresolved questions

But it still not clear is what is mediating the connection, who is at risk, and how the increased risk can be prevented, he said.

He said he also wonders whether the results eliminated all patients with atrial fibrillation, a point the authors acknowledge as well.

Researchers list in the limitations that “asymptomatic AFib or silent cerebral infarction may have been missed by the ARIC adjudication process.”

There is broad understanding that preventing heart disease is important for a wide array of reasons, Dr. Kavinsky noted, and one of the reasons is cognitive deterioration.

He said this study helps identify that “even dysfunction of the upper chambers of the heart contributes to the evolution of dementia.”

The study amplifies the need to shift to prevention with heart disease in general, and more specifically in atrial dysfunction, Dr. Kavinsky said, noting a lot of atrial dysfunction is mediated by underlying hypertension and coronary disease.

Researchers evaluated cognitive decline in all participants with a comprehensive array of neuropsychological tests and interviewed some of the patients.

“A diagnosis of dementia was generated based on testing results by a computer diagnostic algorithm and then decided upon by an expert based on the Diagnostic and Statistical Manual of Mental Disorders and the criteria outlined by the National Institutes of Health and the National Institutes of Health,” they write.

Dr. Johansen reported funding from National Institute of Neurological Disorders and Stroke. Study coauthor disclosures are listed in the paper. Dr. Kavinsky has disclosed no relevant financial relationships.

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

Older adults with atrial cardiopathy may have up to 35% higher risk for dementia even before symptoms develop, new research suggests.

“We cautiously suggest that an understanding of this relationship might provide a basis for new interventional strategies to help thwart the development of dementia,” the authors write.

The research, led by Michelle C. Johansen, MD, department of neurology, Johns Hopkins University, Baltimore, was published online in the Journal of the American Heart Association.

Atrial cardiopathy, characterized by abnormal size and function of the left atrium, has been associated with an increased risk of stroke and atrial fibrillation (AFib), and because both stroke and AFib are associated with an increased dementia risk, the authors write, it was important to investigate whether atrial cardiopathy is linked to dementia.

If that’s the case, they reasoned, the next question was whether that link is independent of AFib and stroke, and their new research suggests that it is.

For this analysis, the researchers conducted a prospective cohort analysis of participants in the Atherosclerosis Risk in Communities (ARIC) study who were attending visit 5 (2011-2013). During their fifth, sixth, and seventh clinical visits, the ARIC participants were evaluated for cognitive decline indicating dementia.

They studied a diverse population of 5,078 older adults living in four U.S. communities: Washington County, Md.; Forsyth County, N.C.; the northwestern suburbs of Minneapolis; and Jackson, Miss.

Just more than a third (34%) had atrial cardiopathy (average age, 75 years; 59% female; 21% Black) and 763 participants developed dementia.

Investigators found that atrial cardiopathy was significantly associated with dementia (adjusted hazard ratio, 1.35 [95% confidence interval, 1.16-1.58]).

They considered ARIC participants to have atrial cardiopathy if they had at least one of the following: P-wave terminal force greater than 5,000 mV·ms in ECG lead V1; NTproBNP greater than 250 pg/mL; or left atrial volume index greater than or equal to 34 mL/m² by transthoracic echocardiography.

The risk of dementia was even stronger when the researchers defined cardiopathy by at least two biomarkers instead of one (aHR, 1.54 [95% CI, 1.25-1.89]).

The authors point out, however, that this study is observational and cannot make a causal link.

Clifford Kavinsky, MD, PhD, head of the Comprehensive Stroke and Cardiology Clinic at Rush University Medical Center, Chicago, told this news organization that much more research would need to be done to show convincingly that atrial cardiopathy causes dementia.

He called the findings “provocative in trying to understand in a general sense how cardiac dysfunction leads to dementia.”

“We all know heart failure leads to dementia, but now we see there may be a relationship with just dysfunction of the upper chambers,” he said.
 

Unresolved questions

But it still not clear is what is mediating the connection, who is at risk, and how the increased risk can be prevented, he said.

He said he also wonders whether the results eliminated all patients with atrial fibrillation, a point the authors acknowledge as well.

Researchers list in the limitations that “asymptomatic AFib or silent cerebral infarction may have been missed by the ARIC adjudication process.”

There is broad understanding that preventing heart disease is important for a wide array of reasons, Dr. Kavinsky noted, and one of the reasons is cognitive deterioration.

He said this study helps identify that “even dysfunction of the upper chambers of the heart contributes to the evolution of dementia.”

The study amplifies the need to shift to prevention with heart disease in general, and more specifically in atrial dysfunction, Dr. Kavinsky said, noting a lot of atrial dysfunction is mediated by underlying hypertension and coronary disease.

Researchers evaluated cognitive decline in all participants with a comprehensive array of neuropsychological tests and interviewed some of the patients.

“A diagnosis of dementia was generated based on testing results by a computer diagnostic algorithm and then decided upon by an expert based on the Diagnostic and Statistical Manual of Mental Disorders and the criteria outlined by the National Institutes of Health and the National Institutes of Health,” they write.

Dr. Johansen reported funding from National Institute of Neurological Disorders and Stroke. Study coauthor disclosures are listed in the paper. Dr. Kavinsky has disclosed no relevant financial relationships.

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

Rural patients with early onset dementia are more likely than urban patients to rely solely on primary care physicians or nurse practitioners for the initial diagnosis and treatment of the disease, a new study has found.

Patients in rural areas are also less likely to see psychologists and undergo neuropsychological testing, according to the study, published in JAMA Network Open.

Patients who forgo such specialist visits and testing may be missing information about their condition that could help them prepare for changes in job responsibilities and future care decisions, said Wendy Yi Xu, PhD, of The Ohio State University, Columbus, who led the research.

“A lot of them are still in the workforce,” Dr. Xu said. Patients in the study were an average age of 56 years, well before the conventional age of retirement.
 

Location, location, location

To examine rural versus urban differences in the use of diagnostic tests and health care visits for early onset Alzheimer’s disease and related dementias, Dr. Xu and colleagues analyzed commercial claims data from 2012-2018. They identified more than 71,000 patients aged 40-64 years with those conditions and focused on health care use by 7,311 patients in urban areas and 1,119 in rural areas within 90 days of a new dementia diagnosis.

The proportion who received neuropsychological testing was 19% among urban patients and 16% among rural patients. Psychological assessments, which are less specialized and detailed than neuropsychological testing, and brain imaging occurred at similar rates in both groups. Similar proportions of rural and urban patients visited neurologists (17.7% and 17.96%, respectively) and psychiatrists (6.02% and 6.47%).

But more urban patients than rural patients visited a psychologist, at 19% versus 15%, according to the researchers.

Approximately 18% of patients in rural areas saw a primary care provider without visiting other specialists, compared with 13% in urban areas.

The researchers found that rural patients were significantly less likely to undergo neuropsychological testing (odds ratio, 0.83; 95% confidence interval, 0.70-0.98) or see a psychologist (OR, 0.72; 95% CI, 0.60-0.85).

Similarly, rural patients had significantly higher odds of having only primary care providers involved in the diagnosis of dementia and symptom management (OR, 1.40; 95% CI, 1.19-1.66).
 

Addressing workforce deficiencies

More primary care training in dementia care and collaboration with specialist colleagues could help address differences in care, Dr. Xu’s group writes. Such efforts are already underway.

In 2018, the Alzheimer’s Association launched telementoring programs focused on dementia care using the Project ECHO (Extension for Community Healthcare Outcomes) model. Researchers originally developed Project ECHO at the University of New Mexico in 2003 to teach primary care clinicians in remote settings how to treat patients infected with the hepatitis C virus.

With the Alzheimer’s and Dementia Care ECHO Program for Clinicians, primary care clinicians can participate in interactive case-based video conferencing sessions to better understand dementia and how to provide high-quality care in community settings, according to the association.

The program covers guidelines for diagnosis, disclosure, and follow-up; the initiation of care planning; managing disease-related challenges; and resources for patients and caregivers.

Since 2018, nearly 100 primary care practices in the United States have completed training in dementia care using Project ECHO, said Morgan Daven, vice president of health systems for the Alzheimer’s Association. Many cases featured in the program are challenging, he added.

“With primary care being on the front lines, it is really important that primary care physicians are equipped to do what they can to detect or diagnose and know when to refer,” Mr. Daven said.

The association has compiled other resources for clinicians as well.

A 2020 report from the association examined the role that primary care physicians play in dementia care. One survey found that 82% of primary care physicians consider themselves on the front lines of providing care for patients with dementia.

Meanwhile, about half say medical professionals are not prepared to meet rising demands associated with Alzheimer’s disease and dementia care.

Mr. Daven said the geographic disparities Dr. Xu and colleagues found are unsurprising. More than half of primary care physicians who care for people with Alzheimer’s disease say dementia specialists in their communities cannot meet demand. The problem is more urgent in rural areas. Roughly half of nonmetropolitan counties in the United States lack a practicing psychologist, according to a 2018 study published in the American Journal of Preventive Medicine.

“We really need to approach this on both sides – build the capacity in primary care, but we also need to address the dementia care specialty shortages,” Mr. Daven said.

The lack of obvious differences in access to neurologists in the new study “was surprising, given the more than fourfold difference between urban and rural areas in the supply of neurologists,” the researchers note. Health plans may maintain more access to neurologists than psychologists because of relatively higher reimbursement for neurologists, they observed.

One of the study coauthors disclosed ties to Aveanna Healthcare, a company that delivers home health and hospice care.

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

Rural patients with early onset dementia are more likely than urban patients to rely solely on primary care physicians or nurse practitioners for the initial diagnosis and treatment of the disease, a new study has found.

Patients in rural areas are also less likely to see psychologists and undergo neuropsychological testing, according to the study, published in JAMA Network Open.

Patients who forgo such specialist visits and testing may be missing information about their condition that could help them prepare for changes in job responsibilities and future care decisions, said Wendy Yi Xu, PhD, of The Ohio State University, Columbus, who led the research.

“A lot of them are still in the workforce,” Dr. Xu said. Patients in the study were an average age of 56 years, well before the conventional age of retirement.
 

Location, location, location

To examine rural versus urban differences in the use of diagnostic tests and health care visits for early onset Alzheimer’s disease and related dementias, Dr. Xu and colleagues analyzed commercial claims data from 2012-2018. They identified more than 71,000 patients aged 40-64 years with those conditions and focused on health care use by 7,311 patients in urban areas and 1,119 in rural areas within 90 days of a new dementia diagnosis.

The proportion who received neuropsychological testing was 19% among urban patients and 16% among rural patients. Psychological assessments, which are less specialized and detailed than neuropsychological testing, and brain imaging occurred at similar rates in both groups. Similar proportions of rural and urban patients visited neurologists (17.7% and 17.96%, respectively) and psychiatrists (6.02% and 6.47%).

But more urban patients than rural patients visited a psychologist, at 19% versus 15%, according to the researchers.

Approximately 18% of patients in rural areas saw a primary care provider without visiting other specialists, compared with 13% in urban areas.

The researchers found that rural patients were significantly less likely to undergo neuropsychological testing (odds ratio, 0.83; 95% confidence interval, 0.70-0.98) or see a psychologist (OR, 0.72; 95% CI, 0.60-0.85).

Similarly, rural patients had significantly higher odds of having only primary care providers involved in the diagnosis of dementia and symptom management (OR, 1.40; 95% CI, 1.19-1.66).
 

Addressing workforce deficiencies

More primary care training in dementia care and collaboration with specialist colleagues could help address differences in care, Dr. Xu’s group writes. Such efforts are already underway.

In 2018, the Alzheimer’s Association launched telementoring programs focused on dementia care using the Project ECHO (Extension for Community Healthcare Outcomes) model. Researchers originally developed Project ECHO at the University of New Mexico in 2003 to teach primary care clinicians in remote settings how to treat patients infected with the hepatitis C virus.

With the Alzheimer’s and Dementia Care ECHO Program for Clinicians, primary care clinicians can participate in interactive case-based video conferencing sessions to better understand dementia and how to provide high-quality care in community settings, according to the association.

The program covers guidelines for diagnosis, disclosure, and follow-up; the initiation of care planning; managing disease-related challenges; and resources for patients and caregivers.

Since 2018, nearly 100 primary care practices in the United States have completed training in dementia care using Project ECHO, said Morgan Daven, vice president of health systems for the Alzheimer’s Association. Many cases featured in the program are challenging, he added.

“With primary care being on the front lines, it is really important that primary care physicians are equipped to do what they can to detect or diagnose and know when to refer,” Mr. Daven said.

The association has compiled other resources for clinicians as well.

A 2020 report from the association examined the role that primary care physicians play in dementia care. One survey found that 82% of primary care physicians consider themselves on the front lines of providing care for patients with dementia.

Meanwhile, about half say medical professionals are not prepared to meet rising demands associated with Alzheimer’s disease and dementia care.

Mr. Daven said the geographic disparities Dr. Xu and colleagues found are unsurprising. More than half of primary care physicians who care for people with Alzheimer’s disease say dementia specialists in their communities cannot meet demand. The problem is more urgent in rural areas. Roughly half of nonmetropolitan counties in the United States lack a practicing psychologist, according to a 2018 study published in the American Journal of Preventive Medicine.

“We really need to approach this on both sides – build the capacity in primary care, but we also need to address the dementia care specialty shortages,” Mr. Daven said.

The lack of obvious differences in access to neurologists in the new study “was surprising, given the more than fourfold difference between urban and rural areas in the supply of neurologists,” the researchers note. Health plans may maintain more access to neurologists than psychologists because of relatively higher reimbursement for neurologists, they observed.

One of the study coauthors disclosed ties to Aveanna Healthcare, a company that delivers home health and hospice care.

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

Rural patients with early onset dementia are more likely than urban patients to rely solely on primary care physicians or nurse practitioners for the initial diagnosis and treatment of the disease, a new study has found.

Patients in rural areas are also less likely to see psychologists and undergo neuropsychological testing, according to the study, published in JAMA Network Open.

Patients who forgo such specialist visits and testing may be missing information about their condition that could help them prepare for changes in job responsibilities and future care decisions, said Wendy Yi Xu, PhD, of The Ohio State University, Columbus, who led the research.

“A lot of them are still in the workforce,” Dr. Xu said. Patients in the study were an average age of 56 years, well before the conventional age of retirement.
 

Location, location, location

To examine rural versus urban differences in the use of diagnostic tests and health care visits for early onset Alzheimer’s disease and related dementias, Dr. Xu and colleagues analyzed commercial claims data from 2012-2018. They identified more than 71,000 patients aged 40-64 years with those conditions and focused on health care use by 7,311 patients in urban areas and 1,119 in rural areas within 90 days of a new dementia diagnosis.

The proportion who received neuropsychological testing was 19% among urban patients and 16% among rural patients. Psychological assessments, which are less specialized and detailed than neuropsychological testing, and brain imaging occurred at similar rates in both groups. Similar proportions of rural and urban patients visited neurologists (17.7% and 17.96%, respectively) and psychiatrists (6.02% and 6.47%).

But more urban patients than rural patients visited a psychologist, at 19% versus 15%, according to the researchers.

Approximately 18% of patients in rural areas saw a primary care provider without visiting other specialists, compared with 13% in urban areas.

The researchers found that rural patients were significantly less likely to undergo neuropsychological testing (odds ratio, 0.83; 95% confidence interval, 0.70-0.98) or see a psychologist (OR, 0.72; 95% CI, 0.60-0.85).

Similarly, rural patients had significantly higher odds of having only primary care providers involved in the diagnosis of dementia and symptom management (OR, 1.40; 95% CI, 1.19-1.66).
 

Addressing workforce deficiencies

More primary care training in dementia care and collaboration with specialist colleagues could help address differences in care, Dr. Xu’s group writes. Such efforts are already underway.

In 2018, the Alzheimer’s Association launched telementoring programs focused on dementia care using the Project ECHO (Extension for Community Healthcare Outcomes) model. Researchers originally developed Project ECHO at the University of New Mexico in 2003 to teach primary care clinicians in remote settings how to treat patients infected with the hepatitis C virus.

With the Alzheimer’s and Dementia Care ECHO Program for Clinicians, primary care clinicians can participate in interactive case-based video conferencing sessions to better understand dementia and how to provide high-quality care in community settings, according to the association.

The program covers guidelines for diagnosis, disclosure, and follow-up; the initiation of care planning; managing disease-related challenges; and resources for patients and caregivers.

Since 2018, nearly 100 primary care practices in the United States have completed training in dementia care using Project ECHO, said Morgan Daven, vice president of health systems for the Alzheimer’s Association. Many cases featured in the program are challenging, he added.

“With primary care being on the front lines, it is really important that primary care physicians are equipped to do what they can to detect or diagnose and know when to refer,” Mr. Daven said.

The association has compiled other resources for clinicians as well.

A 2020 report from the association examined the role that primary care physicians play in dementia care. One survey found that 82% of primary care physicians consider themselves on the front lines of providing care for patients with dementia.

Meanwhile, about half say medical professionals are not prepared to meet rising demands associated with Alzheimer’s disease and dementia care.

Mr. Daven said the geographic disparities Dr. Xu and colleagues found are unsurprising. More than half of primary care physicians who care for people with Alzheimer’s disease say dementia specialists in their communities cannot meet demand. The problem is more urgent in rural areas. Roughly half of nonmetropolitan counties in the United States lack a practicing psychologist, according to a 2018 study published in the American Journal of Preventive Medicine.

“We really need to approach this on both sides – build the capacity in primary care, but we also need to address the dementia care specialty shortages,” Mr. Daven said.

The lack of obvious differences in access to neurologists in the new study “was surprising, given the more than fourfold difference between urban and rural areas in the supply of neurologists,” the researchers note. Health plans may maintain more access to neurologists than psychologists because of relatively higher reimbursement for neurologists, they observed.

One of the study coauthors disclosed ties to Aveanna Healthcare, a company that delivers home health and hospice care.

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

Every day, we depend on our working memory, spatial cognition, and processing speed abilities to optimize productivity, interpersonal interactions, and psychological wellbeing. These cognitive functioning indices relate closely with academic and work performance, managing emotions, physical fitness, and a sense of fulfillment in personal and work relationships. They are linked intimately to complex cognitive skills (van Dijk et al., 2020). It is thus imperative to identify modifiable predictors of cognitive functioning in the brain to protect against aging-related cognitive decline and maximize the quality of life.

Enhancing life satisfaction is a possible way to enhance working memory, spatial cognition, and processing speed or protect against their decline. A decline in life satisfaction can worsen cognitive functioning over long periods via lifestyle factors (e.g., suboptimal diet and nutrition, lack of exercise) (Ratigan et al., 2016). Inadequate engagement in these health-enhancing pursuits could build up inflammation in EF-linked brain areas, thus negatively impacting cognitive functioning in adulthood (Grant et al., 2009). Possible pathways include long-term wear and tear of the hypothalamic-pituitary axis and brain regions linked to executive functioning (Zainal and Newman, 2022a). These processes may deteriorate working memory, spatial cognition, and processing speed across time.

Similarly, it is plausible that a reduction in cognitive functioning may lead to a long-term decrease in life satisfaction. Working memory, processing speed, spatial cognition, and related capacities are essential to meaningful activities and feelings of gratification in personal and professional relationships and other spheres of health throughout life (Baumeister et al., 2007). These cognitive functioning markers safeguard against reduced life satisfaction by facilitating effective problem-solving, and choices (Swanson and Fung, 2016). For example, stronger working memory, processing speed, and related domains coincided with better tolerance for stress and trading off immediate rewards for long-term values and life goals (Hofmann et al., 2012). Therefore, reduction in cognitive functioning abilities could precede a future decline in life satisfaction.

Nonetheless, the literature on this topic has several limitations. Most of the studies have been cross-sectional (i.e., across a single time-point) and thus do not permit inferences between cause and effect (e.g., Toh et al., 2020). Also, most studies used statistical methods that did not differentiate between between-person (trait-like individual differences) and within-person (state-like) relations. Distinguishing within- and between-person relations is necessary because they may vary in magnitude and direction. The preceding theories emphasize change-to-future change relations within persons rather than between persons (Wright and Woods, 2020).
 

Clinical implications

Our recent work (Zainal and Newman, 2022b) added to the literature by using an advanced statistical method to determine the relations between change in life satisfaction and future change in cognitive functioning domains within persons. The choice of an advanced statistical technique minimizes biases due to the passage of time and assessment unreliability. It also adjusts for between-person effects (Klopack and Wickrama, 2020). Improving understanding of the within-person factors leading to the deterioration of cognitive functioning and life satisfaction is crucial given the rising rates of psychiatric and neurocognitive illnesses (Cui et al., 2020). Identifying these changeable risk factors can optimize prevention, early detection, and treatment approaches.

Specifically, we analyzed the publicly available Swedish Adoption/Twin Study of Aging (SATSA) dataset (Petkus et al., 2017). Their dataset comprised 520 middle- to older-aged twin adults without dementia. Participants provided data across 23 years with five time points. Each time lag ranged from 3 to 11 years. The analyses demonstrated that greater decreases in life satisfaction predicted larger future declines in processing speed, verbal working memory, and spatial cognition. Moreover, declines in verbal working memory and processing speed predicted a reduction in life satisfaction. However, change in spatial awareness did not predict change in life satisfaction.

Our study offers multiple theoretical perspectives. Scar theories propose that decreased life satisfaction and related mental health problems can compromise working memory, processing speed, and spatial cognition in the long term. This scarring process occurs through the buildup of allostatic load, such as increased biomarkers of chronic stress (e.g., cortisol) and inflammation (e.g., interleukin-6, C-reactive protein) (Fancourt and Steptoe, 2020; Zainal and Newman, 2021a). Also, findings suggest the importance of executive functioning domains to attain desired milestones and aspirations to enhance a sense of fulfillment (Baddeley, 2013; Toh and Yang, 2020). Reductions in these cognitive functioning capacities could, over time, adversely affect the ability to engage in daily living activities and manage negative moods.

Limitations of our study include the lack of a multiple-assessment approach to measuring diverse cognitive functioning domains. Also, the absence of cognitive self-reports is a shortcoming since perceived cognitive difficulties might not align with performance on cognitive tests. Relatedly, future studies should administer cognitive tests that parallel and transfer to everyday tasks. However, our study’s strengths include the robust findings across different intervals between study waves, advanced statistics, and the large sample size.

If future studies replicate a similar pattern of results, the clinical applications of this study merit attention. Mindfulness-based interventions can promote working memory, sustained awareness, and spatial cognition or protect against cognitive decline (Jha et al., 2019; Zainal and Newman, 2021b). Further, clinical science can profit from exploring cognitive-behavioral therapies to improve adults’ cognitive function or life satisfaction (Sok et al., 2021).
 

Dr. Zainal recently accepted a 2-year postdoctoral research associate position at Harvard Medical School, Boston, starting in summer 2022. She received her Ph.D. from Pennsylvania State University, University Park, and completed a predoctoral clinical fellowship at the HMS-affiliated Massachusetts General Hospital – Cognitive Behavioral Scientist Track. Her research interests focus on how executive functioning, social cognition, and cognitive-behavioral strategies link to the etiology, maintenance, and treatment of anxiety and depressive disorders. Dr. Newman is a professor of psychology and psychiatry, and the director of the Center for the Treatment of Anxiety and Depression, at Pennsylvania State University. She has conducted basic and applied research on anxiety disorders and depression and has published over 200 papers on these topics.

Sources

Baddeley A. Working memory and emotion: Ruminations on a theory of depression. Rev Gen Psychol. 2013;17(1):20-7. doi: 10.1037/a0030029.

Baumeister RF et al. “Self-regulation and the executive function: The self as controlling agent,” in Social Psychology: Handbook of Basic Principles, 2nd ed. (pp. 516-39). The Guilford Press: New York, 2007.

Cui L et al. Prevalence of alzheimer’s disease and parkinson’s disease in China: An updated systematical analysis. Front Aging Neurosci. 2020 Dec 21;12:603854. doi: 10.3389/fnagi.2020.603854.

Fancourt D and Steptoe A. The longitudinal relationship between changes in wellbeing and inflammatory markers: Are associations independent of depression? Brain Behav Immun. 2020 Jan;83:146-52. doi: 10.1016/j.bbi.2019.10.004.

Grant N et al. The relationship between life satisfaction and health behavior: A cross-cultural analysis of young adults. Int J Behav Med. 2009;16(3):259-68. doi: 10.1007/s12529-009-9032-x.

Hofmann W et al. Executive functions and self-regulation. Trends Cogn Sci. 2012 Mar;16(3):174-80. doi: 10.1016/j.tics.2012.01.006.

Jha AP et al. Bolstering cognitive resilience via train-the-trainer delivery of mindfulness training in applied high-demand settings. Mindfulness. 2019;11(3):683-97. doi: 10.1007/s12671-019-01284-7.

Klopack ET and Wickrama K. Modeling latent change score analysis and extensions in Mplus: A practical guide for researchers. Struct Equ Modeling. 2020;27(1):97-110. doi: 10.1080/10705511.2018.1562929.

Petkus AJ et al. Temporal dynamics of cognitive performance and anxiety across older adulthood. Psychol Aging. 2017 May;32(3):278-92. doi: 10.1037/pag0000164.

Ratigan A et al. Sex differences in the association of physical function and cognitive function with life satisfaction in older age: The Rancho Bernardo Study. Maturitas. 2016 Jul;89:29-35. doi: 10.1016/j.maturitas.2016.04.007.

Sok S et al. Effects of cognitive/exercise dual-task program on the cognitive function, health status, depression, and life satisfaction of the elderly living in the community. Int J Environ Res Public Health. 2021 Jul 24;18(15):7848. doi: 10.3390/ijerph18157848.

Swanson HL and Fung W. Working memory components and problem-solving accuracy: Are there multiple pathways? J Educ Psychol. 2016;108(8):1153-77. doi: 10.1037/edu0000116.

Toh WX and Yang H. Executive function moderates the effect of reappraisal on life satisfaction: A latent variable analysis. Emotion. 2020;22(3):554-71. doi: 10.1037/emo0000907.

Toh WX et al. Executive function and subjective wellbeing in middle and late adulthood. J Gerontol B Psychol Sci Soc Sci. 2020 Jun 2;75(6):e69-e77. doi: 10.1093/geronb/gbz006.

van Dijk DM, et al. Cognitive functioning, sleep quality, and work performance in non-clinical burnout: The role of working memory. PLoS One. 2020 Apr 23;15(4):e0231906. doi: 10.1371/journal.pone.0231906.

Wright AGC and Woods WC. Personalized models of psychopathology. Annu Rev Clin Psychol. 2020 May 7;16:49-74. doi: 10.1146/annurev-clinpsy-102419-125032.

Zainal NH and Newman MG. (2021a). Depression and worry symptoms predict future executive functioning impairment via inflammation. Psychol Med. 2021 Mar 3;1-11. doi: 10.1017/S0033291721000398.

Zainal NH and Newman MG. (2021b). Mindfulness enhances cognitive functioning: A meta-analysis of 111 randomized controlled trials. PsyArXiv Preprints. 2021 May 11. doi: 10.31234/osf.io/vzxw7.

Zainal NH and Newman MG. (2022a). Inflammation mediates depression and generalized anxiety symptoms predicting executive function impairment after 18 years. J Affect Disord. 2022 Jan 1;296:465-75. doi: 10.1016/j.jad.2021.08.077.

Zainal NH and Newman MG. (2022b). Life satisfaction prevents decline in working memory, spatial cognition, and processing speed: Latent change score analyses across 23 years. Eur Psychiatry. 2022 Apr 19;65(1):1-55. doi: 10.1192/j.eurpsy.2022.19.

Every day, we depend on our working memory, spatial cognition, and processing speed abilities to optimize productivity, interpersonal interactions, and psychological wellbeing. These cognitive functioning indices relate closely with academic and work performance, managing emotions, physical fitness, and a sense of fulfillment in personal and work relationships. They are linked intimately to complex cognitive skills (van Dijk et al., 2020). It is thus imperative to identify modifiable predictors of cognitive functioning in the brain to protect against aging-related cognitive decline and maximize the quality of life.

Enhancing life satisfaction is a possible way to enhance working memory, spatial cognition, and processing speed or protect against their decline. A decline in life satisfaction can worsen cognitive functioning over long periods via lifestyle factors (e.g., suboptimal diet and nutrition, lack of exercise) (Ratigan et al., 2016). Inadequate engagement in these health-enhancing pursuits could build up inflammation in EF-linked brain areas, thus negatively impacting cognitive functioning in adulthood (Grant et al., 2009). Possible pathways include long-term wear and tear of the hypothalamic-pituitary axis and brain regions linked to executive functioning (Zainal and Newman, 2022a). These processes may deteriorate working memory, spatial cognition, and processing speed across time.

Similarly, it is plausible that a reduction in cognitive functioning may lead to a long-term decrease in life satisfaction. Working memory, processing speed, spatial cognition, and related capacities are essential to meaningful activities and feelings of gratification in personal and professional relationships and other spheres of health throughout life (Baumeister et al., 2007). These cognitive functioning markers safeguard against reduced life satisfaction by facilitating effective problem-solving, and choices (Swanson and Fung, 2016). For example, stronger working memory, processing speed, and related domains coincided with better tolerance for stress and trading off immediate rewards for long-term values and life goals (Hofmann et al., 2012). Therefore, reduction in cognitive functioning abilities could precede a future decline in life satisfaction.

Nonetheless, the literature on this topic has several limitations. Most of the studies have been cross-sectional (i.e., across a single time-point) and thus do not permit inferences between cause and effect (e.g., Toh et al., 2020). Also, most studies used statistical methods that did not differentiate between between-person (trait-like individual differences) and within-person (state-like) relations. Distinguishing within- and between-person relations is necessary because they may vary in magnitude and direction. The preceding theories emphasize change-to-future change relations within persons rather than between persons (Wright and Woods, 2020).
 

Clinical implications

Our recent work (Zainal and Newman, 2022b) added to the literature by using an advanced statistical method to determine the relations between change in life satisfaction and future change in cognitive functioning domains within persons. The choice of an advanced statistical technique minimizes biases due to the passage of time and assessment unreliability. It also adjusts for between-person effects (Klopack and Wickrama, 2020). Improving understanding of the within-person factors leading to the deterioration of cognitive functioning and life satisfaction is crucial given the rising rates of psychiatric and neurocognitive illnesses (Cui et al., 2020). Identifying these changeable risk factors can optimize prevention, early detection, and treatment approaches.

Specifically, we analyzed the publicly available Swedish Adoption/Twin Study of Aging (SATSA) dataset (Petkus et al., 2017). Their dataset comprised 520 middle- to older-aged twin adults without dementia. Participants provided data across 23 years with five time points. Each time lag ranged from 3 to 11 years. The analyses demonstrated that greater decreases in life satisfaction predicted larger future declines in processing speed, verbal working memory, and spatial cognition. Moreover, declines in verbal working memory and processing speed predicted a reduction in life satisfaction. However, change in spatial awareness did not predict change in life satisfaction.

Our study offers multiple theoretical perspectives. Scar theories propose that decreased life satisfaction and related mental health problems can compromise working memory, processing speed, and spatial cognition in the long term. This scarring process occurs through the buildup of allostatic load, such as increased biomarkers of chronic stress (e.g., cortisol) and inflammation (e.g., interleukin-6, C-reactive protein) (Fancourt and Steptoe, 2020; Zainal and Newman, 2021a). Also, findings suggest the importance of executive functioning domains to attain desired milestones and aspirations to enhance a sense of fulfillment (Baddeley, 2013; Toh and Yang, 2020). Reductions in these cognitive functioning capacities could, over time, adversely affect the ability to engage in daily living activities and manage negative moods.

Limitations of our study include the lack of a multiple-assessment approach to measuring diverse cognitive functioning domains. Also, the absence of cognitive self-reports is a shortcoming since perceived cognitive difficulties might not align with performance on cognitive tests. Relatedly, future studies should administer cognitive tests that parallel and transfer to everyday tasks. However, our study’s strengths include the robust findings across different intervals between study waves, advanced statistics, and the large sample size.

If future studies replicate a similar pattern of results, the clinical applications of this study merit attention. Mindfulness-based interventions can promote working memory, sustained awareness, and spatial cognition or protect against cognitive decline (Jha et al., 2019; Zainal and Newman, 2021b). Further, clinical science can profit from exploring cognitive-behavioral therapies to improve adults’ cognitive function or life satisfaction (Sok et al., 2021).
 

Dr. Zainal recently accepted a 2-year postdoctoral research associate position at Harvard Medical School, Boston, starting in summer 2022. She received her Ph.D. from Pennsylvania State University, University Park, and completed a predoctoral clinical fellowship at the HMS-affiliated Massachusetts General Hospital – Cognitive Behavioral Scientist Track. Her research interests focus on how executive functioning, social cognition, and cognitive-behavioral strategies link to the etiology, maintenance, and treatment of anxiety and depressive disorders. Dr. Newman is a professor of psychology and psychiatry, and the director of the Center for the Treatment of Anxiety and Depression, at Pennsylvania State University. She has conducted basic and applied research on anxiety disorders and depression and has published over 200 papers on these topics.

Sources

Baddeley A. Working memory and emotion: Ruminations on a theory of depression. Rev Gen Psychol. 2013;17(1):20-7. doi: 10.1037/a0030029.

Baumeister RF et al. “Self-regulation and the executive function: The self as controlling agent,” in Social Psychology: Handbook of Basic Principles, 2nd ed. (pp. 516-39). The Guilford Press: New York, 2007.

Cui L et al. Prevalence of alzheimer’s disease and parkinson’s disease in China: An updated systematical analysis. Front Aging Neurosci. 2020 Dec 21;12:603854. doi: 10.3389/fnagi.2020.603854.

Fancourt D and Steptoe A. The longitudinal relationship between changes in wellbeing and inflammatory markers: Are associations independent of depression? Brain Behav Immun. 2020 Jan;83:146-52. doi: 10.1016/j.bbi.2019.10.004.

Grant N et al. The relationship between life satisfaction and health behavior: A cross-cultural analysis of young adults. Int J Behav Med. 2009;16(3):259-68. doi: 10.1007/s12529-009-9032-x.

Hofmann W et al. Executive functions and self-regulation. Trends Cogn Sci. 2012 Mar;16(3):174-80. doi: 10.1016/j.tics.2012.01.006.

Jha AP et al. Bolstering cognitive resilience via train-the-trainer delivery of mindfulness training in applied high-demand settings. Mindfulness. 2019;11(3):683-97. doi: 10.1007/s12671-019-01284-7.

Klopack ET and Wickrama K. Modeling latent change score analysis and extensions in Mplus: A practical guide for researchers. Struct Equ Modeling. 2020;27(1):97-110. doi: 10.1080/10705511.2018.1562929.

Petkus AJ et al. Temporal dynamics of cognitive performance and anxiety across older adulthood. Psychol Aging. 2017 May;32(3):278-92. doi: 10.1037/pag0000164.

Ratigan A et al. Sex differences in the association of physical function and cognitive function with life satisfaction in older age: The Rancho Bernardo Study. Maturitas. 2016 Jul;89:29-35. doi: 10.1016/j.maturitas.2016.04.007.

Sok S et al. Effects of cognitive/exercise dual-task program on the cognitive function, health status, depression, and life satisfaction of the elderly living in the community. Int J Environ Res Public Health. 2021 Jul 24;18(15):7848. doi: 10.3390/ijerph18157848.

Swanson HL and Fung W. Working memory components and problem-solving accuracy: Are there multiple pathways? J Educ Psychol. 2016;108(8):1153-77. doi: 10.1037/edu0000116.

Toh WX and Yang H. Executive function moderates the effect of reappraisal on life satisfaction: A latent variable analysis. Emotion. 2020;22(3):554-71. doi: 10.1037/emo0000907.

Toh WX et al. Executive function and subjective wellbeing in middle and late adulthood. J Gerontol B Psychol Sci Soc Sci. 2020 Jun 2;75(6):e69-e77. doi: 10.1093/geronb/gbz006.

van Dijk DM, et al. Cognitive functioning, sleep quality, and work performance in non-clinical burnout: The role of working memory. PLoS One. 2020 Apr 23;15(4):e0231906. doi: 10.1371/journal.pone.0231906.

Wright AGC and Woods WC. Personalized models of psychopathology. Annu Rev Clin Psychol. 2020 May 7;16:49-74. doi: 10.1146/annurev-clinpsy-102419-125032.

Zainal NH and Newman MG. (2021a). Depression and worry symptoms predict future executive functioning impairment via inflammation. Psychol Med. 2021 Mar 3;1-11. doi: 10.1017/S0033291721000398.

Zainal NH and Newman MG. (2021b). Mindfulness enhances cognitive functioning: A meta-analysis of 111 randomized controlled trials. PsyArXiv Preprints. 2021 May 11. doi: 10.31234/osf.io/vzxw7.

Zainal NH and Newman MG. (2022a). Inflammation mediates depression and generalized anxiety symptoms predicting executive function impairment after 18 years. J Affect Disord. 2022 Jan 1;296:465-75. doi: 10.1016/j.jad.2021.08.077.

Zainal NH and Newman MG. (2022b). Life satisfaction prevents decline in working memory, spatial cognition, and processing speed: Latent change score analyses across 23 years. Eur Psychiatry. 2022 Apr 19;65(1):1-55. doi: 10.1192/j.eurpsy.2022.19.

Every day, we depend on our working memory, spatial cognition, and processing speed abilities to optimize productivity, interpersonal interactions, and psychological wellbeing. These cognitive functioning indices relate closely with academic and work performance, managing emotions, physical fitness, and a sense of fulfillment in personal and work relationships. They are linked intimately to complex cognitive skills (van Dijk et al., 2020). It is thus imperative to identify modifiable predictors of cognitive functioning in the brain to protect against aging-related cognitive decline and maximize the quality of life.

Enhancing life satisfaction is a possible way to enhance working memory, spatial cognition, and processing speed or protect against their decline. A decline in life satisfaction can worsen cognitive functioning over long periods via lifestyle factors (e.g., suboptimal diet and nutrition, lack of exercise) (Ratigan et al., 2016). Inadequate engagement in these health-enhancing pursuits could build up inflammation in EF-linked brain areas, thus negatively impacting cognitive functioning in adulthood (Grant et al., 2009). Possible pathways include long-term wear and tear of the hypothalamic-pituitary axis and brain regions linked to executive functioning (Zainal and Newman, 2022a). These processes may deteriorate working memory, spatial cognition, and processing speed across time.

Similarly, it is plausible that a reduction in cognitive functioning may lead to a long-term decrease in life satisfaction. Working memory, processing speed, spatial cognition, and related capacities are essential to meaningful activities and feelings of gratification in personal and professional relationships and other spheres of health throughout life (Baumeister et al., 2007). These cognitive functioning markers safeguard against reduced life satisfaction by facilitating effective problem-solving, and choices (Swanson and Fung, 2016). For example, stronger working memory, processing speed, and related domains coincided with better tolerance for stress and trading off immediate rewards for long-term values and life goals (Hofmann et al., 2012). Therefore, reduction in cognitive functioning abilities could precede a future decline in life satisfaction.

Nonetheless, the literature on this topic has several limitations. Most of the studies have been cross-sectional (i.e., across a single time-point) and thus do not permit inferences between cause and effect (e.g., Toh et al., 2020). Also, most studies used statistical methods that did not differentiate between between-person (trait-like individual differences) and within-person (state-like) relations. Distinguishing within- and between-person relations is necessary because they may vary in magnitude and direction. The preceding theories emphasize change-to-future change relations within persons rather than between persons (Wright and Woods, 2020).
 

Clinical implications

Our recent work (Zainal and Newman, 2022b) added to the literature by using an advanced statistical method to determine the relations between change in life satisfaction and future change in cognitive functioning domains within persons. The choice of an advanced statistical technique minimizes biases due to the passage of time and assessment unreliability. It also adjusts for between-person effects (Klopack and Wickrama, 2020). Improving understanding of the within-person factors leading to the deterioration of cognitive functioning and life satisfaction is crucial given the rising rates of psychiatric and neurocognitive illnesses (Cui et al., 2020). Identifying these changeable risk factors can optimize prevention, early detection, and treatment approaches.

Specifically, we analyzed the publicly available Swedish Adoption/Twin Study of Aging (SATSA) dataset (Petkus et al., 2017). Their dataset comprised 520 middle- to older-aged twin adults without dementia. Participants provided data across 23 years with five time points. Each time lag ranged from 3 to 11 years. The analyses demonstrated that greater decreases in life satisfaction predicted larger future declines in processing speed, verbal working memory, and spatial cognition. Moreover, declines in verbal working memory and processing speed predicted a reduction in life satisfaction. However, change in spatial awareness did not predict change in life satisfaction.

Our study offers multiple theoretical perspectives. Scar theories propose that decreased life satisfaction and related mental health problems can compromise working memory, processing speed, and spatial cognition in the long term. This scarring process occurs through the buildup of allostatic load, such as increased biomarkers of chronic stress (e.g., cortisol) and inflammation (e.g., interleukin-6, C-reactive protein) (Fancourt and Steptoe, 2020; Zainal and Newman, 2021a). Also, findings suggest the importance of executive functioning domains to attain desired milestones and aspirations to enhance a sense of fulfillment (Baddeley, 2013; Toh and Yang, 2020). Reductions in these cognitive functioning capacities could, over time, adversely affect the ability to engage in daily living activities and manage negative moods.

Limitations of our study include the lack of a multiple-assessment approach to measuring diverse cognitive functioning domains. Also, the absence of cognitive self-reports is a shortcoming since perceived cognitive difficulties might not align with performance on cognitive tests. Relatedly, future studies should administer cognitive tests that parallel and transfer to everyday tasks. However, our study’s strengths include the robust findings across different intervals between study waves, advanced statistics, and the large sample size.

If future studies replicate a similar pattern of results, the clinical applications of this study merit attention. Mindfulness-based interventions can promote working memory, sustained awareness, and spatial cognition or protect against cognitive decline (Jha et al., 2019; Zainal and Newman, 2021b). Further, clinical science can profit from exploring cognitive-behavioral therapies to improve adults’ cognitive function or life satisfaction (Sok et al., 2021).
 

Dr. Zainal recently accepted a 2-year postdoctoral research associate position at Harvard Medical School, Boston, starting in summer 2022. She received her Ph.D. from Pennsylvania State University, University Park, and completed a predoctoral clinical fellowship at the HMS-affiliated Massachusetts General Hospital – Cognitive Behavioral Scientist Track. Her research interests focus on how executive functioning, social cognition, and cognitive-behavioral strategies link to the etiology, maintenance, and treatment of anxiety and depressive disorders. Dr. Newman is a professor of psychology and psychiatry, and the director of the Center for the Treatment of Anxiety and Depression, at Pennsylvania State University. She has conducted basic and applied research on anxiety disorders and depression and has published over 200 papers on these topics.

Sources

Baddeley A. Working memory and emotion: Ruminations on a theory of depression. Rev Gen Psychol. 2013;17(1):20-7. doi: 10.1037/a0030029.

Baumeister RF et al. “Self-regulation and the executive function: The self as controlling agent,” in Social Psychology: Handbook of Basic Principles, 2nd ed. (pp. 516-39). The Guilford Press: New York, 2007.

Cui L et al. Prevalence of alzheimer’s disease and parkinson’s disease in China: An updated systematical analysis. Front Aging Neurosci. 2020 Dec 21;12:603854. doi: 10.3389/fnagi.2020.603854.

Fancourt D and Steptoe A. The longitudinal relationship between changes in wellbeing and inflammatory markers: Are associations independent of depression? Brain Behav Immun. 2020 Jan;83:146-52. doi: 10.1016/j.bbi.2019.10.004.

Grant N et al. The relationship between life satisfaction and health behavior: A cross-cultural analysis of young adults. Int J Behav Med. 2009;16(3):259-68. doi: 10.1007/s12529-009-9032-x.

Hofmann W et al. Executive functions and self-regulation. Trends Cogn Sci. 2012 Mar;16(3):174-80. doi: 10.1016/j.tics.2012.01.006.

Jha AP et al. Bolstering cognitive resilience via train-the-trainer delivery of mindfulness training in applied high-demand settings. Mindfulness. 2019;11(3):683-97. doi: 10.1007/s12671-019-01284-7.

Klopack ET and Wickrama K. Modeling latent change score analysis and extensions in Mplus: A practical guide for researchers. Struct Equ Modeling. 2020;27(1):97-110. doi: 10.1080/10705511.2018.1562929.

Petkus AJ et al. Temporal dynamics of cognitive performance and anxiety across older adulthood. Psychol Aging. 2017 May;32(3):278-92. doi: 10.1037/pag0000164.

Ratigan A et al. Sex differences in the association of physical function and cognitive function with life satisfaction in older age: The Rancho Bernardo Study. Maturitas. 2016 Jul;89:29-35. doi: 10.1016/j.maturitas.2016.04.007.

Sok S et al. Effects of cognitive/exercise dual-task program on the cognitive function, health status, depression, and life satisfaction of the elderly living in the community. Int J Environ Res Public Health. 2021 Jul 24;18(15):7848. doi: 10.3390/ijerph18157848.

Swanson HL and Fung W. Working memory components and problem-solving accuracy: Are there multiple pathways? J Educ Psychol. 2016;108(8):1153-77. doi: 10.1037/edu0000116.

Toh WX and Yang H. Executive function moderates the effect of reappraisal on life satisfaction: A latent variable analysis. Emotion. 2020;22(3):554-71. doi: 10.1037/emo0000907.

Toh WX et al. Executive function and subjective wellbeing in middle and late adulthood. J Gerontol B Psychol Sci Soc Sci. 2020 Jun 2;75(6):e69-e77. doi: 10.1093/geronb/gbz006.

van Dijk DM, et al. Cognitive functioning, sleep quality, and work performance in non-clinical burnout: The role of working memory. PLoS One. 2020 Apr 23;15(4):e0231906. doi: 10.1371/journal.pone.0231906.

Wright AGC and Woods WC. Personalized models of psychopathology. Annu Rev Clin Psychol. 2020 May 7;16:49-74. doi: 10.1146/annurev-clinpsy-102419-125032.

Zainal NH and Newman MG. (2021a). Depression and worry symptoms predict future executive functioning impairment via inflammation. Psychol Med. 2021 Mar 3;1-11. doi: 10.1017/S0033291721000398.

Zainal NH and Newman MG. (2021b). Mindfulness enhances cognitive functioning: A meta-analysis of 111 randomized controlled trials. PsyArXiv Preprints. 2021 May 11. doi: 10.31234/osf.io/vzxw7.

Zainal NH and Newman MG. (2022a). Inflammation mediates depression and generalized anxiety symptoms predicting executive function impairment after 18 years. J Affect Disord. 2022 Jan 1;296:465-75. doi: 10.1016/j.jad.2021.08.077.

Zainal NH and Newman MG. (2022b). Life satisfaction prevents decline in working memory, spatial cognition, and processing speed: Latent change score analyses across 23 years. Eur Psychiatry. 2022 Apr 19;65(1):1-55. doi: 10.1192/j.eurpsy.2022.19.

Varicella zoster virus (VZV) infection may activate dormant herpes simplex virus (HSV-1), leading to neuroinflammation and accumulation of Alzheimer’s disease (AD)–related proteins in the brain, new research suggests.

“Our results suggest one pathway to Alzheimer’s disease, caused by a VZV infection which creates inflammatory triggers that awaken HSV in the brain,” lead author Dana Cairns, PhD, research associate, department of biomedical engineering at Tufts University, Boston, said in a news release.

The findings were published online  in Journal of Alzheimer’s Disease.
 

‘One-two punch’

Previous research has suggested a correlation between HSV-1 and AD and involvement of VZV. However, the sequence of events that the viruses create to set the disease in motion has been unclear.

“We think we now have evidence of those events,” co–senior author David Kaplan, PhD, chair of the department of biomedical engineering at Tufts, said in the release.

Working with co–senior author Ruth Itzhaki, PhD, University of Oxford, United Kingdom, the researchers infected human-induced neural stem cells (hiNSCs) and 3D brain tissue models with HSV-1 and/or VZV. Dr. Itzhaki was one of the first to hypothesize a connection between herpes virus and AD.

The investigators found that HSV-1 infection of hiNSCs induces amyloid-beta and P-tau accumulation: the main components of AD plaques and neurofibrillary tangles, respectively.

On the other hand, VZV infection of cultured hiNSCs did not lead to amyloid-beta and P-tau accumulation but instead resulted in gliosis and increased levels of proinflammatory cytokines.

“Strikingly,” VZV infection of cells quiescently infected with HSV-1 caused reactivation of HSV-1, leading to AD-like changes, including amyloid-beta and P-tau accumulation, the investigators report.

This suggests that VZV is unlikely to be a direct cause of AD but rather acts indirectly via reactivation of HSV-1, they add.

Similar findings emerged in similar experiments using 3D human brain tissue models.

“It’s a one-two punch of two viruses that are very common and usually harmless, but the lab studies suggest that if a new exposure to VZV wakes up dormant HSV-1, they could cause trouble,” Dr. Cairns said.

The researchers note that vaccination against VZV has been shown previously to reduce risk for dementia. It is possible, they add, that the vaccine is helping to stop the cycle of viral reactivation, inflammation, and neuronal damage.
 

‘A first step’

Heather M. Snyder, PhD, vice president of Medical & Scientific Relations at the Alzheimer’s Association, said that the study “is using artificial systems with the goal of more clearly and more deeply understanding” the assessed associations.

She added that although it is a first step, it may provide valuable direction for follow-up research.

“This is preliminary work that first needs replication, validation, and further development to understand if any association that is uncovered between viruses and Alzheimer’s/dementia has a mechanistic link,” said Dr. Snyder.

She noted that several past studies have sought to help the research field better understand the links between different viruses and Alzheimer’s and other forms of dementia.

“There have been some challenges in evaluating these associations in our current model systems or in individuals for a number of reasons,” said Dr. Snyder.

However, “the COVID-19 pandemic has created an opportunity to examine and investigate the relationships between different viruses and Alzheimer’s and other dementias by following individuals in more common and well-established ways,” she added.

She reported that her organization is “leading and working with a large global network of studies and investigators to address some of these questions” from during and after the COVID pandemic.

“The lessons we learn and share may inform our understanding of how other viruses are, or are not, connected to Alzheimer’s and other dementia,” Dr. Snyder said.

More information on the Alzheimer’s Association International Cohort Study of Chronic Neurological Sequelae of SARS-CoV-2 is available online.

The study was funded by the National Institutes of Health. Dr. Cairns, Dr. Kaplan, Dr. Itzhaki, and Dr. Snyder have reported no relevant financial relationships.

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

Varicella zoster virus (VZV) infection may activate dormant herpes simplex virus (HSV-1), leading to neuroinflammation and accumulation of Alzheimer’s disease (AD)–related proteins in the brain, new research suggests.

“Our results suggest one pathway to Alzheimer’s disease, caused by a VZV infection which creates inflammatory triggers that awaken HSV in the brain,” lead author Dana Cairns, PhD, research associate, department of biomedical engineering at Tufts University, Boston, said in a news release.

The findings were published online  in Journal of Alzheimer’s Disease.
 

‘One-two punch’

Previous research has suggested a correlation between HSV-1 and AD and involvement of VZV. However, the sequence of events that the viruses create to set the disease in motion has been unclear.

“We think we now have evidence of those events,” co–senior author David Kaplan, PhD, chair of the department of biomedical engineering at Tufts, said in the release.

Working with co–senior author Ruth Itzhaki, PhD, University of Oxford, United Kingdom, the researchers infected human-induced neural stem cells (hiNSCs) and 3D brain tissue models with HSV-1 and/or VZV. Dr. Itzhaki was one of the first to hypothesize a connection between herpes virus and AD.

The investigators found that HSV-1 infection of hiNSCs induces amyloid-beta and P-tau accumulation: the main components of AD plaques and neurofibrillary tangles, respectively.

On the other hand, VZV infection of cultured hiNSCs did not lead to amyloid-beta and P-tau accumulation but instead resulted in gliosis and increased levels of proinflammatory cytokines.

“Strikingly,” VZV infection of cells quiescently infected with HSV-1 caused reactivation of HSV-1, leading to AD-like changes, including amyloid-beta and P-tau accumulation, the investigators report.

This suggests that VZV is unlikely to be a direct cause of AD but rather acts indirectly via reactivation of HSV-1, they add.

Similar findings emerged in similar experiments using 3D human brain tissue models.

“It’s a one-two punch of two viruses that are very common and usually harmless, but the lab studies suggest that if a new exposure to VZV wakes up dormant HSV-1, they could cause trouble,” Dr. Cairns said.

The researchers note that vaccination against VZV has been shown previously to reduce risk for dementia. It is possible, they add, that the vaccine is helping to stop the cycle of viral reactivation, inflammation, and neuronal damage.
 

‘A first step’

Heather M. Snyder, PhD, vice president of Medical & Scientific Relations at the Alzheimer’s Association, said that the study “is using artificial systems with the goal of more clearly and more deeply understanding” the assessed associations.

She added that although it is a first step, it may provide valuable direction for follow-up research.

“This is preliminary work that first needs replication, validation, and further development to understand if any association that is uncovered between viruses and Alzheimer’s/dementia has a mechanistic link,” said Dr. Snyder.

She noted that several past studies have sought to help the research field better understand the links between different viruses and Alzheimer’s and other forms of dementia.

“There have been some challenges in evaluating these associations in our current model systems or in individuals for a number of reasons,” said Dr. Snyder.

However, “the COVID-19 pandemic has created an opportunity to examine and investigate the relationships between different viruses and Alzheimer’s and other dementias by following individuals in more common and well-established ways,” she added.

She reported that her organization is “leading and working with a large global network of studies and investigators to address some of these questions” from during and after the COVID pandemic.

“The lessons we learn and share may inform our understanding of how other viruses are, or are not, connected to Alzheimer’s and other dementia,” Dr. Snyder said.

More information on the Alzheimer’s Association International Cohort Study of Chronic Neurological Sequelae of SARS-CoV-2 is available online.

The study was funded by the National Institutes of Health. Dr. Cairns, Dr. Kaplan, Dr. Itzhaki, and Dr. Snyder have reported no relevant financial relationships.

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

Varicella zoster virus (VZV) infection may activate dormant herpes simplex virus (HSV-1), leading to neuroinflammation and accumulation of Alzheimer’s disease (AD)–related proteins in the brain, new research suggests.

“Our results suggest one pathway to Alzheimer’s disease, caused by a VZV infection which creates inflammatory triggers that awaken HSV in the brain,” lead author Dana Cairns, PhD, research associate, department of biomedical engineering at Tufts University, Boston, said in a news release.

The findings were published online  in Journal of Alzheimer’s Disease.
 

‘One-two punch’

Previous research has suggested a correlation between HSV-1 and AD and involvement of VZV. However, the sequence of events that the viruses create to set the disease in motion has been unclear.

“We think we now have evidence of those events,” co–senior author David Kaplan, PhD, chair of the department of biomedical engineering at Tufts, said in the release.

Working with co–senior author Ruth Itzhaki, PhD, University of Oxford, United Kingdom, the researchers infected human-induced neural stem cells (hiNSCs) and 3D brain tissue models with HSV-1 and/or VZV. Dr. Itzhaki was one of the first to hypothesize a connection between herpes virus and AD.

The investigators found that HSV-1 infection of hiNSCs induces amyloid-beta and P-tau accumulation: the main components of AD plaques and neurofibrillary tangles, respectively.

On the other hand, VZV infection of cultured hiNSCs did not lead to amyloid-beta and P-tau accumulation but instead resulted in gliosis and increased levels of proinflammatory cytokines.

“Strikingly,” VZV infection of cells quiescently infected with HSV-1 caused reactivation of HSV-1, leading to AD-like changes, including amyloid-beta and P-tau accumulation, the investigators report.

This suggests that VZV is unlikely to be a direct cause of AD but rather acts indirectly via reactivation of HSV-1, they add.

Similar findings emerged in similar experiments using 3D human brain tissue models.

“It’s a one-two punch of two viruses that are very common and usually harmless, but the lab studies suggest that if a new exposure to VZV wakes up dormant HSV-1, they could cause trouble,” Dr. Cairns said.

The researchers note that vaccination against VZV has been shown previously to reduce risk for dementia. It is possible, they add, that the vaccine is helping to stop the cycle of viral reactivation, inflammation, and neuronal damage.
 

‘A first step’

Heather M. Snyder, PhD, vice president of Medical & Scientific Relations at the Alzheimer’s Association, said that the study “is using artificial systems with the goal of more clearly and more deeply understanding” the assessed associations.

She added that although it is a first step, it may provide valuable direction for follow-up research.

“This is preliminary work that first needs replication, validation, and further development to understand if any association that is uncovered between viruses and Alzheimer’s/dementia has a mechanistic link,” said Dr. Snyder.

She noted that several past studies have sought to help the research field better understand the links between different viruses and Alzheimer’s and other forms of dementia.

“There have been some challenges in evaluating these associations in our current model systems or in individuals for a number of reasons,” said Dr. Snyder.

However, “the COVID-19 pandemic has created an opportunity to examine and investigate the relationships between different viruses and Alzheimer’s and other dementias by following individuals in more common and well-established ways,” she added.

She reported that her organization is “leading and working with a large global network of studies and investigators to address some of these questions” from during and after the COVID pandemic.

“The lessons we learn and share may inform our understanding of how other viruses are, or are not, connected to Alzheimer’s and other dementia,” Dr. Snyder said.

More information on the Alzheimer’s Association International Cohort Study of Chronic Neurological Sequelae of SARS-CoV-2 is available online.

The study was funded by the National Institutes of Health. Dr. Cairns, Dr. Kaplan, Dr. Itzhaki, and Dr. Snyder have reported no relevant financial relationships.

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

The transcript has been edited for clarity.

Welcome to Impact Factor, your weekly dose of commentary on a new medical study. I’m Dr. F. Perry Wilson of the Yale School of Medicine.

Once again, we’re doing an informal journal club to talk about a really interesting study, “A Neuro-metabolic Account of Why Daylong Cognitive Work Alters the Control of Economic Decisions,” that just came out. It tries to answer the question of why our brains wear out. I’m going to put myself in the corner here. Let’s walk through this study, which appears in Current Biology, by lead author Antonius Wiehler from Paris.

The big question is what’s going on with cognitive fatigue. If you look at chess players who are exerting a lot of cognitive effort, it’s well documented that over hours of play, they get worse and make more mistakes. It takes them longer to make decisions. The question is, why?

Why does your brain get tired?

To date, it’s been a little bit hard to tease that out. Now, there is some suggestion of what is responsible for this. The cognitive control center of the brain is probably somewhere in the left lateral prefrontal cortex (LLPC).

The prefrontal cortex is responsible for higher-level thinking. It’s what causes you to be inhibited. It gets shut off by alcohol and leads to impulsive behaviors. The LLPC, according to functional MRI studies, has reduced activity as people become more and more cognitively fatigued. The LLPC helps you think through choices. As you become more fatigued, this area of the brain isn’t working as well. But why would it not work as well? What is going on in that particular part of the brain? It doesn’t seem to be something simple, like glucose levels; that’s been investigated and glucose levels are pretty constant throughout the brain, regardless of cognitive task. This paper seeks to tease out what is actually going on in the LLPC when you are becoming cognitively tired.

They did an experiment where they induced cognitive fatigue, and it sounds like a painful experiment. For more than 6 hours, volunteers completed sessions during which they had to perform cognitive switching tasks. Investigators showed participants a letter, in either red or green, and the participant would respond with whether it was a vowel or a consonant or whether it was a capital or lowercase letter, based on the color. If it’s red, say whether it’s a consonant or vowel. If it’s green, say whether it’s upper- or lowercase.

It’s hard, and doing it for 6 hours is likely to induce a lot of cognitive fatigue. They had a control group as well, which is really important here. The control group also did a task like this for 6 hours, but for them, investigators didn’t change the color as often – perhaps only once per session. For the study group, they were switching colors back and forth quite a lot. They also incorporated a memory challenge that worked in a similar way.

So, what are the readouts of this study? They had a group who went through the hard cognitive challenge and a group who went through the easy cognitive challenge. They looked at a variety of metrics. I’ll describe a few.

The first is performance decrement. Did they get it wrong? What percentage of the time did the participant say “consonant” when they should have said “lowercase?”

• Have a 25% chance of earning $50 OR a 95% chance of earning $17.30?
• Earn $50, but your next task session will be hard or earn $40 and your next task session will be easy?

Participants had to figure out the better odds – what should they be choosing here? They had to tease out whether they preferred lower cost lower-risk choices – when they are cognitively fatigued, which has been shown in prior studies.

Dr. Wilson is an associate professor of medicine and director of the Clinical and Translational Research Accelerator at Yale University, New Haven, Conn. He reported no relevant conflicts of interest.

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

The transcript has been edited for clarity.

Welcome to Impact Factor, your weekly dose of commentary on a new medical study. I’m Dr. F. Perry Wilson of the Yale School of Medicine.

Once again, we’re doing an informal journal club to talk about a really interesting study, “A Neuro-metabolic Account of Why Daylong Cognitive Work Alters the Control of Economic Decisions,” that just came out. It tries to answer the question of why our brains wear out. I’m going to put myself in the corner here. Let’s walk through this study, which appears in Current Biology, by lead author Antonius Wiehler from Paris.

The big question is what’s going on with cognitive fatigue. If you look at chess players who are exerting a lot of cognitive effort, it’s well documented that over hours of play, they get worse and make more mistakes. It takes them longer to make decisions. The question is, why?

Why does your brain get tired?

To date, it’s been a little bit hard to tease that out. Now, there is some suggestion of what is responsible for this. The cognitive control center of the brain is probably somewhere in the left lateral prefrontal cortex (LLPC).

The prefrontal cortex is responsible for higher-level thinking. It’s what causes you to be inhibited. It gets shut off by alcohol and leads to impulsive behaviors. The LLPC, according to functional MRI studies, has reduced activity as people become more and more cognitively fatigued. The LLPC helps you think through choices. As you become more fatigued, this area of the brain isn’t working as well. But why would it not work as well? What is going on in that particular part of the brain? It doesn’t seem to be something simple, like glucose levels; that’s been investigated and glucose levels are pretty constant throughout the brain, regardless of cognitive task. This paper seeks to tease out what is actually going on in the LLPC when you are becoming cognitively tired.

They did an experiment where they induced cognitive fatigue, and it sounds like a painful experiment. For more than 6 hours, volunteers completed sessions during which they had to perform cognitive switching tasks. Investigators showed participants a letter, in either red or green, and the participant would respond with whether it was a vowel or a consonant or whether it was a capital or lowercase letter, based on the color. If it’s red, say whether it’s a consonant or vowel. If it’s green, say whether it’s upper- or lowercase.

It’s hard, and doing it for 6 hours is likely to induce a lot of cognitive fatigue. They had a control group as well, which is really important here. The control group also did a task like this for 6 hours, but for them, investigators didn’t change the color as often – perhaps only once per session. For the study group, they were switching colors back and forth quite a lot. They also incorporated a memory challenge that worked in a similar way.

So, what are the readouts of this study? They had a group who went through the hard cognitive challenge and a group who went through the easy cognitive challenge. They looked at a variety of metrics. I’ll describe a few.

The first is performance decrement. Did they get it wrong? What percentage of the time did the participant say “consonant” when they should have said “lowercase?”

• Have a 25% chance of earning $50 OR a 95% chance of earning $17.30?
• Earn $50, but your next task session will be hard or earn $40 and your next task session will be easy?

Participants had to figure out the better odds – what should they be choosing here? They had to tease out whether they preferred lower cost lower-risk choices – when they are cognitively fatigued, which has been shown in prior studies.

Dr. Wilson is an associate professor of medicine and director of the Clinical and Translational Research Accelerator at Yale University, New Haven, Conn. He reported no relevant conflicts of interest.

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

The transcript has been edited for clarity.

Welcome to Impact Factor, your weekly dose of commentary on a new medical study. I’m Dr. F. Perry Wilson of the Yale School of Medicine.

Once again, we’re doing an informal journal club to talk about a really interesting study, “A Neuro-metabolic Account of Why Daylong Cognitive Work Alters the Control of Economic Decisions,” that just came out. It tries to answer the question of why our brains wear out. I’m going to put myself in the corner here. Let’s walk through this study, which appears in Current Biology, by lead author Antonius Wiehler from Paris.

The big question is what’s going on with cognitive fatigue. If you look at chess players who are exerting a lot of cognitive effort, it’s well documented that over hours of play, they get worse and make more mistakes. It takes them longer to make decisions. The question is, why?

Why does your brain get tired?

To date, it’s been a little bit hard to tease that out. Now, there is some suggestion of what is responsible for this. The cognitive control center of the brain is probably somewhere in the left lateral prefrontal cortex (LLPC).

The prefrontal cortex is responsible for higher-level thinking. It’s what causes you to be inhibited. It gets shut off by alcohol and leads to impulsive behaviors. The LLPC, according to functional MRI studies, has reduced activity as people become more and more cognitively fatigued. The LLPC helps you think through choices. As you become more fatigued, this area of the brain isn’t working as well. But why would it not work as well? What is going on in that particular part of the brain? It doesn’t seem to be something simple, like glucose levels; that’s been investigated and glucose levels are pretty constant throughout the brain, regardless of cognitive task. This paper seeks to tease out what is actually going on in the LLPC when you are becoming cognitively tired.

They did an experiment where they induced cognitive fatigue, and it sounds like a painful experiment. For more than 6 hours, volunteers completed sessions during which they had to perform cognitive switching tasks. Investigators showed participants a letter, in either red or green, and the participant would respond with whether it was a vowel or a consonant or whether it was a capital or lowercase letter, based on the color. If it’s red, say whether it’s a consonant or vowel. If it’s green, say whether it’s upper- or lowercase.

It’s hard, and doing it for 6 hours is likely to induce a lot of cognitive fatigue. They had a control group as well, which is really important here. The control group also did a task like this for 6 hours, but for them, investigators didn’t change the color as often – perhaps only once per session. For the study group, they were switching colors back and forth quite a lot. They also incorporated a memory challenge that worked in a similar way.

So, what are the readouts of this study? They had a group who went through the hard cognitive challenge and a group who went through the easy cognitive challenge. They looked at a variety of metrics. I’ll describe a few.

The first is performance decrement. Did they get it wrong? What percentage of the time did the participant say “consonant” when they should have said “lowercase?”

• Have a 25% chance of earning $50 OR a 95% chance of earning $17.30?
• Earn $50, but your next task session will be hard or earn $40 and your next task session will be easy?

Participants had to figure out the better odds – what should they be choosing here? They had to tease out whether they preferred lower cost lower-risk choices – when they are cognitively fatigued, which has been shown in prior studies.

Dr. Wilson is an associate professor of medicine and director of the Clinical and Translational Research Accelerator at Yale University, New Haven, Conn. He reported no relevant conflicts of interest.

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

SAN DIEGO – In 1906, a neuroanatomist and psychiatrist named Alois Alzheimer examined the brain of a 50-year-old woman whom he had treated for paranoia, sleep and memory problems, aggression, and confusion. His autopsy revealed plaques and tangles in her brain. The most common components of these tangles are beta-amyloid peptide (A-beta) and the microtubule binding protein tau. Over the past few decades, that finding has launched many clinical development programs and dozens of clinical trials.

To date, all but one program has failed. In 2021, amidst much controversy, FDA granted accelerated approval to Biogen’s Aduhelm, which effectively clears A-beta and tau deposits from patients’ brains. The problem is that the clinical benefit is small, and uptake has been so low that the company was forced to abandon a planned postmarketing observational trial.
 

Chasing the wrong target?

At a session at the 2022 Alzheimer’s Association International Conference, Raymond J. Tesi, MD, rather forcefully refuted that approach. “Amyloid and tau therapies have had 20 years to prove themselves. We have multiple cases where we’ve been able to decrease amyloid, maybe not so much tau, but certainly amyloid, and the benefits are mild at best. So I think that the Alzheimer’s drug development community, whether you look at the NIH, whether you look at academia, whether you look at biopharma, has focused on a target that has not proven itself, and it’s time to move on,” said Dr. Tesi, who is president, CEO, and chief medical officer at INmune Bio.

Later in the session, researchers presented strategies to counter Alzheimer’s disease and other neurodegenerative conditions using strategies including modulation of metabolism and inflammation, support of brain homeostasis, and suppression of a broader range of neurotoxic proteins.

One audience member defended the potential importance of A-beta and tau, especially in astrogliosis, which is a reaction to stress by astrocytes that attempts to limit tissue damage. The questioner suggested that it was still important to measure the effect of a novel drug on A-beta and tau. “What would be the cause of the reactive astrogliosis and microglia activation, if we are not giving a damn about amyloid and tau?” he asked.

After a bit of back and forth, Dr. Tesi replied: “We both have a religious belief here, and sooner or later we’ll get the answer.”
 

A diverse clinical pipeline

The session itself focused on four companies, including Dr. Tesi’s INmune Bio, which have drugs with alternative mechanisms entering the advanced stages of clinical development. That’s good news, according to Heather Snyder, PhD, who is vice president of Medical & Scientific Relations at the Alzheimer’s Association. “One of the things that I think is really important is the diversity of what’s in the clinical pipeline, and it’s not just in the very beginning anymore. We’re seeing [companies] now reporting phase 2 [studies] and planning their next stage. That’s something that as a field we should be excited about. As we understand more and more about the biology, we’re now seeing that translating into clinical trials and we’re seeing that translate through the clinical pipeline of development,” said Dr. Snyder in an interview.

Targeting neuroinflammation

Dr. Tesi kicked off the session describing INmune Bio’s focus on neuroinflammation. The company’s drug candidate targets soluble tumor necrosis factor (TNF), which the company believes is a direct cause of Alzheimer’s disease through promotion of inflammation. He noted that TNF is a primary mediator of inflammation in rheumatoid arthritis, and patients with RA have an eightfold increased risk of developing Alzheimer’s disease, compared with the general population, while patients with RA who are taking anti-TNF medication have a 60% lower risk than the general population.

The company’s TNF inhibitor XPro is also unique in that it induces remyelination in mice, while other TNF inhibitors potentially “abuse” the brain by causing demyelination. Earlier research showed that it reduces neuroinflammation, improves nerve cell survival, and improves synaptic function. The company is conducting two phase 2 clinical trials, one in patients with mild cognitive impairment (MCI) and one in mild Alzheimer’s disease. They also use the MCI Alzheimer’s Cognitive Composite (EMACC) tool for assessing outcomes rather than the more commonly used Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog). “ADAS-Cog is like trying to make sushi with an axe. It is designed for moderate to severe disease, and trying to use it for mild (Alzheimer’s disease) or MCI is a mistake. EMACC is purpose built for mild [AD] and MCI patients,” said Dr. Tesi.
 

Maintaining homeostatis

Next, Hans Moebius, MD, PhD, chief medical officer of Athira Pharma, described his company’s focus on the hepatocyte growth factor (HGF) receptor, also known as tyrosine kinase MET (HGF/MET). It plays an important role in brain development and homeostasis, and it is expressed at lower levels in the frontal cortex and hippocampus of patients with Alzheimer’s disease. The company’s small-molecule drug candidate boosts the HGF/MET pathway, leading to downstream neuroprotection and neurotrophic effects. It also promotes formation of new synapses.

Dr. Moebius presented the results of a phase 2 trial showing that the drug, called fosgonimeton, led to significant cognitive improvement compared with placebo. The company is conducting a phase 3 clinical trial.
 

Type 3 diabetes?

In his talk, John Didsbury, PhD, founder and CEO of T3D Therapeutics, framed Alzheimer’s disease as a disease of metabolic dysfunction. He believes alterations to glucose and lipids in the brain cause structural changes that lead to symptoms. He pointed out that the strongest genetic Alzheimer’s disease risk factor is a mutant form of the lipid transport protein APOE4.

“What we have is dysregulated glucose energy metabolism and lipid metabolism that really cause, in our mind, the structural event changes and the stress event changes – plaques, tangles, inflammation, etc. – but these events perpetuate the dysregulated metabolism. It’s a massive positive feedback loop that many have called type 3 diabetes – a brain-specific form of diabetes,” said Dr. Didsbury.

The company’s approach is to use systems biology to identify a drug target that can bypass multiple aberrant insulin signaling pathways. Its drug candidate regulates the expression of multiple genes involved in glucose metabolism. Dr. Didsbury presented interim results from a phase 2 study showing improvement over placebo.
 

Focusing on neurotoxic proteins

The final presentation of the session was by Maria Maccecchini, PhD, founder, president, and CEO of Annovis Bio. The company’s drug, buntanetap, reduces expression of a range of neurotoxic proteins. The downstream effects include restoration of axonal transport, reduction of inflammation, and protection of nerve cells. The company believes that Alzheimer’s disease results from acute and chronic stress events that lead to high levels of neurotoxic proteins, which include A-beta, tau, alpha-synuclein, and TDP43. The proteins aren’t just players in Alzheimer’s disease – they are present in abnormal levels in Parkinson’s disease and a range of other brain pathologies.

“In the brain of an Alzheimer’s and of a Parkinson’s [patient], you’re going to find all four proteins. You’ll find them in different concentrations, at different time points, in different brain areas. If you just remove one, you still have the other three that cause impairment in axonal transport, and that leads to inflammation that leads to neurodegeneration,” said Dr. Maccecchini.

The company’s drug manages to reduce levels of all four proteins by binding to a segment of messenger RNA (mRNA) shared by all of them. mRNA serves as a template for protein synthesis. Under normal conditions, the neurotoxic protein concentrations are kept low because the mRNA segment remains bound to a regulatory protein that prevents synthesis from occurring. However, when stress leads to high levels of iron, this regulatory binding protein releases the mRNA segment (along with the rest of the mRNA). The freed mRNA becomes available to the cell’s protein synthesis machinery, which starts producing high levels of neurotoxic proteins. Annovis Bio’s drug improves the ability of the regulatory protein to bind to the mRNA segment, preventing protein expression even in high-iron conditions. It works on all four neurotoxic proteins because they all have the regulatory segment in their mRNA.

The drug led to improvements in phase 2 studies of Alzheimer’s disease and Parkinson’s disease, and the company is currently recruiting for a phase 3 study in Parkinson’s disease and a phase 2/3 dose-response study in Alzheimer’s disease.
 

Combination treatments for a complex disease

Taken together, the presentations provided a snapshot of the post–A-beta/tau Alzheimer’s development world, and the future could be messy. Alzheimer’s disease and other dementias are likely to require combination treatments, according to Dr. Snyder. “This is a complex disease, not just Alzheimer’s but other dementias. It’s not going to be a single drug, a single target. It’s going to require some type of combinatorial approach, whether that be with medication and lifestyle interventions, or risk reduction, and different medications,” she said.

The latest results are good news for that approach: “We’re seeing that maturation of the science in these trials,” said Dr. Snyder.

Cheng Fang, PhD, senior vice president of research and development at Annovis Bio, agreed with that sentiment. “I believe [Alzheimer’s disease and dementia] is a very complicated disease. I always call them diseases instead of a disease because it’s a spectrum. I don’t believe one drug can cure them all, as much as I am confident in our drug. I think it’s extremely important to encourage this kind of diverse thinking,” said Dr. Fang.

Dr. Snyder has no relevant financial disclosures. Dr. Tesi, Dr. Moebius, Dr. Didsbury, Dr. Maccecchini, and Dr. Fang are employees and in some cases stockholders of their respective companies.

SAN DIEGO – In 1906, a neuroanatomist and psychiatrist named Alois Alzheimer examined the brain of a 50-year-old woman whom he had treated for paranoia, sleep and memory problems, aggression, and confusion. His autopsy revealed plaques and tangles in her brain. The most common components of these tangles are beta-amyloid peptide (A-beta) and the microtubule binding protein tau. Over the past few decades, that finding has launched many clinical development programs and dozens of clinical trials.

To date, all but one program has failed. In 2021, amidst much controversy, FDA granted accelerated approval to Biogen’s Aduhelm, which effectively clears A-beta and tau deposits from patients’ brains. The problem is that the clinical benefit is small, and uptake has been so low that the company was forced to abandon a planned postmarketing observational trial.
 

Chasing the wrong target?

At a session at the 2022 Alzheimer’s Association International Conference, Raymond J. Tesi, MD, rather forcefully refuted that approach. “Amyloid and tau therapies have had 20 years to prove themselves. We have multiple cases where we’ve been able to decrease amyloid, maybe not so much tau, but certainly amyloid, and the benefits are mild at best. So I think that the Alzheimer’s drug development community, whether you look at the NIH, whether you look at academia, whether you look at biopharma, has focused on a target that has not proven itself, and it’s time to move on,” said Dr. Tesi, who is president, CEO, and chief medical officer at INmune Bio.

Later in the session, researchers presented strategies to counter Alzheimer’s disease and other neurodegenerative conditions using strategies including modulation of metabolism and inflammation, support of brain homeostasis, and suppression of a broader range of neurotoxic proteins.

One audience member defended the potential importance of A-beta and tau, especially in astrogliosis, which is a reaction to stress by astrocytes that attempts to limit tissue damage. The questioner suggested that it was still important to measure the effect of a novel drug on A-beta and tau. “What would be the cause of the reactive astrogliosis and microglia activation, if we are not giving a damn about amyloid and tau?” he asked.

After a bit of back and forth, Dr. Tesi replied: “We both have a religious belief here, and sooner or later we’ll get the answer.”
 

A diverse clinical pipeline

The session itself focused on four companies, including Dr. Tesi’s INmune Bio, which have drugs with alternative mechanisms entering the advanced stages of clinical development. That’s good news, according to Heather Snyder, PhD, who is vice president of Medical & Scientific Relations at the Alzheimer’s Association. “One of the things that I think is really important is the diversity of what’s in the clinical pipeline, and it’s not just in the very beginning anymore. We’re seeing [companies] now reporting phase 2 [studies] and planning their next stage. That’s something that as a field we should be excited about. As we understand more and more about the biology, we’re now seeing that translating into clinical trials and we’re seeing that translate through the clinical pipeline of development,” said Dr. Snyder in an interview.

Targeting neuroinflammation

Dr. Tesi kicked off the session describing INmune Bio’s focus on neuroinflammation. The company’s drug candidate targets soluble tumor necrosis factor (TNF), which the company believes is a direct cause of Alzheimer’s disease through promotion of inflammation. He noted that TNF is a primary mediator of inflammation in rheumatoid arthritis, and patients with RA have an eightfold increased risk of developing Alzheimer’s disease, compared with the general population, while patients with RA who are taking anti-TNF medication have a 60% lower risk than the general population.

The company’s TNF inhibitor XPro is also unique in that it induces remyelination in mice, while other TNF inhibitors potentially “abuse” the brain by causing demyelination. Earlier research showed that it reduces neuroinflammation, improves nerve cell survival, and improves synaptic function. The company is conducting two phase 2 clinical trials, one in patients with mild cognitive impairment (MCI) and one in mild Alzheimer’s disease. They also use the MCI Alzheimer’s Cognitive Composite (EMACC) tool for assessing outcomes rather than the more commonly used Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog). “ADAS-Cog is like trying to make sushi with an axe. It is designed for moderate to severe disease, and trying to use it for mild (Alzheimer’s disease) or MCI is a mistake. EMACC is purpose built for mild [AD] and MCI patients,” said Dr. Tesi.
 

Maintaining homeostatis

Next, Hans Moebius, MD, PhD, chief medical officer of Athira Pharma, described his company’s focus on the hepatocyte growth factor (HGF) receptor, also known as tyrosine kinase MET (HGF/MET). It plays an important role in brain development and homeostasis, and it is expressed at lower levels in the frontal cortex and hippocampus of patients with Alzheimer’s disease. The company’s small-molecule drug candidate boosts the HGF/MET pathway, leading to downstream neuroprotection and neurotrophic effects. It also promotes formation of new synapses.

Dr. Moebius presented the results of a phase 2 trial showing that the drug, called fosgonimeton, led to significant cognitive improvement compared with placebo. The company is conducting a phase 3 clinical trial.
 

Type 3 diabetes?

In his talk, John Didsbury, PhD, founder and CEO of T3D Therapeutics, framed Alzheimer’s disease as a disease of metabolic dysfunction. He believes alterations to glucose and lipids in the brain cause structural changes that lead to symptoms. He pointed out that the strongest genetic Alzheimer’s disease risk factor is a mutant form of the lipid transport protein APOE4.

“What we have is dysregulated glucose energy metabolism and lipid metabolism that really cause, in our mind, the structural event changes and the stress event changes – plaques, tangles, inflammation, etc. – but these events perpetuate the dysregulated metabolism. It’s a massive positive feedback loop that many have called type 3 diabetes – a brain-specific form of diabetes,” said Dr. Didsbury.

The company’s approach is to use systems biology to identify a drug target that can bypass multiple aberrant insulin signaling pathways. Its drug candidate regulates the expression of multiple genes involved in glucose metabolism. Dr. Didsbury presented interim results from a phase 2 study showing improvement over placebo.
 

Focusing on neurotoxic proteins

The final presentation of the session was by Maria Maccecchini, PhD, founder, president, and CEO of Annovis Bio. The company’s drug, buntanetap, reduces expression of a range of neurotoxic proteins. The downstream effects include restoration of axonal transport, reduction of inflammation, and protection of nerve cells. The company believes that Alzheimer’s disease results from acute and chronic stress events that lead to high levels of neurotoxic proteins, which include A-beta, tau, alpha-synuclein, and TDP43. The proteins aren’t just players in Alzheimer’s disease – they are present in abnormal levels in Parkinson’s disease and a range of other brain pathologies.

“In the brain of an Alzheimer’s and of a Parkinson’s [patient], you’re going to find all four proteins. You’ll find them in different concentrations, at different time points, in different brain areas. If you just remove one, you still have the other three that cause impairment in axonal transport, and that leads to inflammation that leads to neurodegeneration,” said Dr. Maccecchini.

The company’s drug manages to reduce levels of all four proteins by binding to a segment of messenger RNA (mRNA) shared by all of them. mRNA serves as a template for protein synthesis. Under normal conditions, the neurotoxic protein concentrations are kept low because the mRNA segment remains bound to a regulatory protein that prevents synthesis from occurring. However, when stress leads to high levels of iron, this regulatory binding protein releases the mRNA segment (along with the rest of the mRNA). The freed mRNA becomes available to the cell’s protein synthesis machinery, which starts producing high levels of neurotoxic proteins. Annovis Bio’s drug improves the ability of the regulatory protein to bind to the mRNA segment, preventing protein expression even in high-iron conditions. It works on all four neurotoxic proteins because they all have the regulatory segment in their mRNA.

The drug led to improvements in phase 2 studies of Alzheimer’s disease and Parkinson’s disease, and the company is currently recruiting for a phase 3 study in Parkinson’s disease and a phase 2/3 dose-response study in Alzheimer’s disease.
 

Combination treatments for a complex disease

Taken together, the presentations provided a snapshot of the post–A-beta/tau Alzheimer’s development world, and the future could be messy. Alzheimer’s disease and other dementias are likely to require combination treatments, according to Dr. Snyder. “This is a complex disease, not just Alzheimer’s but other dementias. It’s not going to be a single drug, a single target. It’s going to require some type of combinatorial approach, whether that be with medication and lifestyle interventions, or risk reduction, and different medications,” she said.

The latest results are good news for that approach: “We’re seeing that maturation of the science in these trials,” said Dr. Snyder.

Cheng Fang, PhD, senior vice president of research and development at Annovis Bio, agreed with that sentiment. “I believe [Alzheimer’s disease and dementia] is a very complicated disease. I always call them diseases instead of a disease because it’s a spectrum. I don’t believe one drug can cure them all, as much as I am confident in our drug. I think it’s extremely important to encourage this kind of diverse thinking,” said Dr. Fang.

Dr. Snyder has no relevant financial disclosures. Dr. Tesi, Dr. Moebius, Dr. Didsbury, Dr. Maccecchini, and Dr. Fang are employees and in some cases stockholders of their respective companies.

SAN DIEGO – In 1906, a neuroanatomist and psychiatrist named Alois Alzheimer examined the brain of a 50-year-old woman whom he had treated for paranoia, sleep and memory problems, aggression, and confusion. His autopsy revealed plaques and tangles in her brain. The most common components of these tangles are beta-amyloid peptide (A-beta) and the microtubule binding protein tau. Over the past few decades, that finding has launched many clinical development programs and dozens of clinical trials.

To date, all but one program has failed. In 2021, amidst much controversy, FDA granted accelerated approval to Biogen’s Aduhelm, which effectively clears A-beta and tau deposits from patients’ brains. The problem is that the clinical benefit is small, and uptake has been so low that the company was forced to abandon a planned postmarketing observational trial.
 

Chasing the wrong target?

At a session at the 2022 Alzheimer’s Association International Conference, Raymond J. Tesi, MD, rather forcefully refuted that approach. “Amyloid and tau therapies have had 20 years to prove themselves. We have multiple cases where we’ve been able to decrease amyloid, maybe not so much tau, but certainly amyloid, and the benefits are mild at best. So I think that the Alzheimer’s drug development community, whether you look at the NIH, whether you look at academia, whether you look at biopharma, has focused on a target that has not proven itself, and it’s time to move on,” said Dr. Tesi, who is president, CEO, and chief medical officer at INmune Bio.

Later in the session, researchers presented strategies to counter Alzheimer’s disease and other neurodegenerative conditions using strategies including modulation of metabolism and inflammation, support of brain homeostasis, and suppression of a broader range of neurotoxic proteins.

One audience member defended the potential importance of A-beta and tau, especially in astrogliosis, which is a reaction to stress by astrocytes that attempts to limit tissue damage. The questioner suggested that it was still important to measure the effect of a novel drug on A-beta and tau. “What would be the cause of the reactive astrogliosis and microglia activation, if we are not giving a damn about amyloid and tau?” he asked.

After a bit of back and forth, Dr. Tesi replied: “We both have a religious belief here, and sooner or later we’ll get the answer.”
 

A diverse clinical pipeline

The session itself focused on four companies, including Dr. Tesi’s INmune Bio, which have drugs with alternative mechanisms entering the advanced stages of clinical development. That’s good news, according to Heather Snyder, PhD, who is vice president of Medical & Scientific Relations at the Alzheimer’s Association. “One of the things that I think is really important is the diversity of what’s in the clinical pipeline, and it’s not just in the very beginning anymore. We’re seeing [companies] now reporting phase 2 [studies] and planning their next stage. That’s something that as a field we should be excited about. As we understand more and more about the biology, we’re now seeing that translating into clinical trials and we’re seeing that translate through the clinical pipeline of development,” said Dr. Snyder in an interview.

Targeting neuroinflammation

Dr. Tesi kicked off the session describing INmune Bio’s focus on neuroinflammation. The company’s drug candidate targets soluble tumor necrosis factor (TNF), which the company believes is a direct cause of Alzheimer’s disease through promotion of inflammation. He noted that TNF is a primary mediator of inflammation in rheumatoid arthritis, and patients with RA have an eightfold increased risk of developing Alzheimer’s disease, compared with the general population, while patients with RA who are taking anti-TNF medication have a 60% lower risk than the general population.

The company’s TNF inhibitor XPro is also unique in that it induces remyelination in mice, while other TNF inhibitors potentially “abuse” the brain by causing demyelination. Earlier research showed that it reduces neuroinflammation, improves nerve cell survival, and improves synaptic function. The company is conducting two phase 2 clinical trials, one in patients with mild cognitive impairment (MCI) and one in mild Alzheimer’s disease. They also use the MCI Alzheimer’s Cognitive Composite (EMACC) tool for assessing outcomes rather than the more commonly used Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog). “ADAS-Cog is like trying to make sushi with an axe. It is designed for moderate to severe disease, and trying to use it for mild (Alzheimer’s disease) or MCI is a mistake. EMACC is purpose built for mild [AD] and MCI patients,” said Dr. Tesi.
 

Maintaining homeostatis

Next, Hans Moebius, MD, PhD, chief medical officer of Athira Pharma, described his company’s focus on the hepatocyte growth factor (HGF) receptor, also known as tyrosine kinase MET (HGF/MET). It plays an important role in brain development and homeostasis, and it is expressed at lower levels in the frontal cortex and hippocampus of patients with Alzheimer’s disease. The company’s small-molecule drug candidate boosts the HGF/MET pathway, leading to downstream neuroprotection and neurotrophic effects. It also promotes formation of new synapses.

Dr. Moebius presented the results of a phase 2 trial showing that the drug, called fosgonimeton, led to significant cognitive improvement compared with placebo. The company is conducting a phase 3 clinical trial.
 

Type 3 diabetes?

In his talk, John Didsbury, PhD, founder and CEO of T3D Therapeutics, framed Alzheimer’s disease as a disease of metabolic dysfunction. He believes alterations to glucose and lipids in the brain cause structural changes that lead to symptoms. He pointed out that the strongest genetic Alzheimer’s disease risk factor is a mutant form of the lipid transport protein APOE4.

“What we have is dysregulated glucose energy metabolism and lipid metabolism that really cause, in our mind, the structural event changes and the stress event changes – plaques, tangles, inflammation, etc. – but these events perpetuate the dysregulated metabolism. It’s a massive positive feedback loop that many have called type 3 diabetes – a brain-specific form of diabetes,” said Dr. Didsbury.

The company’s approach is to use systems biology to identify a drug target that can bypass multiple aberrant insulin signaling pathways. Its drug candidate regulates the expression of multiple genes involved in glucose metabolism. Dr. Didsbury presented interim results from a phase 2 study showing improvement over placebo.
 

Focusing on neurotoxic proteins

The final presentation of the session was by Maria Maccecchini, PhD, founder, president, and CEO of Annovis Bio. The company’s drug, buntanetap, reduces expression of a range of neurotoxic proteins. The downstream effects include restoration of axonal transport, reduction of inflammation, and protection of nerve cells. The company believes that Alzheimer’s disease results from acute and chronic stress events that lead to high levels of neurotoxic proteins, which include A-beta, tau, alpha-synuclein, and TDP43. The proteins aren’t just players in Alzheimer’s disease – they are present in abnormal levels in Parkinson’s disease and a range of other brain pathologies.

“In the brain of an Alzheimer’s and of a Parkinson’s [patient], you’re going to find all four proteins. You’ll find them in different concentrations, at different time points, in different brain areas. If you just remove one, you still have the other three that cause impairment in axonal transport, and that leads to inflammation that leads to neurodegeneration,” said Dr. Maccecchini.

The company’s drug manages to reduce levels of all four proteins by binding to a segment of messenger RNA (mRNA) shared by all of them. mRNA serves as a template for protein synthesis. Under normal conditions, the neurotoxic protein concentrations are kept low because the mRNA segment remains bound to a regulatory protein that prevents synthesis from occurring. However, when stress leads to high levels of iron, this regulatory binding protein releases the mRNA segment (along with the rest of the mRNA). The freed mRNA becomes available to the cell’s protein synthesis machinery, which starts producing high levels of neurotoxic proteins. Annovis Bio’s drug improves the ability of the regulatory protein to bind to the mRNA segment, preventing protein expression even in high-iron conditions. It works on all four neurotoxic proteins because they all have the regulatory segment in their mRNA.

The drug led to improvements in phase 2 studies of Alzheimer’s disease and Parkinson’s disease, and the company is currently recruiting for a phase 3 study in Parkinson’s disease and a phase 2/3 dose-response study in Alzheimer’s disease.
 

Combination treatments for a complex disease

Taken together, the presentations provided a snapshot of the post–A-beta/tau Alzheimer’s development world, and the future could be messy. Alzheimer’s disease and other dementias are likely to require combination treatments, according to Dr. Snyder. “This is a complex disease, not just Alzheimer’s but other dementias. It’s not going to be a single drug, a single target. It’s going to require some type of combinatorial approach, whether that be with medication and lifestyle interventions, or risk reduction, and different medications,” she said.

The latest results are good news for that approach: “We’re seeing that maturation of the science in these trials,” said Dr. Snyder.

Cheng Fang, PhD, senior vice president of research and development at Annovis Bio, agreed with that sentiment. “I believe [Alzheimer’s disease and dementia] is a very complicated disease. I always call them diseases instead of a disease because it’s a spectrum. I don’t believe one drug can cure them all, as much as I am confident in our drug. I think it’s extremely important to encourage this kind of diverse thinking,” said Dr. Fang.

Dr. Snyder has no relevant financial disclosures. Dr. Tesi, Dr. Moebius, Dr. Didsbury, Dr. Maccecchini, and Dr. Fang are employees and in some cases stockholders of their respective companies.

SAN DIEGO – Even after recovery of an acute COVID-19 infection, some patients experience extended or even long-term symptoms that can range from mild to debilitating. Some of these symptoms are neurological: headaches, brain fog, cognitive impairment, loss of taste or smell, and even cerebrovascular complications such stroke. There are even hints that COVID-19 infection could lead to future neurodegeneration.

Those issues have prompted efforts to identify biomarkers that can help track and monitor neurological complications of COVID-19. “Throughout the course of the pandemic, it has become apparent that COVID-19 can cause various neurological symptoms. Because of this, it’s really important for us to find a way to monitor and understand neurological complications occurring in patients with COVID 19,” Jennifer Cooper said during a lecture at the Alzheimer’s Association International Conference. She presented new research suggesting that neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) may prove useful.

Ms. Cooper is a master’s degree student at the University of British Columbia and Canada.
 

Looking for sensitivity and specificity in plasma biomarkers

The researchers turned to plasma-based markers because they can reflect underlying pathology in the central nervous system. They focused on NfL, which reflects axonal damage, and GFAP, which is a marker of astrocyte activation.

The researchers analyzed data from 209 patients with COVID-19 who were admitted to the Vancouver (B.C.) General Hospital intensive care unit. Sixty-four percent were male, and the median age was 61 years. Sixty percent were ventilated, and 17% died.

The researchers determined if an individual patient’s biomarker level at hospital admission fell within a normal biomarker reference interval. A total of 53% had NfL levels outside the normal range, and 42% had GFAP levels outside the normal range. In addition, 31% of patients had both GFAP and NfL levels outside of the normal range.

Among all patients, 12% experienced ischemia, 4% hemorrhage, 2% seizures, and 10% degeneration.

At admission, NfL predicted a neurological complication with an area under the curve (AUC) of 0.702. GFAP had an AUC of 0.722. In combination, they had an AUC of 0.743. At 1 week, NfL had an AUC of 0.802, GFAP an AUC of 0.733, and the combination an AUC of 0.812.

Using age-specific cutoff values, the researchers found increased risks for neurological complications at admission (NfL odds ratio [OR], 2.9; GFAP OR, 1.6; combined OR, 2.1) and at 1 week (NfL OR, not significant; GFAP OR, 4.8; combined OR, 6.6). “We can see that both NFL and GFAP have utility in detecting neurological complications. And combining both of our markers improves detection at both time points. NfL is a marker that provides more sensitivity, where in this cohort GFAP is a marker that provides a little bit more specificity,” said Ms. Cooper.
 

Will additional biomarkers help?

The researchers are continuing to follow up patients at 6 months and 18 months post diagnosis, using neuropsychiatric tests and additional biomarker analysis, as well as PET and MRI scans. The patient sample is being expanded to those in the general hospital ward and some who were not hospitalized.

During the Q&A session, Ms. Cooper was asked if the group had collected reference data from patients who were admitted to the ICU with non-COVID disease. She responded that the group has some of that data, but as the pandemic went on they had difficulty finding patients who had never been infected with COVID to serve as reliable controls. To date, they have identified 33 controls who had a respiratory condition when admitted to the ICU. “What we see is the neurological biomarker levels in COVID are slightly lower than those with another respiratory condition in the ICU. But the data has a massive spread and the significance is very small between the two groups,” said Ms. Cooper.
 

Unanswered questions

The study is interesting, but leaves a lot of unanswered questions, according to Wiesje van der Flier, PhD, who moderated the session where the study was presented. “There are a lot of unknowns still: Will [the biomarkers] become normal again, once the COVID is over? Also, there was an increased risk, but it was not a one-to-one correspondence, so you can also have the increased markers but not have the neurological signs or symptoms. So I thought there were lots of questions as well,” said Dr. van der Flier, professor of neurology at Amsterdam University Medical Center.

She noted that researchers at her institution in Amsterdam have observed similar relationships, and that the associations between neurological complications and plasma biomarkers over time will be an important topic of study.

The work could provide more information on neurological manifestations of long COVID, such as long-haul fatigue. “You might also think that’s some response in their brain. It would be great if we could actually capture that [using biomarkers],” said Dr. van der Flier.

Ms. Cooper and Dr. van der Flier have no relevant financial disclosures.

SAN DIEGO – Even after recovery of an acute COVID-19 infection, some patients experience extended or even long-term symptoms that can range from mild to debilitating. Some of these symptoms are neurological: headaches, brain fog, cognitive impairment, loss of taste or smell, and even cerebrovascular complications such stroke. There are even hints that COVID-19 infection could lead to future neurodegeneration.

Those issues have prompted efforts to identify biomarkers that can help track and monitor neurological complications of COVID-19. “Throughout the course of the pandemic, it has become apparent that COVID-19 can cause various neurological symptoms. Because of this, it’s really important for us to find a way to monitor and understand neurological complications occurring in patients with COVID 19,” Jennifer Cooper said during a lecture at the Alzheimer’s Association International Conference. She presented new research suggesting that neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) may prove useful.

Ms. Cooper is a master’s degree student at the University of British Columbia and Canada.
 

Looking for sensitivity and specificity in plasma biomarkers

The researchers turned to plasma-based markers because they can reflect underlying pathology in the central nervous system. They focused on NfL, which reflects axonal damage, and GFAP, which is a marker of astrocyte activation.

The researchers analyzed data from 209 patients with COVID-19 who were admitted to the Vancouver (B.C.) General Hospital intensive care unit. Sixty-four percent were male, and the median age was 61 years. Sixty percent were ventilated, and 17% died.

The researchers determined if an individual patient’s biomarker level at hospital admission fell within a normal biomarker reference interval. A total of 53% had NfL levels outside the normal range, and 42% had GFAP levels outside the normal range. In addition, 31% of patients had both GFAP and NfL levels outside of the normal range.

Among all patients, 12% experienced ischemia, 4% hemorrhage, 2% seizures, and 10% degeneration.

At admission, NfL predicted a neurological complication with an area under the curve (AUC) of 0.702. GFAP had an AUC of 0.722. In combination, they had an AUC of 0.743. At 1 week, NfL had an AUC of 0.802, GFAP an AUC of 0.733, and the combination an AUC of 0.812.

Using age-specific cutoff values, the researchers found increased risks for neurological complications at admission (NfL odds ratio [OR], 2.9; GFAP OR, 1.6; combined OR, 2.1) and at 1 week (NfL OR, not significant; GFAP OR, 4.8; combined OR, 6.6). “We can see that both NFL and GFAP have utility in detecting neurological complications. And combining both of our markers improves detection at both time points. NfL is a marker that provides more sensitivity, where in this cohort GFAP is a marker that provides a little bit more specificity,” said Ms. Cooper.
 

Will additional biomarkers help?

The researchers are continuing to follow up patients at 6 months and 18 months post diagnosis, using neuropsychiatric tests and additional biomarker analysis, as well as PET and MRI scans. The patient sample is being expanded to those in the general hospital ward and some who were not hospitalized.

During the Q&A session, Ms. Cooper was asked if the group had collected reference data from patients who were admitted to the ICU with non-COVID disease. She responded that the group has some of that data, but as the pandemic went on they had difficulty finding patients who had never been infected with COVID to serve as reliable controls. To date, they have identified 33 controls who had a respiratory condition when admitted to the ICU. “What we see is the neurological biomarker levels in COVID are slightly lower than those with another respiratory condition in the ICU. But the data has a massive spread and the significance is very small between the two groups,” said Ms. Cooper.
 

Unanswered questions

The study is interesting, but leaves a lot of unanswered questions, according to Wiesje van der Flier, PhD, who moderated the session where the study was presented. “There are a lot of unknowns still: Will [the biomarkers] become normal again, once the COVID is over? Also, there was an increased risk, but it was not a one-to-one correspondence, so you can also have the increased markers but not have the neurological signs or symptoms. So I thought there were lots of questions as well,” said Dr. van der Flier, professor of neurology at Amsterdam University Medical Center.

She noted that researchers at her institution in Amsterdam have observed similar relationships, and that the associations between neurological complications and plasma biomarkers over time will be an important topic of study.

The work could provide more information on neurological manifestations of long COVID, such as long-haul fatigue. “You might also think that’s some response in their brain. It would be great if we could actually capture that [using biomarkers],” said Dr. van der Flier.

Ms. Cooper and Dr. van der Flier have no relevant financial disclosures.

SAN DIEGO – Even after recovery of an acute COVID-19 infection, some patients experience extended or even long-term symptoms that can range from mild to debilitating. Some of these symptoms are neurological: headaches, brain fog, cognitive impairment, loss of taste or smell, and even cerebrovascular complications such stroke. There are even hints that COVID-19 infection could lead to future neurodegeneration.

Those issues have prompted efforts to identify biomarkers that can help track and monitor neurological complications of COVID-19. “Throughout the course of the pandemic, it has become apparent that COVID-19 can cause various neurological symptoms. Because of this, it’s really important for us to find a way to monitor and understand neurological complications occurring in patients with COVID 19,” Jennifer Cooper said during a lecture at the Alzheimer’s Association International Conference. She presented new research suggesting that neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) may prove useful.

Ms. Cooper is a master’s degree student at the University of British Columbia and Canada.
 

Looking for sensitivity and specificity in plasma biomarkers

The researchers turned to plasma-based markers because they can reflect underlying pathology in the central nervous system. They focused on NfL, which reflects axonal damage, and GFAP, which is a marker of astrocyte activation.

The researchers analyzed data from 209 patients with COVID-19 who were admitted to the Vancouver (B.C.) General Hospital intensive care unit. Sixty-four percent were male, and the median age was 61 years. Sixty percent were ventilated, and 17% died.

The researchers determined if an individual patient’s biomarker level at hospital admission fell within a normal biomarker reference interval. A total of 53% had NfL levels outside the normal range, and 42% had GFAP levels outside the normal range. In addition, 31% of patients had both GFAP and NfL levels outside of the normal range.

Among all patients, 12% experienced ischemia, 4% hemorrhage, 2% seizures, and 10% degeneration.

At admission, NfL predicted a neurological complication with an area under the curve (AUC) of 0.702. GFAP had an AUC of 0.722. In combination, they had an AUC of 0.743. At 1 week, NfL had an AUC of 0.802, GFAP an AUC of 0.733, and the combination an AUC of 0.812.

Using age-specific cutoff values, the researchers found increased risks for neurological complications at admission (NfL odds ratio [OR], 2.9; GFAP OR, 1.6; combined OR, 2.1) and at 1 week (NfL OR, not significant; GFAP OR, 4.8; combined OR, 6.6). “We can see that both NFL and GFAP have utility in detecting neurological complications. And combining both of our markers improves detection at both time points. NfL is a marker that provides more sensitivity, where in this cohort GFAP is a marker that provides a little bit more specificity,” said Ms. Cooper.
 

Will additional biomarkers help?

The researchers are continuing to follow up patients at 6 months and 18 months post diagnosis, using neuropsychiatric tests and additional biomarker analysis, as well as PET and MRI scans. The patient sample is being expanded to those in the general hospital ward and some who were not hospitalized.

During the Q&A session, Ms. Cooper was asked if the group had collected reference data from patients who were admitted to the ICU with non-COVID disease. She responded that the group has some of that data, but as the pandemic went on they had difficulty finding patients who had never been infected with COVID to serve as reliable controls. To date, they have identified 33 controls who had a respiratory condition when admitted to the ICU. “What we see is the neurological biomarker levels in COVID are slightly lower than those with another respiratory condition in the ICU. But the data has a massive spread and the significance is very small between the two groups,” said Ms. Cooper.
 

Unanswered questions

The study is interesting, but leaves a lot of unanswered questions, according to Wiesje van der Flier, PhD, who moderated the session where the study was presented. “There are a lot of unknowns still: Will [the biomarkers] become normal again, once the COVID is over? Also, there was an increased risk, but it was not a one-to-one correspondence, so you can also have the increased markers but not have the neurological signs or symptoms. So I thought there were lots of questions as well,” said Dr. van der Flier, professor of neurology at Amsterdam University Medical Center.

She noted that researchers at her institution in Amsterdam have observed similar relationships, and that the associations between neurological complications and plasma biomarkers over time will be an important topic of study.

The work could provide more information on neurological manifestations of long COVID, such as long-haul fatigue. “You might also think that’s some response in their brain. It would be great if we could actually capture that [using biomarkers],” said Dr. van der Flier.

Ms. Cooper and Dr. van der Flier have no relevant financial disclosures.