Alzheimer's & Cognition

Patients age 65 and older who receive thyroid hormone therapy and experience low thyrotropin are at increased risk for dementia and other cognitive problems, according to new research published in JAMA Internal Medicine.

The study found that these patients with thyrotoxicosis had a higher likelihood of incident cognitive disorder (adjusted hazard ratio, 1.39; 95% confidence interval, 1.18-1.64; P < .001). Broken down between internal and external causes of thyrotoxicosis, exogenous thyrotoxicosis continued to be a significant risk factor (aHR, 1.34: 95% CI, 1.10-1.63; P = .003), while endogenous thyrotoxicosis did not show a statistically significant risk estimates (aHR, 1.38; 95% CI, 0.96-1.98; P = .08).

The study also found that women were more likely to have low levels of thyrotropin (thyroid-stimulating hormone/TSH) than men and were more likely to be overtreated.

Previous studies looking at the correlation between hyperthyroidism and cognitive disorders often did not include participants who were already taking thyroid hormones, according to Jennifer S. Mammen, MD, PhD, assistant professor of medicine at the Asthma and Allergy Center at John Hopkins University, Baltimore, and the senior author of the study.

“The fact that we see the signal both in people who are being overtreated with thyroid hormone and in people who have endogenous hyperthyroidism is one way that we think that this supports the fact that it’s not just confounding, it’s not just bias,” Dr. Mammen said. “There’s two different sources of hyperthyroidism, and they’re both showing the same relationship.”

In the study, Dr. Mammen and colleagues analyzed electronic health records for patients aged 65 years and older who received primary care in the Johns Hopkins Community Physicians Network over a 10-year period starting in 2014. Patients had to have a minimum of two visits 30 days apart. None had a history of low TSH levels or cognitive disorder diagnoses within 6 months of their first doctor visit.

More than 65,000 patients were included in the study. Slightly more than half (56%) were female, almost 70% were White, 19.3% were Black, 4.6% were Asian, and 0.4% were American Indian. Almost 25,000 low TSH measurements among 2,710 patients were recorded during the study period. The majority of low TSH measurements were exogenous (14,875), followed by origins of unknown cause (5,833), and endogenous (4,159).

During the follow-up period, 7.2% (4,779) patients received a new cognitive disorder diagnosis, which was dementia in 77% of cases.

Dr. Mammen said primary care physicians should carefully consider whether thyroid hormone therapy is necessary for older patients, and, if so, great care should be taken to avoid overtreatment.

“This is yet another reason for us to be vigilant about not overtreating people with thyroid hormone, especially in older adults,” Dr. Mammen said. “We already know that atrial fibrillation rates are increased in people who are hyperthyroid. We know that fracture and osteoporosis is affected by hyperthyroidism. And now we also have an association with higher rates of cognitive disorders.”

Taking a cautious approach to prescribing thyroid hormone therapy for older patients is paramount, according to Jean Chen, MD, partner at Texas Diabetes & Endocrinology, who was not affiliated with the study.

“All medical providers need to be aware that the 65 and older population does not need to be treated as aggressively with their thyroid hormone,” Dr. Chen said. “We are finding more and more complications from overtreatment rather than benefit in this population.”

Often, older patients may complain of symptoms such as constipation, feeling cold, or tiredness, which can be symptoms of hypothyroidism. But these symptoms could also be from anemia, vitamin deficiencies, depression, perimenopause, menopause, insulin resistance, and sleep apnea. If necessary, Dr. Chen recommended primary care physicians consult with an endocrinologist regarding a possible treatment plan and making a differential diagnosis.

In addition, Dr. Chen said other studies have shown that treating patients with thyroid hormone either did not resolve the condition or negatively impacted anxiety, muscle strength, and bone density, or it increased the risk for arrhythmia. Therefore, it’s important to weight the risks versus the benefits.

“There’s so much gray zone here,” Dr. Chen said.

The study was supported by the Richman Family Precision Medicine Center of Excellence in Alzheimer’s Disease, the Richman Family Foundation, the Rick Sharp Alzheimer’s Foundation, the Sharp Family Foundation, among others. The work was also supported by grants from the National Institutes of Health. One coauthor reported personal fees from Karuna, MapLight Therapeutics, Axsome Therapeutics, GIA, GW Research Limited, Merck, EXCIVA, Otsuka, IntraCellular Therapies, and Medesis Pharma for consulting for treatment development in Alzheimer’s disease outside the submitted work. No other disclosures were reported.

A version of this article appeared on Medscape.com.

Patients age 65 and older who receive thyroid hormone therapy and experience low thyrotropin are at increased risk for dementia and other cognitive problems, according to new research published in JAMA Internal Medicine.

The study found that these patients with thyrotoxicosis had a higher likelihood of incident cognitive disorder (adjusted hazard ratio, 1.39; 95% confidence interval, 1.18-1.64; P < .001). Broken down between internal and external causes of thyrotoxicosis, exogenous thyrotoxicosis continued to be a significant risk factor (aHR, 1.34: 95% CI, 1.10-1.63; P = .003), while endogenous thyrotoxicosis did not show a statistically significant risk estimates (aHR, 1.38; 95% CI, 0.96-1.98; P = .08).

The study also found that women were more likely to have low levels of thyrotropin (thyroid-stimulating hormone/TSH) than men and were more likely to be overtreated.

Previous studies looking at the correlation between hyperthyroidism and cognitive disorders often did not include participants who were already taking thyroid hormones, according to Jennifer S. Mammen, MD, PhD, assistant professor of medicine at the Asthma and Allergy Center at John Hopkins University, Baltimore, and the senior author of the study.

“The fact that we see the signal both in people who are being overtreated with thyroid hormone and in people who have endogenous hyperthyroidism is one way that we think that this supports the fact that it’s not just confounding, it’s not just bias,” Dr. Mammen said. “There’s two different sources of hyperthyroidism, and they’re both showing the same relationship.”

In the study, Dr. Mammen and colleagues analyzed electronic health records for patients aged 65 years and older who received primary care in the Johns Hopkins Community Physicians Network over a 10-year period starting in 2014. Patients had to have a minimum of two visits 30 days apart. None had a history of low TSH levels or cognitive disorder diagnoses within 6 months of their first doctor visit.

More than 65,000 patients were included in the study. Slightly more than half (56%) were female, almost 70% were White, 19.3% were Black, 4.6% were Asian, and 0.4% were American Indian. Almost 25,000 low TSH measurements among 2,710 patients were recorded during the study period. The majority of low TSH measurements were exogenous (14,875), followed by origins of unknown cause (5,833), and endogenous (4,159).

During the follow-up period, 7.2% (4,779) patients received a new cognitive disorder diagnosis, which was dementia in 77% of cases.

Dr. Mammen said primary care physicians should carefully consider whether thyroid hormone therapy is necessary for older patients, and, if so, great care should be taken to avoid overtreatment.

“This is yet another reason for us to be vigilant about not overtreating people with thyroid hormone, especially in older adults,” Dr. Mammen said. “We already know that atrial fibrillation rates are increased in people who are hyperthyroid. We know that fracture and osteoporosis is affected by hyperthyroidism. And now we also have an association with higher rates of cognitive disorders.”

Taking a cautious approach to prescribing thyroid hormone therapy for older patients is paramount, according to Jean Chen, MD, partner at Texas Diabetes & Endocrinology, who was not affiliated with the study.

“All medical providers need to be aware that the 65 and older population does not need to be treated as aggressively with their thyroid hormone,” Dr. Chen said. “We are finding more and more complications from overtreatment rather than benefit in this population.”

Often, older patients may complain of symptoms such as constipation, feeling cold, or tiredness, which can be symptoms of hypothyroidism. But these symptoms could also be from anemia, vitamin deficiencies, depression, perimenopause, menopause, insulin resistance, and sleep apnea. If necessary, Dr. Chen recommended primary care physicians consult with an endocrinologist regarding a possible treatment plan and making a differential diagnosis.

In addition, Dr. Chen said other studies have shown that treating patients with thyroid hormone either did not resolve the condition or negatively impacted anxiety, muscle strength, and bone density, or it increased the risk for arrhythmia. Therefore, it’s important to weight the risks versus the benefits.

“There’s so much gray zone here,” Dr. Chen said.

The study was supported by the Richman Family Precision Medicine Center of Excellence in Alzheimer’s Disease, the Richman Family Foundation, the Rick Sharp Alzheimer’s Foundation, the Sharp Family Foundation, among others. The work was also supported by grants from the National Institutes of Health. One coauthor reported personal fees from Karuna, MapLight Therapeutics, Axsome Therapeutics, GIA, GW Research Limited, Merck, EXCIVA, Otsuka, IntraCellular Therapies, and Medesis Pharma for consulting for treatment development in Alzheimer’s disease outside the submitted work. No other disclosures were reported.

A version of this article appeared on Medscape.com.

Patients age 65 and older who receive thyroid hormone therapy and experience low thyrotropin are at increased risk for dementia and other cognitive problems, according to new research published in JAMA Internal Medicine.

The study found that these patients with thyrotoxicosis had a higher likelihood of incident cognitive disorder (adjusted hazard ratio, 1.39; 95% confidence interval, 1.18-1.64; P < .001). Broken down between internal and external causes of thyrotoxicosis, exogenous thyrotoxicosis continued to be a significant risk factor (aHR, 1.34: 95% CI, 1.10-1.63; P = .003), while endogenous thyrotoxicosis did not show a statistically significant risk estimates (aHR, 1.38; 95% CI, 0.96-1.98; P = .08).

The study also found that women were more likely to have low levels of thyrotropin (thyroid-stimulating hormone/TSH) than men and were more likely to be overtreated.

Previous studies looking at the correlation between hyperthyroidism and cognitive disorders often did not include participants who were already taking thyroid hormones, according to Jennifer S. Mammen, MD, PhD, assistant professor of medicine at the Asthma and Allergy Center at John Hopkins University, Baltimore, and the senior author of the study.

“The fact that we see the signal both in people who are being overtreated with thyroid hormone and in people who have endogenous hyperthyroidism is one way that we think that this supports the fact that it’s not just confounding, it’s not just bias,” Dr. Mammen said. “There’s two different sources of hyperthyroidism, and they’re both showing the same relationship.”

In the study, Dr. Mammen and colleagues analyzed electronic health records for patients aged 65 years and older who received primary care in the Johns Hopkins Community Physicians Network over a 10-year period starting in 2014. Patients had to have a minimum of two visits 30 days apart. None had a history of low TSH levels or cognitive disorder diagnoses within 6 months of their first doctor visit.

More than 65,000 patients were included in the study. Slightly more than half (56%) were female, almost 70% were White, 19.3% were Black, 4.6% were Asian, and 0.4% were American Indian. Almost 25,000 low TSH measurements among 2,710 patients were recorded during the study period. The majority of low TSH measurements were exogenous (14,875), followed by origins of unknown cause (5,833), and endogenous (4,159).

During the follow-up period, 7.2% (4,779) patients received a new cognitive disorder diagnosis, which was dementia in 77% of cases.

Dr. Mammen said primary care physicians should carefully consider whether thyroid hormone therapy is necessary for older patients, and, if so, great care should be taken to avoid overtreatment.

“This is yet another reason for us to be vigilant about not overtreating people with thyroid hormone, especially in older adults,” Dr. Mammen said. “We already know that atrial fibrillation rates are increased in people who are hyperthyroid. We know that fracture and osteoporosis is affected by hyperthyroidism. And now we also have an association with higher rates of cognitive disorders.”

Taking a cautious approach to prescribing thyroid hormone therapy for older patients is paramount, according to Jean Chen, MD, partner at Texas Diabetes & Endocrinology, who was not affiliated with the study.

“All medical providers need to be aware that the 65 and older population does not need to be treated as aggressively with their thyroid hormone,” Dr. Chen said. “We are finding more and more complications from overtreatment rather than benefit in this population.”

Often, older patients may complain of symptoms such as constipation, feeling cold, or tiredness, which can be symptoms of hypothyroidism. But these symptoms could also be from anemia, vitamin deficiencies, depression, perimenopause, menopause, insulin resistance, and sleep apnea. If necessary, Dr. Chen recommended primary care physicians consult with an endocrinologist regarding a possible treatment plan and making a differential diagnosis.

In addition, Dr. Chen said other studies have shown that treating patients with thyroid hormone either did not resolve the condition or negatively impacted anxiety, muscle strength, and bone density, or it increased the risk for arrhythmia. Therefore, it’s important to weight the risks versus the benefits.

“There’s so much gray zone here,” Dr. Chen said.

The study was supported by the Richman Family Precision Medicine Center of Excellence in Alzheimer’s Disease, the Richman Family Foundation, the Rick Sharp Alzheimer’s Foundation, the Sharp Family Foundation, among others. The work was also supported by grants from the National Institutes of Health. One coauthor reported personal fees from Karuna, MapLight Therapeutics, Axsome Therapeutics, GIA, GW Research Limited, Merck, EXCIVA, Otsuka, IntraCellular Therapies, and Medesis Pharma for consulting for treatment development in Alzheimer’s disease outside the submitted work. No other disclosures were reported.

A version of this article appeared on Medscape.com.

TOPLINE:

New research suggests terminating metformin may raise the risk for dementia in older adults with type 2 diabetes, providing more evidence of metformin’s potential neuroprotective effects.

METHODOLOGY:

• Researchers evaluated the association between discontinuing metformin for reasons unrelated to kidney dysfunction and dementia incidence.
• The cohort included 12,220 Kaiser Permanente Northern California members who stopped metformin early (with normal kidney function) and 29,126 routine metformin users.
• The cohort of early terminators was 46% women with an average age of 59 years at the start of metformin prescription. The cohort continuing metformin was 47% women, with a start age of 61 years.

TAKEAWAY:

• Adults who stopped metformin early were 21% more likely to be diagnosed with dementia during follow up (hazard ratio, 1.21; 95% confidence interval, 1.12-1.30), compared with routine metformin users.
• This association was largely independent of changes in A1c level and insulin usage.

IN PRACTICE:

The findings “corroborate the largely consistent evidence from other observational studies showing an association between metformin use and lower dementia incidence [and] may have important implications for clinical treatment of adults with diabetes,” the authors write.

SOURCE:

The study, with first author Scott Zimmerman, MPH, University of California, San Francisco, was published online  in JAMA Network Open.

LIMITATIONS:

Dementia diagnosis was obtained based on medical records. Factors such as race, ethnicity, or time on metformin were not evaluated. Information on the exact reason for stopping metformin was not available.

DISCLOSURES:

The study was funded by grants from the National Institutes of Health, National Institute on Aging. Mr. Zimmerman owns stock in AbbVie, Gilead Sciences, CRISPR Therapeutics, and Abbott Laboratories. Disclosure for the other study authors can be found with the original article.

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

TOPLINE:

New research suggests terminating metformin may raise the risk for dementia in older adults with type 2 diabetes, providing more evidence of metformin’s potential neuroprotective effects.

METHODOLOGY:

• Researchers evaluated the association between discontinuing metformin for reasons unrelated to kidney dysfunction and dementia incidence.
• The cohort included 12,220 Kaiser Permanente Northern California members who stopped metformin early (with normal kidney function) and 29,126 routine metformin users.
• The cohort of early terminators was 46% women with an average age of 59 years at the start of metformin prescription. The cohort continuing metformin was 47% women, with a start age of 61 years.

TAKEAWAY:

• Adults who stopped metformin early were 21% more likely to be diagnosed with dementia during follow up (hazard ratio, 1.21; 95% confidence interval, 1.12-1.30), compared with routine metformin users.
• This association was largely independent of changes in A1c level and insulin usage.

IN PRACTICE:

The findings “corroborate the largely consistent evidence from other observational studies showing an association between metformin use and lower dementia incidence [and] may have important implications for clinical treatment of adults with diabetes,” the authors write.

SOURCE:

The study, with first author Scott Zimmerman, MPH, University of California, San Francisco, was published online  in JAMA Network Open.

LIMITATIONS:

Dementia diagnosis was obtained based on medical records. Factors such as race, ethnicity, or time on metformin were not evaluated. Information on the exact reason for stopping metformin was not available.

DISCLOSURES:

The study was funded by grants from the National Institutes of Health, National Institute on Aging. Mr. Zimmerman owns stock in AbbVie, Gilead Sciences, CRISPR Therapeutics, and Abbott Laboratories. Disclosure for the other study authors can be found with the original article.

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

TOPLINE:

New research suggests terminating metformin may raise the risk for dementia in older adults with type 2 diabetes, providing more evidence of metformin’s potential neuroprotective effects.

METHODOLOGY:

• Researchers evaluated the association between discontinuing metformin for reasons unrelated to kidney dysfunction and dementia incidence.
• The cohort included 12,220 Kaiser Permanente Northern California members who stopped metformin early (with normal kidney function) and 29,126 routine metformin users.
• The cohort of early terminators was 46% women with an average age of 59 years at the start of metformin prescription. The cohort continuing metformin was 47% women, with a start age of 61 years.

TAKEAWAY:

• Adults who stopped metformin early were 21% more likely to be diagnosed with dementia during follow up (hazard ratio, 1.21; 95% confidence interval, 1.12-1.30), compared with routine metformin users.
• This association was largely independent of changes in A1c level and insulin usage.

IN PRACTICE:

The findings “corroborate the largely consistent evidence from other observational studies showing an association between metformin use and lower dementia incidence [and] may have important implications for clinical treatment of adults with diabetes,” the authors write.

SOURCE:

The study, with first author Scott Zimmerman, MPH, University of California, San Francisco, was published online  in JAMA Network Open.

LIMITATIONS:

Dementia diagnosis was obtained based on medical records. Factors such as race, ethnicity, or time on metformin were not evaluated. Information on the exact reason for stopping metformin was not available.

DISCLOSURES:

The study was funded by grants from the National Institutes of Health, National Institute on Aging. Mr. Zimmerman owns stock in AbbVie, Gilead Sciences, CRISPR Therapeutics, and Abbott Laboratories. Disclosure for the other study authors can be found with the original article.

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

Should older physicians be forced to undergo cognitive tests to stay on the job? One 84-year-old ophthalmologist is suing her Michigan employer to stop the practice.

Lylas G. Mogk, MD, recently sued Henry Ford Health and Henry Ford Medical Group in federal court, alleging that the mandatory cognitive test violates the Americans with Disabilities Act, the Age Discrimination in Employment Act, and two Michigan laws.

Dr. Mogk’s lawsuit follows a widely watched 2020 case in which the U.S. Equal Employment Opportunity Commission sued Yale New Haven Hospital, the teaching hospital of Yale University, for age discrimination. According to the lawsuit, the hospital illegally required neuropsychological and eye examinations of physicians aged 70 or older who sought to gain or renew staff privileges.

According to the lawsuit, Dr. Mogk is a member of Henry Ford Medical Group, which in 2017 required all members aged 70 and older to undergo cognitive screening tests. The tests would be repeated every 5 years thereafter, the lawsuit said, and anyone who refused would have to resign or be fired.

Dr. Mogk completed the screening, although no information about the results or outcome was mentioned in the lawsuit. It’s not clear whether Henry Ford’s cognitive test mandate remains in place; a spokesperson for Henry Ford Health and attorneys for Dr. Mogk declined to comment.

The number of practicing physicians in their 70s and beyond is rising. A 2021 report found that 12% of U.S. licensed physicians in 2020 were least 70 years old, up from 9% in 2010 and an increase from 75,627 to 120,510. The percentage of doctors aged 60-69 grew to 19% from 16% in 2010.

The number of health systems requiring testing of older physicians isn’t known, although various reports suggest at least a dozen have had mandates.

The University of California, San Diego, offers a physical and mental screening program that health organizations can use to evaluate “late-career physicians,” and a 2021 report noted that “Nebraska’s Children’s Hospital requires physicians aged 70 years and older to undergo an assessment by several peers, a complete physical, and unspecified cognitive screening.” Another system, Hartford HealthCare, mandated an annual reappointment process for clinicians aged 70 or older, requiring them to undergo various exams.

There’s evidence that physician performance declines with age. However, age-based cognitive testing can run afoul of federal and state laws against age discrimination, said Sharona Hoffman, JD, professor of law and bioethics at Case Western Reserve University, Cleveland, in an interview.

Federal law prohibits age-related restrictions on employment but allows exceptions in areas like public safety, said Ms. Hoffman, who’s written about age discrimination and testing requirements. Pilots, law enforcement officers, firefighters, and air controllers, for example, can be forced to retire at specific ages.

It’s not clear how many physicians took the cognitive tests required by Henry Ford Medical Group.

However, details are available about the policy at Yale New Haven Hospital: According to the EEOC lawsuit, from 2016 to 2019, 145 physicians aged 70 or older took the mandatory test. Of those, seven individuals failed either or both of the exams, 14 were listed as “borderline deficient,” and one was listed as “deficient.” Another five refused testing and either resigned or changed their status. The EEOC case against the hospital is still pending.

“You can make an argument that health care is like a public safety job because people put their lives in the hands of doctors,” Ms. Hoffman said.

In defending mandatory cognitive tests, she said, health care systems could say, “it’s not really discrimination; we’re not forcing them to retire, we’re not limiting their work in any way. We’re just doing testing to make sure they perform competently, and the ADA allows us to conduct testing that is job-related.”

Indeed, a Yale New Haven Hospital spokesman made an argument along these lines in a statement regarding the 2020 lawsuit: The “policy is designed to protect our patients from potential harm while including safeguards to ensure that our physicians are treated fairly. The policy is modeled on similar standards in other industries, and we are confident that no discrimination has occurred and will vigorously defend ourselves in this matter.”

However, Ms. Hoffman herself doesn’t buy these arguments. Requiring tests only for older physicians does appear to be discrimination based on age, she said. As an alternative, “employers can do close supervision of people. As soon as there are performance problems or patient complaints, you need to see a doctor or get testing done.”

Another option is to mandate tests at specific ages via licensing boards. “I don’t think that would be legally problematic,” Ms. Hoffman said.

What else can be done to protect patients from clinicians whose skills have significantly declined as they’ve aged? The 2021 report in Neurology Clinical Practice notes that there are disadvantages to several strategies.

One common approach, waiting to evaluate a clinician until an error occurs, can lead to patient harm, the report’s authors wrote. Relying on reporting by peers is problematic because “physicians have been very resistant to reporting colleagues who are impaired” and the “medical apprenticeship model discourages physicians from reporting on senior colleagues.”

Physician self-assessment is yet another option, but “loss of insight may be a component of an individual’s impairment,” the authors wrote.

So what’s the best solution? The authors recommended “a relatively brief cognitive screening followed by more extensive testing for the most impaired individuals.” This approach “appears most reliable in confidentially identifying truly impaired physicians while minimizing the chance of a falsely flagging unimpaired individuals. This strategy allows aging physicians to continue working while safeguarding both their reputations and their patients’ health.”

Ms. Hoffman has no disclosures.

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

Should older physicians be forced to undergo cognitive tests to stay on the job? One 84-year-old ophthalmologist is suing her Michigan employer to stop the practice.

Lylas G. Mogk, MD, recently sued Henry Ford Health and Henry Ford Medical Group in federal court, alleging that the mandatory cognitive test violates the Americans with Disabilities Act, the Age Discrimination in Employment Act, and two Michigan laws.

Dr. Mogk’s lawsuit follows a widely watched 2020 case in which the U.S. Equal Employment Opportunity Commission sued Yale New Haven Hospital, the teaching hospital of Yale University, for age discrimination. According to the lawsuit, the hospital illegally required neuropsychological and eye examinations of physicians aged 70 or older who sought to gain or renew staff privileges.

According to the lawsuit, Dr. Mogk is a member of Henry Ford Medical Group, which in 2017 required all members aged 70 and older to undergo cognitive screening tests. The tests would be repeated every 5 years thereafter, the lawsuit said, and anyone who refused would have to resign or be fired.

Dr. Mogk completed the screening, although no information about the results or outcome was mentioned in the lawsuit. It’s not clear whether Henry Ford’s cognitive test mandate remains in place; a spokesperson for Henry Ford Health and attorneys for Dr. Mogk declined to comment.

The number of practicing physicians in their 70s and beyond is rising. A 2021 report found that 12% of U.S. licensed physicians in 2020 were least 70 years old, up from 9% in 2010 and an increase from 75,627 to 120,510. The percentage of doctors aged 60-69 grew to 19% from 16% in 2010.

The number of health systems requiring testing of older physicians isn’t known, although various reports suggest at least a dozen have had mandates.

The University of California, San Diego, offers a physical and mental screening program that health organizations can use to evaluate “late-career physicians,” and a 2021 report noted that “Nebraska’s Children’s Hospital requires physicians aged 70 years and older to undergo an assessment by several peers, a complete physical, and unspecified cognitive screening.” Another system, Hartford HealthCare, mandated an annual reappointment process for clinicians aged 70 or older, requiring them to undergo various exams.

There’s evidence that physician performance declines with age. However, age-based cognitive testing can run afoul of federal and state laws against age discrimination, said Sharona Hoffman, JD, professor of law and bioethics at Case Western Reserve University, Cleveland, in an interview.

Federal law prohibits age-related restrictions on employment but allows exceptions in areas like public safety, said Ms. Hoffman, who’s written about age discrimination and testing requirements. Pilots, law enforcement officers, firefighters, and air controllers, for example, can be forced to retire at specific ages.

It’s not clear how many physicians took the cognitive tests required by Henry Ford Medical Group.

However, details are available about the policy at Yale New Haven Hospital: According to the EEOC lawsuit, from 2016 to 2019, 145 physicians aged 70 or older took the mandatory test. Of those, seven individuals failed either or both of the exams, 14 were listed as “borderline deficient,” and one was listed as “deficient.” Another five refused testing and either resigned or changed their status. The EEOC case against the hospital is still pending.

“You can make an argument that health care is like a public safety job because people put their lives in the hands of doctors,” Ms. Hoffman said.

In defending mandatory cognitive tests, she said, health care systems could say, “it’s not really discrimination; we’re not forcing them to retire, we’re not limiting their work in any way. We’re just doing testing to make sure they perform competently, and the ADA allows us to conduct testing that is job-related.”

Indeed, a Yale New Haven Hospital spokesman made an argument along these lines in a statement regarding the 2020 lawsuit: The “policy is designed to protect our patients from potential harm while including safeguards to ensure that our physicians are treated fairly. The policy is modeled on similar standards in other industries, and we are confident that no discrimination has occurred and will vigorously defend ourselves in this matter.”

However, Ms. Hoffman herself doesn’t buy these arguments. Requiring tests only for older physicians does appear to be discrimination based on age, she said. As an alternative, “employers can do close supervision of people. As soon as there are performance problems or patient complaints, you need to see a doctor or get testing done.”

Another option is to mandate tests at specific ages via licensing boards. “I don’t think that would be legally problematic,” Ms. Hoffman said.

What else can be done to protect patients from clinicians whose skills have significantly declined as they’ve aged? The 2021 report in Neurology Clinical Practice notes that there are disadvantages to several strategies.

One common approach, waiting to evaluate a clinician until an error occurs, can lead to patient harm, the report’s authors wrote. Relying on reporting by peers is problematic because “physicians have been very resistant to reporting colleagues who are impaired” and the “medical apprenticeship model discourages physicians from reporting on senior colleagues.”

Physician self-assessment is yet another option, but “loss of insight may be a component of an individual’s impairment,” the authors wrote.

So what’s the best solution? The authors recommended “a relatively brief cognitive screening followed by more extensive testing for the most impaired individuals.” This approach “appears most reliable in confidentially identifying truly impaired physicians while minimizing the chance of a falsely flagging unimpaired individuals. This strategy allows aging physicians to continue working while safeguarding both their reputations and their patients’ health.”

Ms. Hoffman has no disclosures.

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

Should older physicians be forced to undergo cognitive tests to stay on the job? One 84-year-old ophthalmologist is suing her Michigan employer to stop the practice.

Lylas G. Mogk, MD, recently sued Henry Ford Health and Henry Ford Medical Group in federal court, alleging that the mandatory cognitive test violates the Americans with Disabilities Act, the Age Discrimination in Employment Act, and two Michigan laws.

Dr. Mogk’s lawsuit follows a widely watched 2020 case in which the U.S. Equal Employment Opportunity Commission sued Yale New Haven Hospital, the teaching hospital of Yale University, for age discrimination. According to the lawsuit, the hospital illegally required neuropsychological and eye examinations of physicians aged 70 or older who sought to gain or renew staff privileges.

According to the lawsuit, Dr. Mogk is a member of Henry Ford Medical Group, which in 2017 required all members aged 70 and older to undergo cognitive screening tests. The tests would be repeated every 5 years thereafter, the lawsuit said, and anyone who refused would have to resign or be fired.

Dr. Mogk completed the screening, although no information about the results or outcome was mentioned in the lawsuit. It’s not clear whether Henry Ford’s cognitive test mandate remains in place; a spokesperson for Henry Ford Health and attorneys for Dr. Mogk declined to comment.

The number of practicing physicians in their 70s and beyond is rising. A 2021 report found that 12% of U.S. licensed physicians in 2020 were least 70 years old, up from 9% in 2010 and an increase from 75,627 to 120,510. The percentage of doctors aged 60-69 grew to 19% from 16% in 2010.

The number of health systems requiring testing of older physicians isn’t known, although various reports suggest at least a dozen have had mandates.

The University of California, San Diego, offers a physical and mental screening program that health organizations can use to evaluate “late-career physicians,” and a 2021 report noted that “Nebraska’s Children’s Hospital requires physicians aged 70 years and older to undergo an assessment by several peers, a complete physical, and unspecified cognitive screening.” Another system, Hartford HealthCare, mandated an annual reappointment process for clinicians aged 70 or older, requiring them to undergo various exams.

There’s evidence that physician performance declines with age. However, age-based cognitive testing can run afoul of federal and state laws against age discrimination, said Sharona Hoffman, JD, professor of law and bioethics at Case Western Reserve University, Cleveland, in an interview.

Federal law prohibits age-related restrictions on employment but allows exceptions in areas like public safety, said Ms. Hoffman, who’s written about age discrimination and testing requirements. Pilots, law enforcement officers, firefighters, and air controllers, for example, can be forced to retire at specific ages.

It’s not clear how many physicians took the cognitive tests required by Henry Ford Medical Group.

However, details are available about the policy at Yale New Haven Hospital: According to the EEOC lawsuit, from 2016 to 2019, 145 physicians aged 70 or older took the mandatory test. Of those, seven individuals failed either or both of the exams, 14 were listed as “borderline deficient,” and one was listed as “deficient.” Another five refused testing and either resigned or changed their status. The EEOC case against the hospital is still pending.

“You can make an argument that health care is like a public safety job because people put their lives in the hands of doctors,” Ms. Hoffman said.

In defending mandatory cognitive tests, she said, health care systems could say, “it’s not really discrimination; we’re not forcing them to retire, we’re not limiting their work in any way. We’re just doing testing to make sure they perform competently, and the ADA allows us to conduct testing that is job-related.”

Indeed, a Yale New Haven Hospital spokesman made an argument along these lines in a statement regarding the 2020 lawsuit: The “policy is designed to protect our patients from potential harm while including safeguards to ensure that our physicians are treated fairly. The policy is modeled on similar standards in other industries, and we are confident that no discrimination has occurred and will vigorously defend ourselves in this matter.”

However, Ms. Hoffman herself doesn’t buy these arguments. Requiring tests only for older physicians does appear to be discrimination based on age, she said. As an alternative, “employers can do close supervision of people. As soon as there are performance problems or patient complaints, you need to see a doctor or get testing done.”

Another option is to mandate tests at specific ages via licensing boards. “I don’t think that would be legally problematic,” Ms. Hoffman said.

What else can be done to protect patients from clinicians whose skills have significantly declined as they’ve aged? The 2021 report in Neurology Clinical Practice notes that there are disadvantages to several strategies.

One common approach, waiting to evaluate a clinician until an error occurs, can lead to patient harm, the report’s authors wrote. Relying on reporting by peers is problematic because “physicians have been very resistant to reporting colleagues who are impaired” and the “medical apprenticeship model discourages physicians from reporting on senior colleagues.”

Physician self-assessment is yet another option, but “loss of insight may be a component of an individual’s impairment,” the authors wrote.

So what’s the best solution? The authors recommended “a relatively brief cognitive screening followed by more extensive testing for the most impaired individuals.” This approach “appears most reliable in confidentially identifying truly impaired physicians while minimizing the chance of a falsely flagging unimpaired individuals. This strategy allows aging physicians to continue working while safeguarding both their reputations and their patients’ health.”

Ms. Hoffman has no disclosures.

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

TOPLINE:

Higher triglyceride levels – a main energy source for the brain – are associated with lower risk for dementia that is not mediated by age, sex, or APOE epsilon-4 allele status, a large study of community-dwelling older adults suggests.

METHODOLOGY:

• The analysis included 18,294 participants, median age 75 years and median triglyceride level 106 mg/dL, from the Aspirin in Reducing Events in the Elderly (ASPREE) study, a placebo-controlled, randomized trial of daily low-dose aspirin in older people without dementia or history of cardiovascular disease (CVD) at recruitment.
• Researchers repeated their main analyses in a sub-cohort of 13,976 subjects with APOE epsilon-4 genetic data, and an external cohort of 68,200 participants, mean age 66.9 years and a median nonfasting triglyceride of 139 mg/dL, from the UK biobank, followed for a median of 12.5 years.
• The main outcome was incident dementia over 6.4 years and secondary outcomes included changes in composite cognitive function and domain-specific cognition.
• Researchers controlled for a number of potential confounders, including age, sex, race, smoking, alcohol consumption, education, family history of dementia, diabetes, hypertension, and statin use.

TAKEAWAY:

• Every doubling of baseline triglycerides was associated with an 18% lower risk of incident dementia across the entire study cohort (adjusted hazard ratio, 0.82) and in participants with genotypic data (aHR, 0.82) and a 17% lower risk in the external UK Biobank cohort (aHR, 0.83) (P ≤ .01 for all).
• In the entire cohort, the risk for dementia was 15% lower in those with triglyceride levels at 63-106 mg/dL (aHR, 0.85); 24% lower in those at 107-186 mg/dL (aHR, 0.76); and 36% lower for those with levels higher than 187 mg/dL (aHR, 0.64), compared with individuals with levels below 62 mg/dL (P for trend <.001).
• The direction and magnitude of the inverse association between triglycerides and dementia risk were not modified by age, sex, or risk factors related to triglycerides or dementia.
• In the entire study cohort, higher triglyceride levels were significantly associated with slower decline in global cognition (P = .02), composite cognition (P = .03), and a borderline significantly slower decline in episodic memory (P = .05).

IN PRACTICE:

“Triglyceride levels may serve as a useful predictor for dementia risk and cognitive decline in older populations,” the investigators write. Higher triglyceride levels may reflect better overall health and/or lifestyle behaviors that protect against dementia.

SOURCE:

The study was led by Zhen Zhou, of Monash University, Melbourne. It was published online in Neurology.

LIMITATIONS:

The study can’t establish a causal relationship between triglyceride levels and dementia or fully exclude reverse causality. As most ASPREE participants had normal to high-normal triglyceride levels, the results can’t be generalized to those with severe hypertriglyceridemia. The findings are unique to older people without CVD and may not be generalizable to other populations.

DISCLOSURES:

The study received support from the Royal Australian College of General Practitioners (RACGP)/HCF Research Foundation. Dr. Zhou reported receiving salary from the RACGP/HCF Research Foundation.

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

TOPLINE:

Higher triglyceride levels – a main energy source for the brain – are associated with lower risk for dementia that is not mediated by age, sex, or APOE epsilon-4 allele status, a large study of community-dwelling older adults suggests.

METHODOLOGY:

• The analysis included 18,294 participants, median age 75 years and median triglyceride level 106 mg/dL, from the Aspirin in Reducing Events in the Elderly (ASPREE) study, a placebo-controlled, randomized trial of daily low-dose aspirin in older people without dementia or history of cardiovascular disease (CVD) at recruitment.
• Researchers repeated their main analyses in a sub-cohort of 13,976 subjects with APOE epsilon-4 genetic data, and an external cohort of 68,200 participants, mean age 66.9 years and a median nonfasting triglyceride of 139 mg/dL, from the UK biobank, followed for a median of 12.5 years.
• The main outcome was incident dementia over 6.4 years and secondary outcomes included changes in composite cognitive function and domain-specific cognition.
• Researchers controlled for a number of potential confounders, including age, sex, race, smoking, alcohol consumption, education, family history of dementia, diabetes, hypertension, and statin use.

TAKEAWAY:

• Every doubling of baseline triglycerides was associated with an 18% lower risk of incident dementia across the entire study cohort (adjusted hazard ratio, 0.82) and in participants with genotypic data (aHR, 0.82) and a 17% lower risk in the external UK Biobank cohort (aHR, 0.83) (P ≤ .01 for all).
• In the entire cohort, the risk for dementia was 15% lower in those with triglyceride levels at 63-106 mg/dL (aHR, 0.85); 24% lower in those at 107-186 mg/dL (aHR, 0.76); and 36% lower for those with levels higher than 187 mg/dL (aHR, 0.64), compared with individuals with levels below 62 mg/dL (P for trend <.001).
• The direction and magnitude of the inverse association between triglycerides and dementia risk were not modified by age, sex, or risk factors related to triglycerides or dementia.
• In the entire study cohort, higher triglyceride levels were significantly associated with slower decline in global cognition (P = .02), composite cognition (P = .03), and a borderline significantly slower decline in episodic memory (P = .05).

IN PRACTICE:

“Triglyceride levels may serve as a useful predictor for dementia risk and cognitive decline in older populations,” the investigators write. Higher triglyceride levels may reflect better overall health and/or lifestyle behaviors that protect against dementia.

SOURCE:

The study was led by Zhen Zhou, of Monash University, Melbourne. It was published online in Neurology.

LIMITATIONS:

The study can’t establish a causal relationship between triglyceride levels and dementia or fully exclude reverse causality. As most ASPREE participants had normal to high-normal triglyceride levels, the results can’t be generalized to those with severe hypertriglyceridemia. The findings are unique to older people without CVD and may not be generalizable to other populations.

DISCLOSURES:

The study received support from the Royal Australian College of General Practitioners (RACGP)/HCF Research Foundation. Dr. Zhou reported receiving salary from the RACGP/HCF Research Foundation.

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

TOPLINE:

Higher triglyceride levels – a main energy source for the brain – are associated with lower risk for dementia that is not mediated by age, sex, or APOE epsilon-4 allele status, a large study of community-dwelling older adults suggests.

METHODOLOGY:

• The analysis included 18,294 participants, median age 75 years and median triglyceride level 106 mg/dL, from the Aspirin in Reducing Events in the Elderly (ASPREE) study, a placebo-controlled, randomized trial of daily low-dose aspirin in older people without dementia or history of cardiovascular disease (CVD) at recruitment.
• Researchers repeated their main analyses in a sub-cohort of 13,976 subjects with APOE epsilon-4 genetic data, and an external cohort of 68,200 participants, mean age 66.9 years and a median nonfasting triglyceride of 139 mg/dL, from the UK biobank, followed for a median of 12.5 years.
• The main outcome was incident dementia over 6.4 years and secondary outcomes included changes in composite cognitive function and domain-specific cognition.
• Researchers controlled for a number of potential confounders, including age, sex, race, smoking, alcohol consumption, education, family history of dementia, diabetes, hypertension, and statin use.

TAKEAWAY:

• Every doubling of baseline triglycerides was associated with an 18% lower risk of incident dementia across the entire study cohort (adjusted hazard ratio, 0.82) and in participants with genotypic data (aHR, 0.82) and a 17% lower risk in the external UK Biobank cohort (aHR, 0.83) (P ≤ .01 for all).
• In the entire cohort, the risk for dementia was 15% lower in those with triglyceride levels at 63-106 mg/dL (aHR, 0.85); 24% lower in those at 107-186 mg/dL (aHR, 0.76); and 36% lower for those with levels higher than 187 mg/dL (aHR, 0.64), compared with individuals with levels below 62 mg/dL (P for trend <.001).
• The direction and magnitude of the inverse association between triglycerides and dementia risk were not modified by age, sex, or risk factors related to triglycerides or dementia.
• In the entire study cohort, higher triglyceride levels were significantly associated with slower decline in global cognition (P = .02), composite cognition (P = .03), and a borderline significantly slower decline in episodic memory (P = .05).

IN PRACTICE:

“Triglyceride levels may serve as a useful predictor for dementia risk and cognitive decline in older populations,” the investigators write. Higher triglyceride levels may reflect better overall health and/or lifestyle behaviors that protect against dementia.

SOURCE:

The study was led by Zhen Zhou, of Monash University, Melbourne. It was published online in Neurology.

LIMITATIONS:

The study can’t establish a causal relationship between triglyceride levels and dementia or fully exclude reverse causality. As most ASPREE participants had normal to high-normal triglyceride levels, the results can’t be generalized to those with severe hypertriglyceridemia. The findings are unique to older people without CVD and may not be generalizable to other populations.

DISCLOSURES:

The study received support from the Royal Australian College of General Practitioners (RACGP)/HCF Research Foundation. Dr. Zhou reported receiving salary from the RACGP/HCF Research Foundation.

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

TOPLINE:

Detection rates of mild cognitive impairment (MCI) in primary care are extremely low, with only about 8% of expected cases diagnosed on average, a finding that points to an urgent need to improve early detection in primary care.

METHODOLOGY:

• Researchers estimated MCI detection rates among 226,756 primary care clinicians and 54,597 practices that had at least 25 patients enrolled in Medicare between 2017 and 2019. 
• They compared the expected number of MCI cases, based on a predictive model, to actual diagnosed cases as documented in claims and encounter data.
• They accounted for uncertainty in these estimates to determine whether detection rates are within the expected range or significantly higher or lower.

TAKEAWAY:

• More than 25% of clinicians and practices did not have a single patient with diagnosed MCI; the average detection rate was 0.01 for both clinicians and practices.
• The modeled expected MCI detection rate, however, was much higher (average 0.19 for clinicians and 0.20 for practices).
• Average detection rates for clinicians and practices was 0.08, with more than 99% of clinicians and practices underdiagnosing MCI; clinicians practicing geriatric medicine had higher detection rates than others.

IN PRACTICE:

The findings are “concerning not only because patients might not get identified for a disease-modifying AD treatment in time, but also because numerous causes of MCI – such as hypothyroidism and medication side effects – are reversible, and the condition itself can be stabilized by lifestyle modification interventions,” the authors write.

SOURCE:

The study was published online in the Journal of Prevention of Alzheimer’s Disease. The first author was Ying Liu, PhD, of the University of Southern California, Los Angeles.

LIMITATIONS:

The predictive model based on demographic information has only moderate accuracy. Expected prevalence of MCI was based on cognitive test scores, which is not the same as a true clinical diagnosis.

DISCLOSURES:

The study was partially funded by a contract from Genentech to the University of Southern California. Coauthors Soeren Mattke and Christopher Wallick have disclosed relationships with Genentech.

A version of this article appeared on Medscape.com.

TOPLINE:

Detection rates of mild cognitive impairment (MCI) in primary care are extremely low, with only about 8% of expected cases diagnosed on average, a finding that points to an urgent need to improve early detection in primary care.

METHODOLOGY:

• Researchers estimated MCI detection rates among 226,756 primary care clinicians and 54,597 practices that had at least 25 patients enrolled in Medicare between 2017 and 2019. 
• They compared the expected number of MCI cases, based on a predictive model, to actual diagnosed cases as documented in claims and encounter data.
• They accounted for uncertainty in these estimates to determine whether detection rates are within the expected range or significantly higher or lower.

TAKEAWAY:

• More than 25% of clinicians and practices did not have a single patient with diagnosed MCI; the average detection rate was 0.01 for both clinicians and practices.
• The modeled expected MCI detection rate, however, was much higher (average 0.19 for clinicians and 0.20 for practices).
• Average detection rates for clinicians and practices was 0.08, with more than 99% of clinicians and practices underdiagnosing MCI; clinicians practicing geriatric medicine had higher detection rates than others.

IN PRACTICE:

The findings are “concerning not only because patients might not get identified for a disease-modifying AD treatment in time, but also because numerous causes of MCI – such as hypothyroidism and medication side effects – are reversible, and the condition itself can be stabilized by lifestyle modification interventions,” the authors write.

SOURCE:

The study was published online in the Journal of Prevention of Alzheimer’s Disease. The first author was Ying Liu, PhD, of the University of Southern California, Los Angeles.

LIMITATIONS:

The predictive model based on demographic information has only moderate accuracy. Expected prevalence of MCI was based on cognitive test scores, which is not the same as a true clinical diagnosis.

DISCLOSURES:

The study was partially funded by a contract from Genentech to the University of Southern California. Coauthors Soeren Mattke and Christopher Wallick have disclosed relationships with Genentech.

A version of this article appeared on Medscape.com.

TOPLINE:

Detection rates of mild cognitive impairment (MCI) in primary care are extremely low, with only about 8% of expected cases diagnosed on average, a finding that points to an urgent need to improve early detection in primary care.

METHODOLOGY:

• Researchers estimated MCI detection rates among 226,756 primary care clinicians and 54,597 practices that had at least 25 patients enrolled in Medicare between 2017 and 2019. 
• They compared the expected number of MCI cases, based on a predictive model, to actual diagnosed cases as documented in claims and encounter data.
• They accounted for uncertainty in these estimates to determine whether detection rates are within the expected range or significantly higher or lower.

TAKEAWAY:

• More than 25% of clinicians and practices did not have a single patient with diagnosed MCI; the average detection rate was 0.01 for both clinicians and practices.
• The modeled expected MCI detection rate, however, was much higher (average 0.19 for clinicians and 0.20 for practices).
• Average detection rates for clinicians and practices was 0.08, with more than 99% of clinicians and practices underdiagnosing MCI; clinicians practicing geriatric medicine had higher detection rates than others.

IN PRACTICE:

The findings are “concerning not only because patients might not get identified for a disease-modifying AD treatment in time, but also because numerous causes of MCI – such as hypothyroidism and medication side effects – are reversible, and the condition itself can be stabilized by lifestyle modification interventions,” the authors write.

SOURCE:

The study was published online in the Journal of Prevention of Alzheimer’s Disease. The first author was Ying Liu, PhD, of the University of Southern California, Los Angeles.

LIMITATIONS:

The predictive model based on demographic information has only moderate accuracy. Expected prevalence of MCI was based on cognitive test scores, which is not the same as a true clinical diagnosis.

DISCLOSURES:

The study was partially funded by a contract from Genentech to the University of Southern California. Coauthors Soeren Mattke and Christopher Wallick have disclosed relationships with Genentech.

A version of this article appeared on Medscape.com.

Ultraprocessed foods (UPFs) make up nearly three-quarters of the entire U.S. food supply and about 60% of Americans’ daily caloric intake. A significant body of research has tied consumption of these foods – awash in added sugar, salt, fat, artificial colors, or preservatives – to cancer, diabetes, and heart disease.
 

Now, a growing number of studies also link them to poor brain health, including an increased risk of dementia, depression, and anxiety, and some experts are calling for public health policies aimed at reducing UPF consumption.

But what’s the science behind the link between UPFs and brain health and what does it mean for clinicians and their patients?
 

Under srutiny

A mainstay of diets in countries around the world, UPFs have come under increasing scrutiny because of their link to major diseases. The ingredients in UPFs add little or no nutritional value. Their primary function is to increase a product’s shelf life and palatability. Some recent evidence suggests these foods may be as addictive as tobacco. In addition, two pooled analysis studies using the Yale Food Addiction Scale showed that 14% of adults and 12% of children in the United States may have a UPF addiction.

The most widely used measure of what is, and what is not, a UPF was developed in 2009 by researchers in Brazil. The NOVA food classification system assigns food and beverages to one of four groups:

• Unprocessed and minimally processed foods, such as fruits, vegetables, milk, and meat.
• Processed culinary ingredients, including white sugar, butter, and oils derived from seeds, nuts, and fruits.
• Processed foods, such as tomato paste, bacon, canned tuna, and wine.
• Ultraprocessed foods, such as soda, ice cream, breakfast cereal, and prepackaged meals.

Those sounding the alarm about the potential harmful effects of UPFs are particularly concerned about their consumption by young people. The National Health and Nutrition Examination Survey showed that from 1999 to 2018, highly processed foods accounted for the majority of energy intake in those aged 2-19 years.

One of the most commonly used additives in UPFs, the artificial sweetener aspartame, garnered headlines this summer when the World Health Organization classified it as a likely carcinogen in humans. Aspartame is used in thousands of products, from soda to chewing gum to chewable vitamins.

The U.S. Food and Drug Administration strongly disagreed with the WHO’s position and is sticking by its recommended daily limit of 50 mg/kg of body weight – equivalent to 75 packets of the sweetener Equal – as safe for human consumption.

“Aspartame is one of the most studied food additives in the human food supply,” FDA officials said in a statement, adding that the agency found “significant shortcomings” in the studies the WHO used to justify the new classification. “FDA scientists do not have safety concerns when aspartame is used under the approved conditions.”

Increased attention to consumption of UPFs in general and aspartame particularly in recent years has yielded several studies pointing to the foods’ association with compromised brain health.
 

Link to depression, dementia

A recent report on UPF consumption and mental well-being among nearly 300,000 people across 70 countries showed that 53% of those who consumed UPFs several times a day were distressed or were struggling with their mental well-being, compared with 18% of those who rarely or never consumed UPFs.

Part of the Global Mind Project run by the nonprofit Sapien Labs in Arlington, Va., the report also showed that individuals with the highest rates of UPF consumption reported higher levels of confusion, slowed thinking, unwanted or obsessive thoughts, irritability, and feelings of sadness.

“There seems to be a much broader effect than just depression symptoms,” Tara Thiagarajan, PhD, founder and chief scientist of Sapien Labs and coauthor of the report, said in an interview.

The report, which has not been peer reviewed, comes on the heels of several other studies, including one from the Nurses Health Study II that showed that participants who consumed more than eight servings of UPFs daily had about a 50% higher depression risk, compared with those who consumed half that much.

“We found that UPFs in general, and artificial sweeteners and beverages in particular, were associated with increased risk,” said lead investigator Andrew T. Chan, MD, MPH, professor of medicine at Harvard Medical School and chief of the clinical and translational epidemiology unit, Massachusetts General Hospital, both in Boston.

“This was an interesting finding that correlates with data from animal studies that artificial sweeteners may trigger the transmission of particular signaling molecules in the brain that are important for mood,” he told this news organization.

Cognition may also be affected. An analysis of more than 72,000 people in the UK Biobank showed that those who consumed a high levels of UPFs were 50% more likely to develop dementia than those who consumed fewer processed foods. For every 10% increase in UPF consumption, the odds of developing any kind of dementia increased by 25%.

Another study of nearly 11,000 people showed that higher UPF consumption was associated with a significantly faster decline in executive and global cognitive function.
 

Epigenetic changes

While these and other studies suggest a link between UPF consumption and brain health, they are designed to demonstrate correlation. To date, no human study has proven that eating highly processed foods directly causes a decline in mental health or cognition.

Animal studies could provide that causal link. Earlier this year, researchers at Florida State University in Tallahassee reported learning and memory deficits in two groups of male mice that completed a maze test after being fed water mixed with aspartame for about 20% of their adult lives, compared with a group of mice that drank water only. Animals that ingested aspartame could finish the test, but it took them longer, and they needed help.

The amount of aspartame used in the study was just 7% and 15% of the FDA’s recommended maximum intake of aspartame (equivalent to two to four 8-ounce diet sodas daily).

Most intriguing was that offspring of the mice in the aspartame groups demonstrated the same levels of cognitive decline and anxiety as their fathers, even though they had never ingested the artificial sweetener. Researchers theorize that in addition to changes in brain gene expression, aspartame also caused epigenetic changes in germ cells.

“Epigenetic changes in germ cells due to environmental exposures are both good and bad,” lead investigator Pradeep G. Bhide, PhD, professor of developmental neuroscience and director of the Center for Brain Repair at FSU, told this news organization. “They are bad because the next generation is affected. But they’re good because as long as the exposure no longer occurs, 2 or 3 generations later, that’s gone.”

The mice, which lacked taste receptors for aspartame, were the same age and weight in all three groups. Because the only difference was exposure to the artificial sweetener, Dr. Bhide says it suggests a causal link.

“Extrapolation of data from well-controlled laboratory experiments in mice to humans is always risky,” Dr. Bhide said. “The extrapolations give us insights into what could happen rather than what will happen.”
 

Potential mechanisms

Although scientists can’t say for certain how UPFs affect brain health, there are several theories. UPFs may influence an inflammatory immune response, which has been linked to depression and dementia. Consumption of highly processed foods may also disrupt the gut microbiome, Dr. Chan said, which, in turn, may increase depression risk.

“This is an important potential mechanism linking ultraprocessed food to depression since there is emerging evidence that microbes in the gut have been linked with mood through their role in metabolizing and producing proteins that have activity in the brain,” he said.

In addition, with UPFs that contain aspartame, there could be a more direct link to brain function. In the gastrointestinal track, the sweetener is quickly broken down into methanol, aspartic acid, and phenylalanine. All three enter the bloodstream, cross the blood-brain barrier, and are neuroactive.

“Phenylalanine is a precursor for neurotransmitters in the brain, and aspartic acid activates the glutamate excitatory neurotransmitter receptor,” Dr. Bhide said. “The effects we’ve seen could be due to these metabolites that have a direct effect on the brain function.”
 

Time to act?

Some researchers are building a case for classifying UPFs as addictive substances. Others are calling for additional research on UPF safety that is conducted outside the food industry.

There has also been some discussion of placing warning labels on UPFs. However, there is disagreement about what information should be included and how consumers might interpret it. The question of which food products are UPFs and which are not also isn’t settled. The NOVA system may be widely used, but it still has its detractors who believe it misclassifies some healthy foods as ultraprocessed.

Dr. Chan and other experts say the research conducted thus far requires additional corroboration to inform appropriate public health interventions. That would likely take the form of a large, randomized trial with one group of participants eating a healthy diet and the other consuming large amounts of UPFs.

“This type of study is extremely challenging given the number of people that would have to be willing to participate and be willing to eat a very specific diet over a long period of time,” Dr. Chan said. “I am also not sure it would be ethical to assign people to such a diet, given what we already know about the potential health effects of UPFs.”

Dr. Thiagarajan and others have called on funding agencies to direct more grant monies toward studies of UPFs to better understand their effect on brain health.

“Given the magnitude of the problem and given that there is a fair bit of evidence that points to a potential causal link, then we damn well better put money into this and get to the bottom of it,” she said.

Others are looking to the FDA to increase the agency’s scrutiny of food additives. While some additives such as artificial sweeteners have a place in diets of people with diabetes or obesity, Dr. Bhide suggests it may be wise for healthy individuals to reduce their daily intake of UPFs.

“Our data raise this to a different level because of the transgenerational transmission, which has never been shown before,” he said. “We are saying that the FDA should look in preclinical models at germ cells and maybe transgenerational transmission before approving any food additive.”

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

Ultraprocessed foods (UPFs) make up nearly three-quarters of the entire U.S. food supply and about 60% of Americans’ daily caloric intake. A significant body of research has tied consumption of these foods – awash in added sugar, salt, fat, artificial colors, or preservatives – to cancer, diabetes, and heart disease.
 

Now, a growing number of studies also link them to poor brain health, including an increased risk of dementia, depression, and anxiety, and some experts are calling for public health policies aimed at reducing UPF consumption.

But what’s the science behind the link between UPFs and brain health and what does it mean for clinicians and their patients?
 

Under srutiny

A mainstay of diets in countries around the world, UPFs have come under increasing scrutiny because of their link to major diseases. The ingredients in UPFs add little or no nutritional value. Their primary function is to increase a product’s shelf life and palatability. Some recent evidence suggests these foods may be as addictive as tobacco. In addition, two pooled analysis studies using the Yale Food Addiction Scale showed that 14% of adults and 12% of children in the United States may have a UPF addiction.

The most widely used measure of what is, and what is not, a UPF was developed in 2009 by researchers in Brazil. The NOVA food classification system assigns food and beverages to one of four groups:

• Unprocessed and minimally processed foods, such as fruits, vegetables, milk, and meat.
• Processed culinary ingredients, including white sugar, butter, and oils derived from seeds, nuts, and fruits.
• Processed foods, such as tomato paste, bacon, canned tuna, and wine.
• Ultraprocessed foods, such as soda, ice cream, breakfast cereal, and prepackaged meals.

Those sounding the alarm about the potential harmful effects of UPFs are particularly concerned about their consumption by young people. The National Health and Nutrition Examination Survey showed that from 1999 to 2018, highly processed foods accounted for the majority of energy intake in those aged 2-19 years.

One of the most commonly used additives in UPFs, the artificial sweetener aspartame, garnered headlines this summer when the World Health Organization classified it as a likely carcinogen in humans. Aspartame is used in thousands of products, from soda to chewing gum to chewable vitamins.

The U.S. Food and Drug Administration strongly disagreed with the WHO’s position and is sticking by its recommended daily limit of 50 mg/kg of body weight – equivalent to 75 packets of the sweetener Equal – as safe for human consumption.

“Aspartame is one of the most studied food additives in the human food supply,” FDA officials said in a statement, adding that the agency found “significant shortcomings” in the studies the WHO used to justify the new classification. “FDA scientists do not have safety concerns when aspartame is used under the approved conditions.”

Increased attention to consumption of UPFs in general and aspartame particularly in recent years has yielded several studies pointing to the foods’ association with compromised brain health.
 

Link to depression, dementia

A recent report on UPF consumption and mental well-being among nearly 300,000 people across 70 countries showed that 53% of those who consumed UPFs several times a day were distressed or were struggling with their mental well-being, compared with 18% of those who rarely or never consumed UPFs.

Part of the Global Mind Project run by the nonprofit Sapien Labs in Arlington, Va., the report also showed that individuals with the highest rates of UPF consumption reported higher levels of confusion, slowed thinking, unwanted or obsessive thoughts, irritability, and feelings of sadness.

“There seems to be a much broader effect than just depression symptoms,” Tara Thiagarajan, PhD, founder and chief scientist of Sapien Labs and coauthor of the report, said in an interview.

The report, which has not been peer reviewed, comes on the heels of several other studies, including one from the Nurses Health Study II that showed that participants who consumed more than eight servings of UPFs daily had about a 50% higher depression risk, compared with those who consumed half that much.

“We found that UPFs in general, and artificial sweeteners and beverages in particular, were associated with increased risk,” said lead investigator Andrew T. Chan, MD, MPH, professor of medicine at Harvard Medical School and chief of the clinical and translational epidemiology unit, Massachusetts General Hospital, both in Boston.

“This was an interesting finding that correlates with data from animal studies that artificial sweeteners may trigger the transmission of particular signaling molecules in the brain that are important for mood,” he told this news organization.

Cognition may also be affected. An analysis of more than 72,000 people in the UK Biobank showed that those who consumed a high levels of UPFs were 50% more likely to develop dementia than those who consumed fewer processed foods. For every 10% increase in UPF consumption, the odds of developing any kind of dementia increased by 25%.

Another study of nearly 11,000 people showed that higher UPF consumption was associated with a significantly faster decline in executive and global cognitive function.
 

Epigenetic changes

While these and other studies suggest a link between UPF consumption and brain health, they are designed to demonstrate correlation. To date, no human study has proven that eating highly processed foods directly causes a decline in mental health or cognition.

Animal studies could provide that causal link. Earlier this year, researchers at Florida State University in Tallahassee reported learning and memory deficits in two groups of male mice that completed a maze test after being fed water mixed with aspartame for about 20% of their adult lives, compared with a group of mice that drank water only. Animals that ingested aspartame could finish the test, but it took them longer, and they needed help.

The amount of aspartame used in the study was just 7% and 15% of the FDA’s recommended maximum intake of aspartame (equivalent to two to four 8-ounce diet sodas daily).

Most intriguing was that offspring of the mice in the aspartame groups demonstrated the same levels of cognitive decline and anxiety as their fathers, even though they had never ingested the artificial sweetener. Researchers theorize that in addition to changes in brain gene expression, aspartame also caused epigenetic changes in germ cells.

“Epigenetic changes in germ cells due to environmental exposures are both good and bad,” lead investigator Pradeep G. Bhide, PhD, professor of developmental neuroscience and director of the Center for Brain Repair at FSU, told this news organization. “They are bad because the next generation is affected. But they’re good because as long as the exposure no longer occurs, 2 or 3 generations later, that’s gone.”

The mice, which lacked taste receptors for aspartame, were the same age and weight in all three groups. Because the only difference was exposure to the artificial sweetener, Dr. Bhide says it suggests a causal link.

“Extrapolation of data from well-controlled laboratory experiments in mice to humans is always risky,” Dr. Bhide said. “The extrapolations give us insights into what could happen rather than what will happen.”
 

Potential mechanisms

Although scientists can’t say for certain how UPFs affect brain health, there are several theories. UPFs may influence an inflammatory immune response, which has been linked to depression and dementia. Consumption of highly processed foods may also disrupt the gut microbiome, Dr. Chan said, which, in turn, may increase depression risk.

“This is an important potential mechanism linking ultraprocessed food to depression since there is emerging evidence that microbes in the gut have been linked with mood through their role in metabolizing and producing proteins that have activity in the brain,” he said.

In addition, with UPFs that contain aspartame, there could be a more direct link to brain function. In the gastrointestinal track, the sweetener is quickly broken down into methanol, aspartic acid, and phenylalanine. All three enter the bloodstream, cross the blood-brain barrier, and are neuroactive.

“Phenylalanine is a precursor for neurotransmitters in the brain, and aspartic acid activates the glutamate excitatory neurotransmitter receptor,” Dr. Bhide said. “The effects we’ve seen could be due to these metabolites that have a direct effect on the brain function.”
 

Time to act?

Some researchers are building a case for classifying UPFs as addictive substances. Others are calling for additional research on UPF safety that is conducted outside the food industry.

There has also been some discussion of placing warning labels on UPFs. However, there is disagreement about what information should be included and how consumers might interpret it. The question of which food products are UPFs and which are not also isn’t settled. The NOVA system may be widely used, but it still has its detractors who believe it misclassifies some healthy foods as ultraprocessed.

Dr. Chan and other experts say the research conducted thus far requires additional corroboration to inform appropriate public health interventions. That would likely take the form of a large, randomized trial with one group of participants eating a healthy diet and the other consuming large amounts of UPFs.

“This type of study is extremely challenging given the number of people that would have to be willing to participate and be willing to eat a very specific diet over a long period of time,” Dr. Chan said. “I am also not sure it would be ethical to assign people to such a diet, given what we already know about the potential health effects of UPFs.”

Dr. Thiagarajan and others have called on funding agencies to direct more grant monies toward studies of UPFs to better understand their effect on brain health.

“Given the magnitude of the problem and given that there is a fair bit of evidence that points to a potential causal link, then we damn well better put money into this and get to the bottom of it,” she said.

Others are looking to the FDA to increase the agency’s scrutiny of food additives. While some additives such as artificial sweeteners have a place in diets of people with diabetes or obesity, Dr. Bhide suggests it may be wise for healthy individuals to reduce their daily intake of UPFs.

“Our data raise this to a different level because of the transgenerational transmission, which has never been shown before,” he said. “We are saying that the FDA should look in preclinical models at germ cells and maybe transgenerational transmission before approving any food additive.”

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

Ultraprocessed foods (UPFs) make up nearly three-quarters of the entire U.S. food supply and about 60% of Americans’ daily caloric intake. A significant body of research has tied consumption of these foods – awash in added sugar, salt, fat, artificial colors, or preservatives – to cancer, diabetes, and heart disease.
 

Now, a growing number of studies also link them to poor brain health, including an increased risk of dementia, depression, and anxiety, and some experts are calling for public health policies aimed at reducing UPF consumption.

But what’s the science behind the link between UPFs and brain health and what does it mean for clinicians and their patients?
 

Under srutiny

A mainstay of diets in countries around the world, UPFs have come under increasing scrutiny because of their link to major diseases. The ingredients in UPFs add little or no nutritional value. Their primary function is to increase a product’s shelf life and palatability. Some recent evidence suggests these foods may be as addictive as tobacco. In addition, two pooled analysis studies using the Yale Food Addiction Scale showed that 14% of adults and 12% of children in the United States may have a UPF addiction.

The most widely used measure of what is, and what is not, a UPF was developed in 2009 by researchers in Brazil. The NOVA food classification system assigns food and beverages to one of four groups:

• Unprocessed and minimally processed foods, such as fruits, vegetables, milk, and meat.
• Processed culinary ingredients, including white sugar, butter, and oils derived from seeds, nuts, and fruits.
• Processed foods, such as tomato paste, bacon, canned tuna, and wine.
• Ultraprocessed foods, such as soda, ice cream, breakfast cereal, and prepackaged meals.

Those sounding the alarm about the potential harmful effects of UPFs are particularly concerned about their consumption by young people. The National Health and Nutrition Examination Survey showed that from 1999 to 2018, highly processed foods accounted for the majority of energy intake in those aged 2-19 years.

One of the most commonly used additives in UPFs, the artificial sweetener aspartame, garnered headlines this summer when the World Health Organization classified it as a likely carcinogen in humans. Aspartame is used in thousands of products, from soda to chewing gum to chewable vitamins.

The U.S. Food and Drug Administration strongly disagreed with the WHO’s position and is sticking by its recommended daily limit of 50 mg/kg of body weight – equivalent to 75 packets of the sweetener Equal – as safe for human consumption.

“Aspartame is one of the most studied food additives in the human food supply,” FDA officials said in a statement, adding that the agency found “significant shortcomings” in the studies the WHO used to justify the new classification. “FDA scientists do not have safety concerns when aspartame is used under the approved conditions.”

Increased attention to consumption of UPFs in general and aspartame particularly in recent years has yielded several studies pointing to the foods’ association with compromised brain health.
 

Link to depression, dementia

A recent report on UPF consumption and mental well-being among nearly 300,000 people across 70 countries showed that 53% of those who consumed UPFs several times a day were distressed or were struggling with their mental well-being, compared with 18% of those who rarely or never consumed UPFs.

Part of the Global Mind Project run by the nonprofit Sapien Labs in Arlington, Va., the report also showed that individuals with the highest rates of UPF consumption reported higher levels of confusion, slowed thinking, unwanted or obsessive thoughts, irritability, and feelings of sadness.

“There seems to be a much broader effect than just depression symptoms,” Tara Thiagarajan, PhD, founder and chief scientist of Sapien Labs and coauthor of the report, said in an interview.

The report, which has not been peer reviewed, comes on the heels of several other studies, including one from the Nurses Health Study II that showed that participants who consumed more than eight servings of UPFs daily had about a 50% higher depression risk, compared with those who consumed half that much.

“We found that UPFs in general, and artificial sweeteners and beverages in particular, were associated with increased risk,” said lead investigator Andrew T. Chan, MD, MPH, professor of medicine at Harvard Medical School and chief of the clinical and translational epidemiology unit, Massachusetts General Hospital, both in Boston.

“This was an interesting finding that correlates with data from animal studies that artificial sweeteners may trigger the transmission of particular signaling molecules in the brain that are important for mood,” he told this news organization.

Cognition may also be affected. An analysis of more than 72,000 people in the UK Biobank showed that those who consumed a high levels of UPFs were 50% more likely to develop dementia than those who consumed fewer processed foods. For every 10% increase in UPF consumption, the odds of developing any kind of dementia increased by 25%.

Another study of nearly 11,000 people showed that higher UPF consumption was associated with a significantly faster decline in executive and global cognitive function.
 

Epigenetic changes

While these and other studies suggest a link between UPF consumption and brain health, they are designed to demonstrate correlation. To date, no human study has proven that eating highly processed foods directly causes a decline in mental health or cognition.

Animal studies could provide that causal link. Earlier this year, researchers at Florida State University in Tallahassee reported learning and memory deficits in two groups of male mice that completed a maze test after being fed water mixed with aspartame for about 20% of their adult lives, compared with a group of mice that drank water only. Animals that ingested aspartame could finish the test, but it took them longer, and they needed help.

The amount of aspartame used in the study was just 7% and 15% of the FDA’s recommended maximum intake of aspartame (equivalent to two to four 8-ounce diet sodas daily).

Most intriguing was that offspring of the mice in the aspartame groups demonstrated the same levels of cognitive decline and anxiety as their fathers, even though they had never ingested the artificial sweetener. Researchers theorize that in addition to changes in brain gene expression, aspartame also caused epigenetic changes in germ cells.

“Epigenetic changes in germ cells due to environmental exposures are both good and bad,” lead investigator Pradeep G. Bhide, PhD, professor of developmental neuroscience and director of the Center for Brain Repair at FSU, told this news organization. “They are bad because the next generation is affected. But they’re good because as long as the exposure no longer occurs, 2 or 3 generations later, that’s gone.”

The mice, which lacked taste receptors for aspartame, were the same age and weight in all three groups. Because the only difference was exposure to the artificial sweetener, Dr. Bhide says it suggests a causal link.

“Extrapolation of data from well-controlled laboratory experiments in mice to humans is always risky,” Dr. Bhide said. “The extrapolations give us insights into what could happen rather than what will happen.”
 

Potential mechanisms

Although scientists can’t say for certain how UPFs affect brain health, there are several theories. UPFs may influence an inflammatory immune response, which has been linked to depression and dementia. Consumption of highly processed foods may also disrupt the gut microbiome, Dr. Chan said, which, in turn, may increase depression risk.

“This is an important potential mechanism linking ultraprocessed food to depression since there is emerging evidence that microbes in the gut have been linked with mood through their role in metabolizing and producing proteins that have activity in the brain,” he said.

In addition, with UPFs that contain aspartame, there could be a more direct link to brain function. In the gastrointestinal track, the sweetener is quickly broken down into methanol, aspartic acid, and phenylalanine. All three enter the bloodstream, cross the blood-brain barrier, and are neuroactive.

“Phenylalanine is a precursor for neurotransmitters in the brain, and aspartic acid activates the glutamate excitatory neurotransmitter receptor,” Dr. Bhide said. “The effects we’ve seen could be due to these metabolites that have a direct effect on the brain function.”
 

Time to act?

Some researchers are building a case for classifying UPFs as addictive substances. Others are calling for additional research on UPF safety that is conducted outside the food industry.

There has also been some discussion of placing warning labels on UPFs. However, there is disagreement about what information should be included and how consumers might interpret it. The question of which food products are UPFs and which are not also isn’t settled. The NOVA system may be widely used, but it still has its detractors who believe it misclassifies some healthy foods as ultraprocessed.

Dr. Chan and other experts say the research conducted thus far requires additional corroboration to inform appropriate public health interventions. That would likely take the form of a large, randomized trial with one group of participants eating a healthy diet and the other consuming large amounts of UPFs.

“This type of study is extremely challenging given the number of people that would have to be willing to participate and be willing to eat a very specific diet over a long period of time,” Dr. Chan said. “I am also not sure it would be ethical to assign people to such a diet, given what we already know about the potential health effects of UPFs.”

Dr. Thiagarajan and others have called on funding agencies to direct more grant monies toward studies of UPFs to better understand their effect on brain health.

“Given the magnitude of the problem and given that there is a fair bit of evidence that points to a potential causal link, then we damn well better put money into this and get to the bottom of it,” she said.

Others are looking to the FDA to increase the agency’s scrutiny of food additives. While some additives such as artificial sweeteners have a place in diets of people with diabetes or obesity, Dr. Bhide suggests it may be wise for healthy individuals to reduce their daily intake of UPFs.

“Our data raise this to a different level because of the transgenerational transmission, which has never been shown before,” he said. “We are saying that the FDA should look in preclinical models at germ cells and maybe transgenerational transmission before approving any food additive.”

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

T3D-959, an oral dual delta/gamma peroxisome proliferator-activated nuclear receptor (PPAR) agonist, has shown promise in a phase 2 randomized, placebo-controlled study of adults with mild to moderate Alzheimer’s disease (AD).

Topline results provide “clinical evidence of a modification of multiple AD pathologies associated with amyloid plaque burden,” said John Didsbury, PhD, chief executive officer of T3D Therapeutics Inc., the company developing the drug.

While the primary cognitive endpoints were not met in the overall study population, the data suggest that a “high plasma pTau-217/non–pTau-217 ratio, a marker of AD pathology, likely defines an AD population responsive to T3D-959 therapy,” Dr. Didsbury said.

He said it’s important to note that no PET imaging (amyloid/tau) or biomarkers were used as entry criteria and, in hindsight, some participants likely did not have AD, which likely played a role in the negative primary outcome.

The findings from the PIONEER study were presented at the annual Clinical Trials on Alzheimer’s Disease conference.
 

‘Surprised and shocked’

The PPAR family of proteins helps regulate blood sugar and triglyceride levels. The rationale for evaluating PPAR agonists in AD is based on the hypothesis that sporadic AD is fundamentally an age-related metabolic disease.

T3D-959 is the first PPAR delta-activating compound to be developed for the treatment of AD. Uniquely, this drug also activates PPAR gamma, which may provide potential additive or synergistic effects in regulating dysfunctional brain glucose energy and lipid metabolism in AD.

The PIONEER tested three doses of T3D-959 (15 mg, 30 mg, and 45 mg) vs. placebo in 250 adults with mild to moderate AD (Mini-Mental State Examination [MMSE] 14-26, Clinical Dementia Rating (CDR)-Global 0.5-2.0, and Sum of Boxes [CDR-SB] ≥ 3.0). T3D-959 or placebo was taken once daily for 24 weeks.

In the overall population, the primary endpoints – Alzheimer Disease Assessment Scale-Cognitive subscale (ADAS-Cog11) and Clinical Global Impression of Change (CGIC) – were not met.

“Plain and simple, when we saw this data, we were surprised and shocked,” said Dr. Didsbury, and wondered, “How can placebo be doing so well on a 6-month AD trial?”

“We suspect the presence of non-AD subjects in the trial based on the lower-than-typical number of ApoE4 positive subjects, increased cognitive performance and learning effects observed, and only 45% of trial subjects having a low pTau-217 ratio, a biomarker indicating that they would have no AD pathology plasma,” he explained.

Plasma baseline pTau-217 ratio correlates with AD risk and severity and is a marker of AD pathology; in the subgroup with high pTau-217 ratio, the ADAS-Cog11 endpoint was met in the 30-mg T3D-959 group vs. the placebo group (–0.74 vs. 1.27; P = .112), “consistent with clinical benefit,” Dr. Didsbury noted.

The secondary endpoint of change in plasma amyloid-beta (Ab)42/40 ratio was also met in the 30-mg T3D-959 group – increasing at week 24 with T3D-959 vs. decreasing with placebo (P = .0206), with even greater improvement in the high pTau-217 ratio group. In this group, improvement of Ab42/40 ratio was nearly twofold greater than the overall group.

T3D-959 had a similar magnitude of effect on Ab42/40 as lecanemab (Leqembi) at 6 months, the researchers point out in their late-breaking abstract.

Biomarkers of all three AD diagnostic criteria (amyloid/tau/neurodegeneration) were improved, as well as markers of inflammation, insulin resistance, and dysfunctional lipid metabolism – results that demonstrate “peripheral targeted engagement,” Dr. Didsbury said.

“Along with the strong safety profile of T3D-959, the evidence supports a larger study evaluating T3D-959 30 mg/day in patients with mild to moderate AD and a baseline plasma p-Tau-217/non–pTau-217 ratio of ≥ 0.015,” the researchers conclude in their abstract.
 

Lessons learned

Commenting on the research for this article, Rebecca Edelmayer, PhD, senior director of scientific engagement for the Alzheimer’s Association, noted that “the idea behind this treatment is that impaired glucose metabolism in the brain leads to toxic misfolded proteins, including amyloid and tau in people with Alzheimer’s disease.”

“The treatment focuses on improving regulation of glucose and lipid metabolism in the brain. This is one of more than 140 approaches that are being tested today to target the biological drivers and contributors to Alzheimer’s disease,” Dr. Edelmayer said.

Because biomarkers were not used to enroll participants, “there was a high population of people in the trial who did not have Alzheimer’s. This very likely contributed to the negative result,” she noted.

However, the results also suggest that those taking the drug who had a high pTau217 ratio – and are likely to have brain amyloid plaques – had less cognitive decline, she noted.

Lessons learned from this negative trial include “the proper dose to balance efficacy and safety, and how to screen participants for their next study,” Dr. Edelmayer said.

Funding for the study was provided by the National Institute on Aging/National Institutes of Health and the Alzheimer’s Association. Dr. Didsbury and Dr. Edelmayer report no relevant financial relationships.

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

T3D-959, an oral dual delta/gamma peroxisome proliferator-activated nuclear receptor (PPAR) agonist, has shown promise in a phase 2 randomized, placebo-controlled study of adults with mild to moderate Alzheimer’s disease (AD).

Topline results provide “clinical evidence of a modification of multiple AD pathologies associated with amyloid plaque burden,” said John Didsbury, PhD, chief executive officer of T3D Therapeutics Inc., the company developing the drug.

While the primary cognitive endpoints were not met in the overall study population, the data suggest that a “high plasma pTau-217/non–pTau-217 ratio, a marker of AD pathology, likely defines an AD population responsive to T3D-959 therapy,” Dr. Didsbury said.

He said it’s important to note that no PET imaging (amyloid/tau) or biomarkers were used as entry criteria and, in hindsight, some participants likely did not have AD, which likely played a role in the negative primary outcome.

The findings from the PIONEER study were presented at the annual Clinical Trials on Alzheimer’s Disease conference.
 

‘Surprised and shocked’

The PPAR family of proteins helps regulate blood sugar and triglyceride levels. The rationale for evaluating PPAR agonists in AD is based on the hypothesis that sporadic AD is fundamentally an age-related metabolic disease.

T3D-959 is the first PPAR delta-activating compound to be developed for the treatment of AD. Uniquely, this drug also activates PPAR gamma, which may provide potential additive or synergistic effects in regulating dysfunctional brain glucose energy and lipid metabolism in AD.

The PIONEER tested three doses of T3D-959 (15 mg, 30 mg, and 45 mg) vs. placebo in 250 adults with mild to moderate AD (Mini-Mental State Examination [MMSE] 14-26, Clinical Dementia Rating (CDR)-Global 0.5-2.0, and Sum of Boxes [CDR-SB] ≥ 3.0). T3D-959 or placebo was taken once daily for 24 weeks.

In the overall population, the primary endpoints – Alzheimer Disease Assessment Scale-Cognitive subscale (ADAS-Cog11) and Clinical Global Impression of Change (CGIC) – were not met.

“Plain and simple, when we saw this data, we were surprised and shocked,” said Dr. Didsbury, and wondered, “How can placebo be doing so well on a 6-month AD trial?”

“We suspect the presence of non-AD subjects in the trial based on the lower-than-typical number of ApoE4 positive subjects, increased cognitive performance and learning effects observed, and only 45% of trial subjects having a low pTau-217 ratio, a biomarker indicating that they would have no AD pathology plasma,” he explained.

Plasma baseline pTau-217 ratio correlates with AD risk and severity and is a marker of AD pathology; in the subgroup with high pTau-217 ratio, the ADAS-Cog11 endpoint was met in the 30-mg T3D-959 group vs. the placebo group (–0.74 vs. 1.27; P = .112), “consistent with clinical benefit,” Dr. Didsbury noted.

The secondary endpoint of change in plasma amyloid-beta (Ab)42/40 ratio was also met in the 30-mg T3D-959 group – increasing at week 24 with T3D-959 vs. decreasing with placebo (P = .0206), with even greater improvement in the high pTau-217 ratio group. In this group, improvement of Ab42/40 ratio was nearly twofold greater than the overall group.

T3D-959 had a similar magnitude of effect on Ab42/40 as lecanemab (Leqembi) at 6 months, the researchers point out in their late-breaking abstract.

Biomarkers of all three AD diagnostic criteria (amyloid/tau/neurodegeneration) were improved, as well as markers of inflammation, insulin resistance, and dysfunctional lipid metabolism – results that demonstrate “peripheral targeted engagement,” Dr. Didsbury said.

“Along with the strong safety profile of T3D-959, the evidence supports a larger study evaluating T3D-959 30 mg/day in patients with mild to moderate AD and a baseline plasma p-Tau-217/non–pTau-217 ratio of ≥ 0.015,” the researchers conclude in their abstract.
 

Lessons learned

Commenting on the research for this article, Rebecca Edelmayer, PhD, senior director of scientific engagement for the Alzheimer’s Association, noted that “the idea behind this treatment is that impaired glucose metabolism in the brain leads to toxic misfolded proteins, including amyloid and tau in people with Alzheimer’s disease.”

“The treatment focuses on improving regulation of glucose and lipid metabolism in the brain. This is one of more than 140 approaches that are being tested today to target the biological drivers and contributors to Alzheimer’s disease,” Dr. Edelmayer said.

Because biomarkers were not used to enroll participants, “there was a high population of people in the trial who did not have Alzheimer’s. This very likely contributed to the negative result,” she noted.

However, the results also suggest that those taking the drug who had a high pTau217 ratio – and are likely to have brain amyloid plaques – had less cognitive decline, she noted.

Lessons learned from this negative trial include “the proper dose to balance efficacy and safety, and how to screen participants for their next study,” Dr. Edelmayer said.

Funding for the study was provided by the National Institute on Aging/National Institutes of Health and the Alzheimer’s Association. Dr. Didsbury and Dr. Edelmayer report no relevant financial relationships.

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

T3D-959, an oral dual delta/gamma peroxisome proliferator-activated nuclear receptor (PPAR) agonist, has shown promise in a phase 2 randomized, placebo-controlled study of adults with mild to moderate Alzheimer’s disease (AD).

Topline results provide “clinical evidence of a modification of multiple AD pathologies associated with amyloid plaque burden,” said John Didsbury, PhD, chief executive officer of T3D Therapeutics Inc., the company developing the drug.

While the primary cognitive endpoints were not met in the overall study population, the data suggest that a “high plasma pTau-217/non–pTau-217 ratio, a marker of AD pathology, likely defines an AD population responsive to T3D-959 therapy,” Dr. Didsbury said.

He said it’s important to note that no PET imaging (amyloid/tau) or biomarkers were used as entry criteria and, in hindsight, some participants likely did not have AD, which likely played a role in the negative primary outcome.

The findings from the PIONEER study were presented at the annual Clinical Trials on Alzheimer’s Disease conference.
 

‘Surprised and shocked’

The PPAR family of proteins helps regulate blood sugar and triglyceride levels. The rationale for evaluating PPAR agonists in AD is based on the hypothesis that sporadic AD is fundamentally an age-related metabolic disease.

T3D-959 is the first PPAR delta-activating compound to be developed for the treatment of AD. Uniquely, this drug also activates PPAR gamma, which may provide potential additive or synergistic effects in regulating dysfunctional brain glucose energy and lipid metabolism in AD.

The PIONEER tested three doses of T3D-959 (15 mg, 30 mg, and 45 mg) vs. placebo in 250 adults with mild to moderate AD (Mini-Mental State Examination [MMSE] 14-26, Clinical Dementia Rating (CDR)-Global 0.5-2.0, and Sum of Boxes [CDR-SB] ≥ 3.0). T3D-959 or placebo was taken once daily for 24 weeks.

In the overall population, the primary endpoints – Alzheimer Disease Assessment Scale-Cognitive subscale (ADAS-Cog11) and Clinical Global Impression of Change (CGIC) – were not met.

“Plain and simple, when we saw this data, we were surprised and shocked,” said Dr. Didsbury, and wondered, “How can placebo be doing so well on a 6-month AD trial?”

“We suspect the presence of non-AD subjects in the trial based on the lower-than-typical number of ApoE4 positive subjects, increased cognitive performance and learning effects observed, and only 45% of trial subjects having a low pTau-217 ratio, a biomarker indicating that they would have no AD pathology plasma,” he explained.

Plasma baseline pTau-217 ratio correlates with AD risk and severity and is a marker of AD pathology; in the subgroup with high pTau-217 ratio, the ADAS-Cog11 endpoint was met in the 30-mg T3D-959 group vs. the placebo group (–0.74 vs. 1.27; P = .112), “consistent with clinical benefit,” Dr. Didsbury noted.

The secondary endpoint of change in plasma amyloid-beta (Ab)42/40 ratio was also met in the 30-mg T3D-959 group – increasing at week 24 with T3D-959 vs. decreasing with placebo (P = .0206), with even greater improvement in the high pTau-217 ratio group. In this group, improvement of Ab42/40 ratio was nearly twofold greater than the overall group.

T3D-959 had a similar magnitude of effect on Ab42/40 as lecanemab (Leqembi) at 6 months, the researchers point out in their late-breaking abstract.

Biomarkers of all three AD diagnostic criteria (amyloid/tau/neurodegeneration) were improved, as well as markers of inflammation, insulin resistance, and dysfunctional lipid metabolism – results that demonstrate “peripheral targeted engagement,” Dr. Didsbury said.

“Along with the strong safety profile of T3D-959, the evidence supports a larger study evaluating T3D-959 30 mg/day in patients with mild to moderate AD and a baseline plasma p-Tau-217/non–pTau-217 ratio of ≥ 0.015,” the researchers conclude in their abstract.
 

Lessons learned

Commenting on the research for this article, Rebecca Edelmayer, PhD, senior director of scientific engagement for the Alzheimer’s Association, noted that “the idea behind this treatment is that impaired glucose metabolism in the brain leads to toxic misfolded proteins, including amyloid and tau in people with Alzheimer’s disease.”

“The treatment focuses on improving regulation of glucose and lipid metabolism in the brain. This is one of more than 140 approaches that are being tested today to target the biological drivers and contributors to Alzheimer’s disease,” Dr. Edelmayer said.

Because biomarkers were not used to enroll participants, “there was a high population of people in the trial who did not have Alzheimer’s. This very likely contributed to the negative result,” she noted.

However, the results also suggest that those taking the drug who had a high pTau217 ratio – and are likely to have brain amyloid plaques – had less cognitive decline, she noted.

Lessons learned from this negative trial include “the proper dose to balance efficacy and safety, and how to screen participants for their next study,” Dr. Edelmayer said.

Funding for the study was provided by the National Institute on Aging/National Institutes of Health and the Alzheimer’s Association. Dr. Didsbury and Dr. Edelmayer report no relevant financial relationships.

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

TOPLINE:

Challenging conventional wisdom, new research suggests that hitting the snooze button does not lead to cognitive impairment on waking and may actually provide cognitive benefits.

METHODOLOGY:

• Researchers did two studies to determine why intermittent morning alarms are used and how they affect sleep, cognition, cortisol, and mood.
• Study 1 was a survey of 1,732 healthy adults (mean age 34 years; 66% women) designed to elucidate the characteristics of people who snooze and why they choose to delay their waking in this way.
• Study 2 was a within-subject polysomnography study of 31 healthy habitual snoozers (mean age 27 years; 18 women) designed to explore the acute effects of snoozing on sleep architecture, sleepiness, cognitive ability, mood, and cortisol awakening response.

TAKEAWAY:

• Overall, 69% reported using the snooze button or setting multiple alarms at least sometimes, most often on workdays (71%), with an average snooze time per morning of 22 minutes.
• Sleep quality did not differ between snoozers and nonsnoozers, but snoozers were more likely to feel mentally drowsy on waking (odds ratio, 3.0; P < .001) and had slightly shorter sleep time on workdays (13 minutes).
• In the polysomnography study, compared with waking up abruptly, 30 minutes of snoozing in the morning improved or did not affect performance on standard cognitive tests completed directly on final awakening.
• Snoozing resulted in about 6 minutes of lost sleep, but it prevented awakening from slow-wave sleep and had no clear effects on the cortisol awakening response, morning sleepiness, mood, or overnight sleep architecture.

IN PRACTICE:

“The findings indicate that there is no reason to stop snoozing in the morning if you enjoy it, at least not for snooze times around 30 minutes. In fact, it may even help those with morning drowsiness to be slightly more awake once they get up,” corresponding author Tina Sundelin, PhD, of Stockholm University, said in a statement.

SOURCE:

The study was published online in the Journal of Sleep Research.

LIMITATIONS:

Study 1 focused on waking preferences in a convenience sample of adults. Study 2 included only habitual snoozers making it difficult to generalize the findings to people who don’t usually snooze. The study investigated only the effect of 30 minutes of snoozing on the studied parameters. It’s possible that shorter or longer snooze times have different cognitive effects.

DISCLOSURES:

Support for the study was provided by the Stress Research Institute, Stockholm University, and a grant from Vetenskapsrådet. The authors disclosed no relevant conflicts of interest.

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

TOPLINE:

Challenging conventional wisdom, new research suggests that hitting the snooze button does not lead to cognitive impairment on waking and may actually provide cognitive benefits.

METHODOLOGY:

• Researchers did two studies to determine why intermittent morning alarms are used and how they affect sleep, cognition, cortisol, and mood.
• Study 1 was a survey of 1,732 healthy adults (mean age 34 years; 66% women) designed to elucidate the characteristics of people who snooze and why they choose to delay their waking in this way.
• Study 2 was a within-subject polysomnography study of 31 healthy habitual snoozers (mean age 27 years; 18 women) designed to explore the acute effects of snoozing on sleep architecture, sleepiness, cognitive ability, mood, and cortisol awakening response.

TAKEAWAY:

• Overall, 69% reported using the snooze button or setting multiple alarms at least sometimes, most often on workdays (71%), with an average snooze time per morning of 22 minutes.
• Sleep quality did not differ between snoozers and nonsnoozers, but snoozers were more likely to feel mentally drowsy on waking (odds ratio, 3.0; P < .001) and had slightly shorter sleep time on workdays (13 minutes).
• In the polysomnography study, compared with waking up abruptly, 30 minutes of snoozing in the morning improved or did not affect performance on standard cognitive tests completed directly on final awakening.
• Snoozing resulted in about 6 minutes of lost sleep, but it prevented awakening from slow-wave sleep and had no clear effects on the cortisol awakening response, morning sleepiness, mood, or overnight sleep architecture.

IN PRACTICE:

“The findings indicate that there is no reason to stop snoozing in the morning if you enjoy it, at least not for snooze times around 30 minutes. In fact, it may even help those with morning drowsiness to be slightly more awake once they get up,” corresponding author Tina Sundelin, PhD, of Stockholm University, said in a statement.

SOURCE:

The study was published online in the Journal of Sleep Research.

LIMITATIONS:

Study 1 focused on waking preferences in a convenience sample of adults. Study 2 included only habitual snoozers making it difficult to generalize the findings to people who don’t usually snooze. The study investigated only the effect of 30 minutes of snoozing on the studied parameters. It’s possible that shorter or longer snooze times have different cognitive effects.

DISCLOSURES:

Support for the study was provided by the Stress Research Institute, Stockholm University, and a grant from Vetenskapsrådet. The authors disclosed no relevant conflicts of interest.

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

TOPLINE:

Challenging conventional wisdom, new research suggests that hitting the snooze button does not lead to cognitive impairment on waking and may actually provide cognitive benefits.

METHODOLOGY:

• Researchers did two studies to determine why intermittent morning alarms are used and how they affect sleep, cognition, cortisol, and mood.
• Study 1 was a survey of 1,732 healthy adults (mean age 34 years; 66% women) designed to elucidate the characteristics of people who snooze and why they choose to delay their waking in this way.
• Study 2 was a within-subject polysomnography study of 31 healthy habitual snoozers (mean age 27 years; 18 women) designed to explore the acute effects of snoozing on sleep architecture, sleepiness, cognitive ability, mood, and cortisol awakening response.

TAKEAWAY:

• Overall, 69% reported using the snooze button or setting multiple alarms at least sometimes, most often on workdays (71%), with an average snooze time per morning of 22 minutes.
• Sleep quality did not differ between snoozers and nonsnoozers, but snoozers were more likely to feel mentally drowsy on waking (odds ratio, 3.0; P < .001) and had slightly shorter sleep time on workdays (13 minutes).
• In the polysomnography study, compared with waking up abruptly, 30 minutes of snoozing in the morning improved or did not affect performance on standard cognitive tests completed directly on final awakening.
• Snoozing resulted in about 6 minutes of lost sleep, but it prevented awakening from slow-wave sleep and had no clear effects on the cortisol awakening response, morning sleepiness, mood, or overnight sleep architecture.

IN PRACTICE:

“The findings indicate that there is no reason to stop snoozing in the morning if you enjoy it, at least not for snooze times around 30 minutes. In fact, it may even help those with morning drowsiness to be slightly more awake once they get up,” corresponding author Tina Sundelin, PhD, of Stockholm University, said in a statement.

SOURCE:

The study was published online in the Journal of Sleep Research.

LIMITATIONS:

Study 1 focused on waking preferences in a convenience sample of adults. Study 2 included only habitual snoozers making it difficult to generalize the findings to people who don’t usually snooze. The study investigated only the effect of 30 minutes of snoozing on the studied parameters. It’s possible that shorter or longer snooze times have different cognitive effects.

DISCLOSURES:

Support for the study was provided by the Stress Research Institute, Stockholm University, and a grant from Vetenskapsrådet. The authors disclosed no relevant conflicts of interest.

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

PHILADELPHIA – Acute stress in peri- and postmenopausal women is associated with more depressive symptoms, while chronic stress showed greater association with memory and concentration problems, according to research presented at the annual meeting of the Menopause Society (formerly the North American Menopause Society).

“This work suggests that markers of hypothalamic-pituitary-axis activation that capture total cortisol secretion over multiple months, [such as] hair cortisol, strongly correlate with cognitive performance on attention and working memory tasks, whereas measures of more acute cortisol, [such as] salivary cortisol, may be more strongly associated with depression symptom severity and verbal learning,” Christina Metcalf, PhD, an assistant professor of psychiatry in the Colorado Center for Women’s Behavioral Health and Wellness at the University of Colorado at Denver, Aurora, told attendees. “Given the associations with chronic stress, there’s a lot of potential here to increase our knowledge about how women are doing and managing stress and life stressors during this life transition,” she said.

Measuring hair cortisol more feasible

The study was conducted remotely, with participants using video conferencing to communicate with the study personnel and then completing study procedures at home, including 2 days of cognitive testing with the California Verbal Learning Test – Third Edition and the n-back and continuous performance tasks. The participants also completed the Center for Epidemiologic Studies Depression Scale (CES-D).

Participants with higher levels of hair cortisol and salivary cortisol also had more severe depression symptoms (P < .001). Hair cortisol was also significantly associated with attention and working memory: Women with higher levels had fewer correct answers on the 0-back and 1-back trials (P < .01) and made more mistakes on the 2-back trial (P < .001). They also scored with less specificity on the continuous performance tasks (P = .022).

Although no association existed between hair cortisol levels and verbal learning or verbal memory (P > .05), participants with higher hair cortisol did score worse on the immediate recall trials (P = .034). Salivary cortisol levels, on the other hand, showed no association with memory recall trials, attention or working memory (P > .05).

Measuring cortisol from hair samples is more feasible than using saliva samples and may offer valuable insights regarding hypothalamic-pituitary-axis activity “to consider alongside the cognitive and mental health of late peri-/early postmenopausal women,” Dr. Metcalf told attendees. The next step is to find out whether the hypothalamic-pituitary-axis axis is a modifiable biomarker that can be used to improve executive function.

The study was limited by its small population, its cross-sectional design, and the lack of covariates in the current analyses.
 

Monitor symptoms in midlife

Hadine Joffe, MD, MSc, a professor of psychiatry and executive director of the Mary Horrigan Connors Center for Women’s Health and Gender Biology at Brigham and Women’s Hospital and Harvard Medical School, both in Boston, said the study findings were not surprising given how common the complaints of stress and depressive symptoms are.

“Mood changes are linked with acute, immediate cortisol levels at the same point in time, and cognitive symptoms were linked to more chronically elevated cortisol levels,” Dr. Joffe said in an interview. “Women and their providers should monitor for these challenging brain symptoms in midlife as they affect performance and quality of life and are linked with changes in the HPA axis as stress biomarkers.”

Because the study is small and has a cross-sectional design, it’s not possible to determine the direction of the associations or to make any inferences about causation, Dr. Joffe said.

“We cannot make the conclusion that stress is adversely affecting mood and cognitive performance given the design limitations. It is possible that mood and cognitive issues contributed to these stress markers,” Dr. Joffe said.“However, it is known that the experience of stress is linked with vulnerability to mood and cognitive symptoms, and also that mood and cognitive symptoms induce significant stress.”

The research was funded by the Menopause Society, Colorado University, the Ludeman Family Center for Women’s Health Research, the National Institute of Mental Health, and the National Institute of Aging. Dr. Metcalf had no disclosures. Dr. Joffe has received grant support from Merck, Pfizer and Sage, and has been a consultant or advisor for Bayer, Merck and Hello Therapeutics.

PHILADELPHIA – Acute stress in peri- and postmenopausal women is associated with more depressive symptoms, while chronic stress showed greater association with memory and concentration problems, according to research presented at the annual meeting of the Menopause Society (formerly the North American Menopause Society).

“This work suggests that markers of hypothalamic-pituitary-axis activation that capture total cortisol secretion over multiple months, [such as] hair cortisol, strongly correlate with cognitive performance on attention and working memory tasks, whereas measures of more acute cortisol, [such as] salivary cortisol, may be more strongly associated with depression symptom severity and verbal learning,” Christina Metcalf, PhD, an assistant professor of psychiatry in the Colorado Center for Women’s Behavioral Health and Wellness at the University of Colorado at Denver, Aurora, told attendees. “Given the associations with chronic stress, there’s a lot of potential here to increase our knowledge about how women are doing and managing stress and life stressors during this life transition,” she said.

Measuring hair cortisol more feasible

The study was conducted remotely, with participants using video conferencing to communicate with the study personnel and then completing study procedures at home, including 2 days of cognitive testing with the California Verbal Learning Test – Third Edition and the n-back and continuous performance tasks. The participants also completed the Center for Epidemiologic Studies Depression Scale (CES-D).

Participants with higher levels of hair cortisol and salivary cortisol also had more severe depression symptoms (P < .001). Hair cortisol was also significantly associated with attention and working memory: Women with higher levels had fewer correct answers on the 0-back and 1-back trials (P < .01) and made more mistakes on the 2-back trial (P < .001). They also scored with less specificity on the continuous performance tasks (P = .022).

Although no association existed between hair cortisol levels and verbal learning or verbal memory (P > .05), participants with higher hair cortisol did score worse on the immediate recall trials (P = .034). Salivary cortisol levels, on the other hand, showed no association with memory recall trials, attention or working memory (P > .05).

Measuring cortisol from hair samples is more feasible than using saliva samples and may offer valuable insights regarding hypothalamic-pituitary-axis activity “to consider alongside the cognitive and mental health of late peri-/early postmenopausal women,” Dr. Metcalf told attendees. The next step is to find out whether the hypothalamic-pituitary-axis axis is a modifiable biomarker that can be used to improve executive function.

The study was limited by its small population, its cross-sectional design, and the lack of covariates in the current analyses.
 

Monitor symptoms in midlife

Hadine Joffe, MD, MSc, a professor of psychiatry and executive director of the Mary Horrigan Connors Center for Women’s Health and Gender Biology at Brigham and Women’s Hospital and Harvard Medical School, both in Boston, said the study findings were not surprising given how common the complaints of stress and depressive symptoms are.

“Mood changes are linked with acute, immediate cortisol levels at the same point in time, and cognitive symptoms were linked to more chronically elevated cortisol levels,” Dr. Joffe said in an interview. “Women and their providers should monitor for these challenging brain symptoms in midlife as they affect performance and quality of life and are linked with changes in the HPA axis as stress biomarkers.”

Because the study is small and has a cross-sectional design, it’s not possible to determine the direction of the associations or to make any inferences about causation, Dr. Joffe said.

“We cannot make the conclusion that stress is adversely affecting mood and cognitive performance given the design limitations. It is possible that mood and cognitive issues contributed to these stress markers,” Dr. Joffe said.“However, it is known that the experience of stress is linked with vulnerability to mood and cognitive symptoms, and also that mood and cognitive symptoms induce significant stress.”

The research was funded by the Menopause Society, Colorado University, the Ludeman Family Center for Women’s Health Research, the National Institute of Mental Health, and the National Institute of Aging. Dr. Metcalf had no disclosures. Dr. Joffe has received grant support from Merck, Pfizer and Sage, and has been a consultant or advisor for Bayer, Merck and Hello Therapeutics.

PHILADELPHIA – Acute stress in peri- and postmenopausal women is associated with more depressive symptoms, while chronic stress showed greater association with memory and concentration problems, according to research presented at the annual meeting of the Menopause Society (formerly the North American Menopause Society).

“This work suggests that markers of hypothalamic-pituitary-axis activation that capture total cortisol secretion over multiple months, [such as] hair cortisol, strongly correlate with cognitive performance on attention and working memory tasks, whereas measures of more acute cortisol, [such as] salivary cortisol, may be more strongly associated with depression symptom severity and verbal learning,” Christina Metcalf, PhD, an assistant professor of psychiatry in the Colorado Center for Women’s Behavioral Health and Wellness at the University of Colorado at Denver, Aurora, told attendees. “Given the associations with chronic stress, there’s a lot of potential here to increase our knowledge about how women are doing and managing stress and life stressors during this life transition,” she said.

Measuring hair cortisol more feasible

The study was conducted remotely, with participants using video conferencing to communicate with the study personnel and then completing study procedures at home, including 2 days of cognitive testing with the California Verbal Learning Test – Third Edition and the n-back and continuous performance tasks. The participants also completed the Center for Epidemiologic Studies Depression Scale (CES-D).

Participants with higher levels of hair cortisol and salivary cortisol also had more severe depression symptoms (P < .001). Hair cortisol was also significantly associated with attention and working memory: Women with higher levels had fewer correct answers on the 0-back and 1-back trials (P < .01) and made more mistakes on the 2-back trial (P < .001). They also scored with less specificity on the continuous performance tasks (P = .022).

Although no association existed between hair cortisol levels and verbal learning or verbal memory (P > .05), participants with higher hair cortisol did score worse on the immediate recall trials (P = .034). Salivary cortisol levels, on the other hand, showed no association with memory recall trials, attention or working memory (P > .05).

Measuring cortisol from hair samples is more feasible than using saliva samples and may offer valuable insights regarding hypothalamic-pituitary-axis activity “to consider alongside the cognitive and mental health of late peri-/early postmenopausal women,” Dr. Metcalf told attendees. The next step is to find out whether the hypothalamic-pituitary-axis axis is a modifiable biomarker that can be used to improve executive function.

The study was limited by its small population, its cross-sectional design, and the lack of covariates in the current analyses.
 

Monitor symptoms in midlife

Hadine Joffe, MD, MSc, a professor of psychiatry and executive director of the Mary Horrigan Connors Center for Women’s Health and Gender Biology at Brigham and Women’s Hospital and Harvard Medical School, both in Boston, said the study findings were not surprising given how common the complaints of stress and depressive symptoms are.

“Mood changes are linked with acute, immediate cortisol levels at the same point in time, and cognitive symptoms were linked to more chronically elevated cortisol levels,” Dr. Joffe said in an interview. “Women and their providers should monitor for these challenging brain symptoms in midlife as they affect performance and quality of life and are linked with changes in the HPA axis as stress biomarkers.”

Because the study is small and has a cross-sectional design, it’s not possible to determine the direction of the associations or to make any inferences about causation, Dr. Joffe said.

“We cannot make the conclusion that stress is adversely affecting mood and cognitive performance given the design limitations. It is possible that mood and cognitive issues contributed to these stress markers,” Dr. Joffe said.“However, it is known that the experience of stress is linked with vulnerability to mood and cognitive symptoms, and also that mood and cognitive symptoms induce significant stress.”

The research was funded by the Menopause Society, Colorado University, the Ludeman Family Center for Women’s Health Research, the National Institute of Mental Health, and the National Institute of Aging. Dr. Metcalf had no disclosures. Dr. Joffe has received grant support from Merck, Pfizer and Sage, and has been a consultant or advisor for Bayer, Merck and Hello Therapeutics.

The enteric nervous system (ENS), which is regarded as our second brain, is the part of the autonomic nervous system that controls the digestive tract. Housed along the entire length of the digestive tract, it is made up of more than 100 million neurons. It plays a central role in controlling the regulation of gastrointestinal motility, absorption of nutrients, and control of the intestinal barrier that protects the body from external pathogens.

Braak’s hypothesis suggests that the digestive tract could be the starting point for Parkinson’s disease. The fact that nearly all patients with Parkinson’s disease experience digestive problems and have neuropathological lesions in intrinsic and extrinsic innervation of the gastrointestinal tract suggests that Parkinson’s disease also has a gastrointestinal component.

Besides the ascending pathway formulated by Braak, a descending etiology in which gastrointestinal symptoms are present in early stages when neurological signposts have not yet been noticed is supported by evidence from trials. These gastrointestinal symptoms then represent a risk factor. Links have also been described between a history of gastrointestinal symptoms and Alzheimer’s disease and cerebrovascular diseases (CVD), thus justifying studies on a larger scale.
 

Large combined study

The authors have conducted a combined case-control and cohort study using TriNetX, a national network of medical records based in the United States. They identified 24,624 patients with idiopathic Parkinson’s disease in the case-control analysis and compared them with control subjects without neurological disease. They also identified subjects with Alzheimer’s disease and CVD, to study previous gastrointestinal signs. Secondly, 18 cohorts with each exposure (various gastrointestinal symptoms, appendectomy, vagotomy) were compared with their negative controls (NC) for the development of Parkinson’s disease, Alzheimer’s disease, or CVD in 5 years.

Gastroparesis, dysphagia, and irritable bowel syndrome (IBS) without diarrhea or constipation were shown to have specific associations with Parkinson’s disease (vs. NC, Alzheimer’s disease, and CVD) in both case-controls (odds ratios all P < .0001) and cohort analyses (relative risks all P < .05). While functional dyspepsia, IBS with diarrhea, diarrhea, and fecal incontinence were not specific to Parkinson’s disease, IBS with constipation and intestinal pseudo-obstruction showed specificity to Parkinson’s disease in the case-control (OR, 4.11) and cohort (RR, 1.84) analyses. Appendectomy reduced the risk of Parkinson’s disease in the cohort study (RR, 0.48). Neither inflammatory bowel disease nor vagotomy was associated with Parkinson’s disease.
 

A ‘second brain’

This broad study attempted to explore the gut-brain axis by looking for associations between neurological diagnoses and prior gastrointestinal symptoms and later development of Parkinson’s disease. After adjustment to account for multiple comparisons and acknowledgment of the initial risk in patients with Alzheimer’s disease and CVD, only dysphagia, gastroparesis, IBS without diarrhea, and isolated constipation were significantly and specifically associated with Parkinson’s disease.

Numerous literature reviews mention that ENS lesions are responsible for gastrointestinal disorders observed in patients with Parkinson’s disease. Tests on gastrointestinal autopsy and biopsy specimens have established that alpha synuclein clusters, which are morphologically similar to Lewy bodies in the CNS, are seen in the vagus nerve and in the ENS in most subjects with Parkinson’s disease. However, these studies have not shown any loss of neurons in the ENS in Parkinson’s disease, and the presence of alpha synuclein deposits in the ENS is not sufficient in itself to explain these gastrointestinal disorders.

It therefore remains to be determined whether vagal nerve damage alone can explain gastrointestinal disorders or whether dysfunction of enteric neurons without neuronal loss is occurring. So, damage to the ENS from alpha synuclein deposits would be early and would precede damage to the CNS, thus affording evidence in support of Braak’s hypothesis, which relies on autopsy data that does not allow for longitudinal monitoring in a single individual.

Appendectomy appeared to be protective, leading to additional speculation about its role in the pathophysiology of Parkinson’s disease. Additional mechanistic studies are therefore needed to establish causality and confirm the gut-brain axis or the role of dysbiosis and of intestinal permeability problems.

In conclusion, this large, first-of-its-kind multicenter study conducted on a national scale shows that early gastrointestinal symptoms (dysphagia, gastroparesis, constipation, and IBS without diarrhea) are associated with an increased risk of Parkinson’s disease, as is suggested by Braak’s hypothesis. Subject to future longitudinal mechanistic studies, early detection of these gastrointestinal disorders could aid in identifying patients at risk of Parkinson’s, and it could then be assumed that disease-modifying treatments could, at this early stage, halt progression of the disease linked to toxic clusters of alpha synuclein.

This article was translated from JIM, which is part of the Medscape professional network.

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

The enteric nervous system (ENS), which is regarded as our second brain, is the part of the autonomic nervous system that controls the digestive tract. Housed along the entire length of the digestive tract, it is made up of more than 100 million neurons. It plays a central role in controlling the regulation of gastrointestinal motility, absorption of nutrients, and control of the intestinal barrier that protects the body from external pathogens.

Braak’s hypothesis suggests that the digestive tract could be the starting point for Parkinson’s disease. The fact that nearly all patients with Parkinson’s disease experience digestive problems and have neuropathological lesions in intrinsic and extrinsic innervation of the gastrointestinal tract suggests that Parkinson’s disease also has a gastrointestinal component.

Besides the ascending pathway formulated by Braak, a descending etiology in which gastrointestinal symptoms are present in early stages when neurological signposts have not yet been noticed is supported by evidence from trials. These gastrointestinal symptoms then represent a risk factor. Links have also been described between a history of gastrointestinal symptoms and Alzheimer’s disease and cerebrovascular diseases (CVD), thus justifying studies on a larger scale.
 

Large combined study

The authors have conducted a combined case-control and cohort study using TriNetX, a national network of medical records based in the United States. They identified 24,624 patients with idiopathic Parkinson’s disease in the case-control analysis and compared them with control subjects without neurological disease. They also identified subjects with Alzheimer’s disease and CVD, to study previous gastrointestinal signs. Secondly, 18 cohorts with each exposure (various gastrointestinal symptoms, appendectomy, vagotomy) were compared with their negative controls (NC) for the development of Parkinson’s disease, Alzheimer’s disease, or CVD in 5 years.

Gastroparesis, dysphagia, and irritable bowel syndrome (IBS) without diarrhea or constipation were shown to have specific associations with Parkinson’s disease (vs. NC, Alzheimer’s disease, and CVD) in both case-controls (odds ratios all P < .0001) and cohort analyses (relative risks all P < .05). While functional dyspepsia, IBS with diarrhea, diarrhea, and fecal incontinence were not specific to Parkinson’s disease, IBS with constipation and intestinal pseudo-obstruction showed specificity to Parkinson’s disease in the case-control (OR, 4.11) and cohort (RR, 1.84) analyses. Appendectomy reduced the risk of Parkinson’s disease in the cohort study (RR, 0.48). Neither inflammatory bowel disease nor vagotomy was associated with Parkinson’s disease.
 

A ‘second brain’

This broad study attempted to explore the gut-brain axis by looking for associations between neurological diagnoses and prior gastrointestinal symptoms and later development of Parkinson’s disease. After adjustment to account for multiple comparisons and acknowledgment of the initial risk in patients with Alzheimer’s disease and CVD, only dysphagia, gastroparesis, IBS without diarrhea, and isolated constipation were significantly and specifically associated with Parkinson’s disease.

Numerous literature reviews mention that ENS lesions are responsible for gastrointestinal disorders observed in patients with Parkinson’s disease. Tests on gastrointestinal autopsy and biopsy specimens have established that alpha synuclein clusters, which are morphologically similar to Lewy bodies in the CNS, are seen in the vagus nerve and in the ENS in most subjects with Parkinson’s disease. However, these studies have not shown any loss of neurons in the ENS in Parkinson’s disease, and the presence of alpha synuclein deposits in the ENS is not sufficient in itself to explain these gastrointestinal disorders.

It therefore remains to be determined whether vagal nerve damage alone can explain gastrointestinal disorders or whether dysfunction of enteric neurons without neuronal loss is occurring. So, damage to the ENS from alpha synuclein deposits would be early and would precede damage to the CNS, thus affording evidence in support of Braak’s hypothesis, which relies on autopsy data that does not allow for longitudinal monitoring in a single individual.

Appendectomy appeared to be protective, leading to additional speculation about its role in the pathophysiology of Parkinson’s disease. Additional mechanistic studies are therefore needed to establish causality and confirm the gut-brain axis or the role of dysbiosis and of intestinal permeability problems.

In conclusion, this large, first-of-its-kind multicenter study conducted on a national scale shows that early gastrointestinal symptoms (dysphagia, gastroparesis, constipation, and IBS without diarrhea) are associated with an increased risk of Parkinson’s disease, as is suggested by Braak’s hypothesis. Subject to future longitudinal mechanistic studies, early detection of these gastrointestinal disorders could aid in identifying patients at risk of Parkinson’s, and it could then be assumed that disease-modifying treatments could, at this early stage, halt progression of the disease linked to toxic clusters of alpha synuclein.

This article was translated from JIM, which is part of the Medscape professional network.

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

The enteric nervous system (ENS), which is regarded as our second brain, is the part of the autonomic nervous system that controls the digestive tract. Housed along the entire length of the digestive tract, it is made up of more than 100 million neurons. It plays a central role in controlling the regulation of gastrointestinal motility, absorption of nutrients, and control of the intestinal barrier that protects the body from external pathogens.

Braak’s hypothesis suggests that the digestive tract could be the starting point for Parkinson’s disease. The fact that nearly all patients with Parkinson’s disease experience digestive problems and have neuropathological lesions in intrinsic and extrinsic innervation of the gastrointestinal tract suggests that Parkinson’s disease also has a gastrointestinal component.

Besides the ascending pathway formulated by Braak, a descending etiology in which gastrointestinal symptoms are present in early stages when neurological signposts have not yet been noticed is supported by evidence from trials. These gastrointestinal symptoms then represent a risk factor. Links have also been described between a history of gastrointestinal symptoms and Alzheimer’s disease and cerebrovascular diseases (CVD), thus justifying studies on a larger scale.
 

Large combined study

The authors have conducted a combined case-control and cohort study using TriNetX, a national network of medical records based in the United States. They identified 24,624 patients with idiopathic Parkinson’s disease in the case-control analysis and compared them with control subjects without neurological disease. They also identified subjects with Alzheimer’s disease and CVD, to study previous gastrointestinal signs. Secondly, 18 cohorts with each exposure (various gastrointestinal symptoms, appendectomy, vagotomy) were compared with their negative controls (NC) for the development of Parkinson’s disease, Alzheimer’s disease, or CVD in 5 years.

Gastroparesis, dysphagia, and irritable bowel syndrome (IBS) without diarrhea or constipation were shown to have specific associations with Parkinson’s disease (vs. NC, Alzheimer’s disease, and CVD) in both case-controls (odds ratios all P < .0001) and cohort analyses (relative risks all P < .05). While functional dyspepsia, IBS with diarrhea, diarrhea, and fecal incontinence were not specific to Parkinson’s disease, IBS with constipation and intestinal pseudo-obstruction showed specificity to Parkinson’s disease in the case-control (OR, 4.11) and cohort (RR, 1.84) analyses. Appendectomy reduced the risk of Parkinson’s disease in the cohort study (RR, 0.48). Neither inflammatory bowel disease nor vagotomy was associated with Parkinson’s disease.
 

A ‘second brain’

This broad study attempted to explore the gut-brain axis by looking for associations between neurological diagnoses and prior gastrointestinal symptoms and later development of Parkinson’s disease. After adjustment to account for multiple comparisons and acknowledgment of the initial risk in patients with Alzheimer’s disease and CVD, only dysphagia, gastroparesis, IBS without diarrhea, and isolated constipation were significantly and specifically associated with Parkinson’s disease.

Numerous literature reviews mention that ENS lesions are responsible for gastrointestinal disorders observed in patients with Parkinson’s disease. Tests on gastrointestinal autopsy and biopsy specimens have established that alpha synuclein clusters, which are morphologically similar to Lewy bodies in the CNS, are seen in the vagus nerve and in the ENS in most subjects with Parkinson’s disease. However, these studies have not shown any loss of neurons in the ENS in Parkinson’s disease, and the presence of alpha synuclein deposits in the ENS is not sufficient in itself to explain these gastrointestinal disorders.

It therefore remains to be determined whether vagal nerve damage alone can explain gastrointestinal disorders or whether dysfunction of enteric neurons without neuronal loss is occurring. So, damage to the ENS from alpha synuclein deposits would be early and would precede damage to the CNS, thus affording evidence in support of Braak’s hypothesis, which relies on autopsy data that does not allow for longitudinal monitoring in a single individual.

Appendectomy appeared to be protective, leading to additional speculation about its role in the pathophysiology of Parkinson’s disease. Additional mechanistic studies are therefore needed to establish causality and confirm the gut-brain axis or the role of dysbiosis and of intestinal permeability problems.

In conclusion, this large, first-of-its-kind multicenter study conducted on a national scale shows that early gastrointestinal symptoms (dysphagia, gastroparesis, constipation, and IBS without diarrhea) are associated with an increased risk of Parkinson’s disease, as is suggested by Braak’s hypothesis. Subject to future longitudinal mechanistic studies, early detection of these gastrointestinal disorders could aid in identifying patients at risk of Parkinson’s, and it could then be assumed that disease-modifying treatments could, at this early stage, halt progression of the disease linked to toxic clusters of alpha synuclein.

This article was translated from JIM, which is part of the Medscape professional network.

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