Research Highlights From Padmaja Genesh (May 2020)

Published: Jun 03, 2020

How Aerobic Exercise Helps us Keep Our Wits About Us As We Age

University of Calgary study shows it is never too late to see the brain benefits from regular exercise.

A study published in the American Academy of Neurology journal  (May 13) suggests older adults can perform certain thinking and memory tests at the same level as someone four to six years their junior after just six months of aerobic exercise.

Participants in Dr. Poulin’s Brain in Motion study were people from the Calgary area, generally healthy but not very active, between 50 and 83 years old with no cognitive complaints. They were given thinking and memory tests at the start of the study, as well as an ultrasound to measure blood flow in the brain. Physical testing was repeated at three months, and thinking and physical testing repeated at the end of the six months.

Over 6 months of exercise intervention period blood flow to critical parts of the brain increased by 2.8 per cent.  The increase in blood flow was associated with a number of modest but significant improvements in aspects of thinking that usually decline as we age.

Verbal fluency, which tests how well you can retrieve information, increased by 2.4 per cent, equivalent to being five years younger. Participants’ recall of words from a list improved by 2.6 per cent, equivalent to being four years younger, while an evaluation of executive functioning, which examines more complex aspects of reasoning, showed an increase of 5.7 per cent, performing like adults almost six years younger.

Fast-paced walking, jogging, dancing, or any activity that would not allow you to sing or talk while you're doing it would be beneficial to promote and maintain brain health..

Next, Poulin and his team plan to work with community and government partners to implement physical activity strategies into the community.

Poulin’s lab is now recruiting for the Brain in Motion II study, looking for adults age 50-80 who are at increased risk of Alzheimer’s disease and related dementias. For more information, call the study coordinator at 403-210-7315 or reach out by email at bimstudy@ucalgary.ca,

Source: Neurology Journal Published May 13 online

 

 

Potential Agitation Treatment, AXS-05, Shows Efficacy and Safety in Phase 2/3 Trial

Axsome Therapeutics‘ investigational oral therapy AXS-05 significantly and rapidly lessened agitation in patients with Alzheimer’s disease, top-line results from a Phase 2/3 trial show. The therapy was also found to be generally well-tolerated and safe, without affecting cognition.

 Currently, no treatments are approved for managing agitation, which is a common feature in dementia.

AXS-05 has two main active components, dextromethorphan and bupropion. Dextromethorphan works by modulating the activity of neurotransmitters, including glutamateserotonin, and norepinephrine, which have been linked to cognitive and behavioral changes in people with Alzheimer’s disease. 

Bupropion complements the action of dextromethorphan by stabilizing it, and also increases the availability of dopamine and norepinephrine, and acts on another neurotransmitter called acetylcholine, which is also thought to be involved in agitation.

The ADVANCE-1 Phase 2/3 trial (NCT03226522) was a double-blind and multicenter U.S. study in 366 patients diagnosed with probable Alzheimer’s disease and related agitation, ages 69 to 90. The study’s primary endpoint, or goal, was to evaluate the efficacy and safety of AXS-05 in this patient group.

Patients were randomly allocated to either AXS-05 (159 patients), bupropion only (49 patients), or placebo (158 patients) tablets for five weeks.

73% of patients who received AXS-05 achieved a clinical response defined as a 30% or greater improvement in their agitation inventory score. This was statistically significantly higher than the 57% of participants who achieved a clinical response in the placebo group.

No evidence of cognitive decline was observed in patients treated with AXS-05, as assessed by the Mini-Mental State Examination — a measure of general cognitive function. The most common adverse events reported by patients taking AXS-05 were somnolence, dizziness, and diarrhea.

 

Source: https://alzheimersnewstoday.com/2020/05/11/potential-oral-agitation-therapy-axs-05-safe-effective-in-phase-2-3-clinical-trial-axsome-reports

 

 

FDA Filing of Alzheimer’s Therapy Aducanumab Delayed to Late 2020, Biogen Says 

Biogen is pushing back the submission of Aducanumab, its investigational treatment for Alzheimer’s disease, to the U.S. Food and Drug Administration (FDA) to the third quarter of this year due to the COVID-19 pandemic, the company announced.

The company had originally anticipated filing the biologics license application with the FDA by early this year.

Aducanumab, in development by Biogen and Eisai, is an investigational human monoclonal antibody that works by targeting the toxic clumps of amyloid beta, thought to be the underlying cause of Alzheimer’s.

Aducanumab was investigated in ENGAGE (NCT02477800) and EMERGE (NCT02484547), two Phase 3 trials that evaluated two doses of Aducanumab in people with mild cognitive impairment due to Alzheimer’s and mild Alzheimer’s dementia.

In March 2019, after 1,748 patients in both trials completed the 18 months of treatment, a monitoring committee said Aducanumab was not likely to produce meaningful benefits for patients. This led to the halt of both trials and two other trials testing Aducanumab in Alzheimer’s.

A later analysis — including a larger population of 3,285 patients, 2,066 of whom completed the full 18 months of treatment — ultimately showed that EMERGE met its primary goal. In that analysis, high-dose Aducanumab significantly slowed the progression of cognitive and functional impairment, compared with a placebo. Secondary measures of cognitive functioning were also significantly better for patients receiving Aducanumab over the 18 months, compared to placebo.

These findings led Biogen to announce it would seek approval of Aducanumab for Alzheimer’s disease. If approved, this would be the first Alzheimer’s therapy that treats the disease directly rather than alleviating symptoms, and would be the first new Alzheimer’s treatment for nearly two decades.

To continue studying the long-term safety and tolerability of Aducanumab, Biogen launched the open-label Phase 3 EMBARK trial to start re-dosing Alzheimer’s patients who participated in the four studies halted in 2019. The first patient has been dosed in the Phase 3 EMBARK clinical trial (NCT04241068).

Source: https://alzheimersnewstoday.com/2020/04/27/fda-filing-of-alzheimers-therapy-aducanumb-delayed-to-late-2020/

 

 

Flortaucipir Autopsy Study Published

Results from a large autopsy validation study suggest that flortaucipir PET can help clinicians diagnose late-stage Alzheimer’s disease. In the April 27 JAMA Neurology, researchers led by Adam Fleisher at Avid Radiopharmaceuticals/Eli Lilly, Indianapolis, report that visual reads of brain scans predict tau pathology with a sensitivity above 92 percent.

The study (A 16) involved 156 volunteers, who were terminally ill and who had agreed to a flortaucipir scan.

Tau positivity also predicted AD pathology-  both plaques and tangles as outlined by the NIA-AA neuropathologic criteria for AD. In a JAMA Neurology editorial, William Jagust, University of California, Berkeley, wrote that the study is a step toward validating methods crucial to improving the understanding of brain aging and AD

Other experts too agreed that the study is very well performed one and supports the use of flortaucipir in the clinical diagnostic work-up of patients with cognitive impairment where AD is considered to be one of several possible etiologies.

Senior author Mark Mintun, also from Avid, presented the bulk of the data at the 2018 CTAD meeting in Barcelona, Spain (Nov 2018 conference news).

 How, or if, this scan may be used in the clinic remains unclear. The first PET ligand for amyloid, Avid’s florbetapir, was approved by the FDA eight years ago, and two more quickly followed suit (Apr 2012 newsNov 2013 newsMay 2014 news). However, they have not yet been cleared for reimbursement by the Centers for Medicare and Medicaid Services, despite data showing that amyloid PET scans help doctors tailor patient care (Aug 2017 news).

Source: https://www.alzforum.org/news/research-news/flortaucipir-autopsy-study-published

 

 

Large Study Finds No Evidence That Low-dose Aspirin Reduces Alzheimer’s Risk

Taking daily low-dose aspirin does not seem to reduce the risk of dementia, cognitive decline, or Alzheimer’s disease, new clinical trial data show.

Aspirin is a widely-used anti-inflammatory medication. Increased inflammation, particularly in the brain, has been associated with the development of Alzheimer’s disease. Because of this, low-dose daily aspirin is thought to potentially help reduce the risk of Alzheimer’s, but this idea hasn’t been rigorously tested.

The Aspirin in Reducing Events in the Elderly (ASPREE) clinical trial (NCT01038583) enrolled 19,114 people, 70 or older, in Australia and the United States. For African-American and Hispanic participants in the U.S., the age limit was lowered to 65 years, because of their higher risk of disease. At enrollment, all participants had no signs of dementia or heart disease.

Participants were randomized to take 100 mg daily of aspirin (9,525 people), or a placebo (9,589). Participants were followed via regular phone calls and annual in-person meetings. A battery of cognitive assessments was administered after the first year, then every other year.

Participants in both groups were followed for a median of 4.7 years (range 3.6–5.7 years). In this time, 283 people in the aspirin group were diagnosed with dementia, as were 292 people in the placebo group.

The disease rate was not significantly different at just under three events per 1,000 person-years in each group. The rate of cognitive decline (a significant decrease in cognition scores over time) — about 25 events per 1,000 person-years — was also not significantly different between the groups.  No differences were found between the groups in subgroup analyses, including age, sex, ethnicity, health factors, and prior use of aspirin or related anti-inflammatory medicines.

It is worth noting that the rates of dementia and MCI in the ASPREE study are somewhat lower than what has been reported in other published studies, which may have decreased the statistical power of this study to detect significant differences between the groups. The researchers who authored the study speculated that “this lower incidence is likely explained by the inclusion of participants who were relatively healthy at baseline.”

Source: https://alzheimersnewstoday.com/2020/05/04/low-dose-aspirin-no-evidence-reduce-alzheimers-risk-large-study/

 

 

Study of US Veterans Points to a Connection Between Late-Onset Seizures and Dementia

An analysis of data from the US Veterans Health Administration National Patient Care Database suggests that late-onset seizures of unknown etiology are associated with an increased risk of dementia in older veterans.

Late-onset seizures may be an early sign of dementia, according to a retrospective study involving nearly 300,000 veterans.

Veterans who were diagnosed with late-onset seizures of unknown cause were nearly twice as likely to be diagnosed with dementia over the next several years.

“While seizures are commonly thought to occur in late stages of dementia, these findings suggest unexplained seizures in older adults may be a first sign of neurodegenerative disease,” said the authors of the study, reported online in JAMA Neurology.

Ophir Keret, MD, the study's first author and an Atlantic Fellow at the Global Brain Health Institute at the University of California, San Francisco (UCSF), said that while more research is needed on the relationship between late-onset seizures and dementia, the new findings should “encourage clinicians to follow these patients more closely for cognitive decline and possible intervention.”

Dr. Keret, who conducted the study with senior investigator, Kristine Yaffe, MD, professor of psychiatry, neurology and epidemiology at UCSF, said a prospective study of non-veterans with late-onset seizures of unknown origin would help to better understand the risk and course of cognitive decline.

Because the UCSF study focused solely on veterans, almost all male, the findings may not apply to the general population. People who get their care at the VA also tend to have poorer health overall, which may have influenced the results. Another limitation of the study is that it relied on diagnostic codes, which aren't always accurate, as opposed to reviewing medical records. Data on seizure severity and subtype as well as dementia subtype were limited.

Source: https://journals.lww.com/neurotodayonline/Fulltext/2020/05070/Study_of_US_Veterans_Points_to_a_Connection.7.aspx