Research Highlights From Padmaja Genesh (June 2020)

Published: Jul 08, 2020

Study Results Offer New Hope for Treatment of Patients with Dementia

Minimum dose of hydromethylthionine could slow clinical decline and brain atrophy in behavioural variant fronto-temporal dementia as well as Alzheimer’s Disease.

In a paper published online in the Journal of Alzheimer’s Disease, TauRx reported that the drug it is developing for treatment of Alzheimer’s disease (hydromethylthionine) also has significant pharmacological activity in behavioural variant fronto-temporal dementia (bvFTD).

The study reports  the relationship between treatment dose, blood levels and pharmacological activity of the drug hydromethylthionine on the brain in 176 patients with bvFTD.

The results showed that, even at the lowest dose of hydromethylthionine tested (8 mg/day), the drug (taken as a tablet) produced statistically significant concentration-dependent effects on clinical decline and brain atrophy with results similar to those reported recently in Alzheimer’s disease (AD).

Hydromethylthionine blocks abnormal aggregation in the brain of the proteins linked to over 80% of bvFTD (tau protein and TDP-43 protein).

The analyses suggest that a dose of about 30 mg/day would be optimal for treating bvFTD and could reduce the rate of disease progression even more. TauRx now plans to test this dose in a placebo-controlled confirmatory trial.




Association of Hypercholesterolemia with Alzheimer’s Disease Pathology and Cerebral Amyloid Angiopathy

The association of high cholesterol (HC) levels in blood with Alzheimer’s Disease (AD) in human studies has not been consistently established.

The researchers aimed to investigate the relationship between HC and risk of AD neuropathology in a large national sample with autopsies.

This study used neuropathological and clinical data from 3,508 subjects from the National Alzheimer’s Coordinating Center (NACC) who underwent autopsies from 2005 to 2017. Demographic and clinical characteristics, as well as neuropathological outcomes were compared between subjects with and without HC. Associations between HC and AD neuropathology were examined by multivariate ordinal logistic regressions adjusting for potential confounders.

HC was not associated with any AD neuropathology in a model only adjusting for demographic variables. However, HC was significantly associated with higher neuritic and diffuse plaque burden, more neurodegeneration, and more severe cerebral amyloid angiopathy when analyzed in a multivariate model controlling for comorbidities.

Conclusion: This study suggested that HC was associated with increased severity of AD brain changes, which could only be partially accounted for by ApoE genotype. The associations were not mediated by cerebrovascular conditions.

Journal: Journal of Alzheimer's Disease, vol. 73, no. 4, pp. 1305-1311, 2020


Living in Racially Segregated Neighborhoods May Not Be Good for Cognitive Health

Black individuals who lived in racially segregated neighborhoods throughout young adulthood performed worse on certain cognitive tests as early as midlife. Black Americans who live in segregated neighborhoods throughout young adulthood may have signs of possible cognitive decline by the time they reach midlife, according to a new study that tracked where participants lived over a span of 25 years.

While the study indicates an association, not a causal effect, between living in racially segregated neighborhoods and worse performance on cognitive testing in middle age, its findings point to yet another possible reason why there is a well-documented disparity in the risk of dementia for older black Americans compared with their white counterparts.

“The way we think conceptually about this is that residential segregation is really a factor upstream for a lot of other factors. When neighborhoods are segregated by race, that causes downstream effects such as low income and environmental exposures,” said lead author Michelle Caunca, PhD, who is a third-year medical student in the MD/PhD program at University of Miami Miller School of Medicine.

“The study gives us insight into how social and other contextual factors can play into cognitive pathology down the road,” Dr. Caunca said.



Loss of Functional Dentition is Associated with Cognitive Impairment

Although tooth loss is known to increase the risk of cognitive impairment and dementia, few studies have investigated the association between functional teeth including rehabilitated lost teeth and cognitive function.

The researchers investigated the associations of the numbers of functional teeth and functional occlusal units with cognitive impairment and cognitive function in late life.

The current study was conducted as a part of the Korean Longitudinal Study on Cognitive Aging and Dementia (KLOSCAD), a community-based elderly cohort study. The researchers analyzed 411 participants who have agreed with the additional dental exam. Geriatric psychiatrists and neuropsychologists administered the Consortium to Establish a Registry for Alzheimer’s disease Assessment Packet Clinical and Neuropsychological Assessment Battery to all participants, and dentists examined their dental status.

Higher number of functional teeth and higher number of functional occlusal units, especially in the pre-molar region  were associated with lower odds of cognitive impairment.

Conclusion: Loss of functional teeth and functional occlusal units (especially in the premolar region) were associated with increased cognitive impairment.


Mouth Bacteria Can Infect Brain Cells, Research Finds, Supporting Alzheimer’s Link

A type of mouth bacteria involved in gum disease is able to infect human brain cells, new research shows. The infection results in cellular changes that are similar to what is seen in Alzheimer’s, supporting a link between the bacteria and the neurodegenerative disease.

Porphyromonas gingivalis is a type of bacteria best known as a cause of gum (periodontal) disease. However, this bacteria in recent years also has been implicated in Alzheimer’s disease (AD).

It produces toxins called gingipains, which have been detected in more than 90% of post-mortem Alzheimer’s brains.

Now, researchers from the biopharmaceutical company Cortexyme and Virginia Tech have directly demonstrated that P. gingivalis can infect brain cells.

Their findings also support the idea that treatments targeting P. gingivalis could have therapeutic benefit in Alzheimer’s.

Cortexyme is currently developing an investigational Alzheimer’s therapeutic candidate called COR388, which is an inhibitor of gingipains. COR388 was found to be safe and well-tolerated in a Phase 1 clinical trial (NCT03331900) conducted in healthy volunteers.

Its efficacy, safety, and tolerability in people with Alzheimer’s is now being investigated in the Phase 2/3 clinical trial GAIN (GingipAIN Inhibitor for Treatment of Alzheimer’s Disease; NCT03823404). The GAIN trial is currently recruiting participants at multiple locations in the United States and Europe. Additional information can be found here.



Anavex 2-73 Trial for Early Alzheimer’s Expanded to Canada, UK 

Anavex Life Sciences will expand its Phase 2b/3 clinical trial testing the efficacy and safety of Anavex 2-73 (blarcamesine) for the treatment of early Alzheimer’s disease into Canada and the United Kingdom (U.K.) following the go-ahead from Health Canada and the U.K.’s Medicines and Healthcare products Regulatory Agency (MHRA). 

The clinical trial, dubbed Anavex 2-73-AD-004 (NCT03790709), is a placebo-controlled study currently underway in Australia, with more than 50% of the 450 patients enrolled. Participants are age 60 to 85 with mild cognitive impairment or early stage mild dementia due to Alzheimer’s. (More information about recruitment is available here.)

Given as an oral capsule, trial participants will receive one of two doses (a middle and high dose) of Anavex 2-73, or placebo, for about one year. 

The primary outcome will be any changes in cognitive ability as assessed by the Alzheimer’s Disease Assessment Scale in cognition (ADAS-Cog), and the Alzheimer’s disease cooperative study-activities of daily living (ADCS-ADL). This test measures the competence of Alzheimer’s disease patients in daily living activities.

Patients who complete this study will be able to enroll in ATTENTION-AD, an open-label extension study, for an additional two years of Anavex 2-73 treatment.

Anavex 2-73 works by activating a cellular receptor called Sigma-1, known to have neuroprotective effects by reducing neuroinflammation, oxidative stress and blocking the accumulation of beta-amyloid and tau proteins. Of note, oxidative stress is an imbalance between the production of free radicals and the ability of cells to detoxify them, leading to cellular damage.

People with Alzheimer’s disease have fewer sigma-1 receptors in their brains compared to healthy people the same age. Activation of these receptors may improve the symptoms and protect against neurologic changes.



Neurotrope Launches Long-term Trial of Bryostatin-1 

Neurotrope has announced the launch of a Phase 2 clinical trial to investigate the long-term use of bryostatin-1 for moderate and moderately severe Alzheimer’s disease

Bryostatin-1 is a small molecule designed to penetrate the blood-brain barrier and specifically activate the protein kinase C, which plays an important role in learning and memory, and in maintaining the health of synapses — junctions where nerve cells come into contact and communicate with each other.

The new Phase 2 clinical trial intends to enroll approximately 100 patients with moderate and moderately severe Alzheimer’s disease, as measured by Mini-Mental State Exam scores.

Patients will be given bryostatin-1 in the absence of Namenda (memantine, a common Alzheimer’s therapy) for two 11-week dosing cycles, over a period of six months.

The trial will focus on evaluating sustained cognitive benefit measured by the Severe Impairment Battery (SIB) score — a test designed to assess cognitive function in people with dementia who are unable to complete other psychological tests. Higher scores indicate better functionality (i.e., less evidence of dementia).

The study will be conducted in partnership with the National Institutes of Health, who has awarded nearly $2.7 million in funding to Neurotrope.

The effects of bryostatin-1 on cognition have been tested in a previous Phase 2 trial (NCT02431468), which enrolled 147 patients with moderate-to-severe Alzheimer’s disease. Participants were randomly assigned to receive bryostatin-1 at 20 or 40 microgram (mcg) doses, or a placebo, administered intravenously (into the vein) every other week for 12 weeks.

Bryostatin-1 was seen to be safe and have a good tolerability profile. SIB scores showed that only patients treated with 20 mcg doses of bryostatin-1 had sustained improvements in cognitive function compared to the placebo group.

Neurotrop has engaged Worldwide Clinical Trials to start site recruitment and activation for the trial.