Research Highlights from Padmaja Genesh (August 2020)
Trial of Potential Alzheimer’s Vaccine Advances to Medium Dose Group
ACI-35.030, mimics the structure of the toxic phosphorylated version of the tau protein that underlies key features of Alzheimer’s pathology, such as disrupted communication between nerve cells.
By triggering an immune reaction to phosphorylated tau, the antibodies generated by ACI-35.030 have the potential to limit the occurrence and spread of tau pathology throughout the brain.
ACI-35.030 had shown a positive safety profile and high specificity for toxic forms of tau in preclinical studies, triggering a strong and long-lived antibody immune response against phosphorylated tau.
The placebo-controlled trial (NCT04445831) is assessing the safety, tolerability, and immunogenicity (its ability to provoke an immune response) of different doses of ACI-35.030 over 48 weeks of treatment in people with early Alzheimer’s. Secondary endpoints include clinical and cognitive changes, as well as additional immunogenicity and safety parameters. About 24 adults, ages 50 to 75, from Finlands, Netherlands and the UK are planned to take part in this study.
AC Immune is also advancing Semorinemab, its monoclonal antibody against phosphorylated tau, in a Phase 2 clinical trial (NCT03828747), that is recruiting an estimated 260 adults with moderate Alzheimer’s at sites in the U.S., France, Poland, and Spain.
Aducanumab Wins FDA Priority Review, Moves Closer to US Approval
While the Prescription Drug User Fee Act (PDUFA) action date is set for March 7, 2021 — meaning a decision is due by then — the agency said it plans to act early on this application under an expedited review.
The supplemental biologics license application (BLA) was based on data from two Phase 3 trials — EMERGE (NCT02484547) and ENGAGE (NCT02477800) — and from the Phase 1b PRIME trial (NCT01677572). That data demonstrated that aducanumab significantly slows cognitive decline and helps patients live an independent life for longer periods.
The treatment also significantly slowed the rate at which patients lost their ability to perform daily life activities, including managing their personal finances, performing household chores, and traveling independently.
In the two trials, both doses of aducanumab also were accompanied by a significant reduction in the amount of amyloid plaques found in the patients’ brains.
The most commonly reported adverse events were amyloid-related imaging abnormalities-edema, which usually resolved within one to four months without causing symptoms, and headaches.
If approved, aducanumab will become the first therapy with the potential to slow clinical decline in Alzheimer’s patients, as well as the first to demonstrate that reducing the buildup of toxic amyloid plaques in the brain leads to better outcomes.
Dementia prevention, intervention, and care: 2020 report of the Lancet Commission
New evidence supports adding three modifiable risk factors—excessive alcohol consumption, head injury, and air pollution—to 2017 Lancet Commission on dementia prevention, intervention, and care life-course model of nine factors (less education, hypertension, hearing impairment, smoking, obesity, depression, physical inactivity, diabetes, and infrequent social contact). Modifying these 12 risk factors might prevent or delay up to 40% of dementias.
Contributions to the risk and mitigation of dementia begin early and continue throughout life, so it is never too early or too late. These actions require both public health programs and individually tailored interventions. In addition to population strategies, policy should address high-risk groups to increase social, cognitive, and physical activity; and vascular health.
Specific actions for risk factors across the life course
• Aim to maintain systolic BP of 130 mm Hg or less in midlife from around age 40 years
• Encourage use of hearing aids for hearing loss and reduce hearing loss by protection of ears from excessive noise exposure.
• Reduce exposure to air pollution and second-hand tobacco smoke.
• Prevent head injury.
• Limit alcohol use, as alcohol misuse and drinking more than 21 units weekly increase the risk of dementia.
• Avoid smoking and support smoking cessation to stop smoking, as this reduces the risk of dementia even in later life.
• Provide all children with primary and secondary education.
• Reduce obesity and the linked condition of diabetes.
- Sustain midlife, and possibly later life physical activity.
• Addressing other putative risk factors for dementia, like sleep, through lifestyle interventions, will improve general health.
For those with dementia, recommendations are:
• Provide holistic post-diagnostic care
Post-diagnostic care for people with dementia should address physical and mental health, social care, and support. Most people with dementia have other illnesses and might struggle to look after their health and this might result in potentially preventable hospitalizations.
• Manage neuropsychiatric symptoms
Specific multicomponent interventions decrease neuropsychiatric symptoms in people with dementia and are the treatments of choice. Psychotropic drugs are often ineffective and might have severe adverse effects.
• Care for family carers
Specific interventions for family caregivers can have long-lasting effects on depression and anxiety symptoms, increase quality of life, are cost-effective and might save money.
Source: https://doi.org/10.1016S0140-6736(20)30367-6 Published Online July 30, 2020
Tinnitus May Warn of Increased Risk for Alzheimer’s, Parkinson’s
Rates of tinnitus increase with age and studies have found that hearing loss, as well as central auditory dysfunction more generally, are associated with higher risks of cognitive dysfunction, particularly dementia, control of attention, and working memory.
Past studies, however, have not examined the relationship between tinnitus, Parkinson’s, and Alzheimer’s in a population-based way.
A team of researchers from various Taiwanese institutions recently examined this association using records from Taiwan’s National Health Insurance (NHI) system. The NHI records provide a large and nationally representative patient sample with long follow-up periods, as participation is nationwide and mandatory.
After adjusting for confounding factors like diabetes, head injuries, and income, the researchers determined that patients with tinnitus were 1.54 times more likely to develop Alzheimer’s and 1.56 times more likely to develop Parkinson’s. If these findings can be replicated and validated in future studies, they open new avenues for research into the pathology of both Parkinson’s and Alzheimer’s.
A possible cause-and-effect relationship between tinnitus and either Parkinson’s or Alzheimer’s raises the question of whether preventing and treating tinnitus could prove effective at reducing their incidence. One possible mechanism, with which to explore such a relationship could be inflammation. Inflammation can trigger tinnitus and is known to contribute to neurodegeneration. By this reasoning, they suggest that the clinical features of tinnitus may be driven by the underlying processes that contribute to the progression of Alzheimer’s and/or Parkinson’s.
Concussion Linked With 57% Higher Risk of Parkinson’s in Study
People who had a concussion are more likely to be diagnosed later in life with Parkinson’s disease and other neurologic disorders than those who never had this type of brain injury, a database study reports.
Some studies have linked concussions with later neurological problems, including Parkinson’s disease. However, these studies often relied on self-reported data, which aren’t always accurate, and failed to account for important factors like co-existing health conditions that could complicate the findings.
They identified 47,483 people diagnosed with a concussion between 1990 and 2015: For each person with a concussion, the researchers also identified three people without a concussion matched in terms of sex, age, and geographical location.
Using these two groups, they calculated the relative risk of being later diagnosed with any of four disorders: Parkinson’s disease, attention deficit/hyperactivity disorder (ADHD), mood and anxiety disorders (MADs), and dementia.
Concussion was associated with a significantly increased risk of all four disorders: by 57% for Parkinson’s, by 39% for ADHD, by 72% for MADs, and by 72% for dementia.
Females had a significantly higher risk of ADHD (by 28%) and MADs (by 7%) following a concussion than did males, whereas no sex-based differences were found in concussion risk for Parkinson’s or dementia.
Having more than one concussion didn’t affect ADHD risk. However, having two concussions significantly increased the risk of dementia (by 62% compared to just one concussion), and having more than three significantly increased the risk of Parkinson’s (by over 200%) and mood and anxiety disorders (by 22%) compared to one concussion.
Young People May Exhibit Risks Associated With Alzheimer’s Disease, Research Finds
This year’s Alzheimer’s Association International Conference (AAIC) revealed surprising news about risk factors related to Alzheimer’s, adolescents, young adults, and diagnosis.
For years, researchers have believed and touted that on average, Alzheimer’s patients are diagnosed at 80, and symptoms appear after 60. However, new research reveals that the risk factors surrounding Alzheimer’s disease may appear much earlier — even in the teens or early 20s.
The new findings revealed at AAIC also indicate that these risk factors, such as high blood pressure, high cholesterol, and diabetes, disproportionately affect African Americans. This is critical information when you consider that older African American adults are twice as likely to be diagnosed with Alzheimer’s disease than older white adults.
Perhaps if young adults are diagnosed and treated for contributing diseases, it would reduce the number of senior African American adults who are diagnosed with Alzheimer’s later in life.
The Alzheimer’s Association is conducting a large study to determine how lifestyle interventions can affect risk factors that lead to dementia. The study also will test whether those interventions protect cognitive function. The two-year clinical trial, titled “U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk” (U.S. POINTER), will include a large cross section of Americans and is the first of its kind. Hopefully, the study will assist in preventing cognitive decline.
Diagnostic experience reported by caregivers of patients with frontotemporal degeneration
The objective of the study was to describe the experience of obtaining a diagnosis of frontotemporal degeneration (FTD) for patients and caregivers.
Data came from a 2017 web-based survey of 698 FTD caregivers. Clinical characteristics and diagnostic experiences were described according to the phenotype of the patient with FTD (behavioral variant FTD, primary progressive aphasia, FTD with motor neuron disease, or progressive supranuclear palsy/corticobasal syndrome). Unadjusted and adjusted logistic regression analyses determined associations between patient with FTD and caregiver characteristics and (1) receiving a diagnosis >1 year after initial symptoms and (2) first receiving a non-FTD diagnosis.
Results Mean age was 66 ± 9 years for patients with FTD and 61 ± 10 years for FTD caregivers. Forty-four percent of patients took more than 1 year; 65% saw 3 or more doctors; and 84% required 3 or more visits to establish an FTD diagnosis. Initial diagnosis was depression or other psychiatric condition in 21% of patients.
Twenty-eight percent of caregivers and 26% of patients lost ≥11 workdays seeking diagnosis. The majority of diagnoses (66%) were made by neurologists. Patient and caregiver age, having a spouse caregiver, rural residency, and mood changes as first symptom were associated with a longer time to receive FTD diagnosis. Caregivers frequently rated diagnosing doctors as good/excellent in knowledge of FTD but as inadequate/poor on knowledge of available community resources.
Conclusions This study, which quantifies the patient with FTD and caregiver burden before receiving the FTD diagnosis, can inform clinical practice, interventions to address diagnostic delays, and programs and services to support patients/caregivers during and following the diagnosis.
AC Immune Moves Closer to Clinical Studies of Anti-TDP-43 Antibody
AC Immune is planning to advance its investigational anti-TDP-43 antibody into clinical testing for neurodegenerative diseases in which TPD-43 protein aggregates play a major role in brain damage, including diseases such as Alzheimer’s, amyotrophic lateral sclerosis, and frontotemporal lobar degeneration with TDP-43 pathology.
TDP-43 has emerged as a potential therapeutic target for certain neurodegenerative diseases. This protein is normally found within the cell nucleus where it stabilizes RNA — DNA ‘blueprints’ that serve as intermediaries in the production of proteins.
Evidence has shown that specific mutations can cause TDP-43 to become abnormally shaped and accumulate in the cytoplasm, instead of the nucleus, leading to its accumulation and clumping within nerve cells.
In fact, approximately 50% of Alzheimer’s patients show signs of TDP-43 aggregation, which is thought to contribute to symptom severity.
Researchers at AC Immune have used the company’s proprietary SupraAntigen platform to generate antibodies that can specifically target TDP-43 and block its ability to form aggregates.
Recently, the company shared data at the virtual Advances in Alzheimer’s and Parkinson’s Therapies Focus Meeting, showing that its antibody mitigated brain damage in a mouse model of TDP-43-associated neurodegeneration.
The antibody is the first to show efficacy in living organisms, the company stated, and may become the first anti-TDP-43 antibody in the world reaching clinical development.
GAIN Trial Reaches Milestone With 500 Patients Enrolled
Cortexyme has reached a milestone after enrolling 500 patients with mild to moderate Alzheimer’s disease in its ongoing Phase 2/3 GAIN clinical trial testing the company’s investigational treatment COR388 (atuzaginstat).
Data from an interim analysis — scheduled to occur after 300 patients reach 24 weeks of treatment with COR388 — is expected by the end of 2020. A full analysis of the trial data, which will occur after all patients have reached one year of treatment, is expected by the end of 2021.
COR388 is designed to inhibit toxic protease enzymes, also called gingipains, produced by the bacteria P. gingivalis. Gingipain proteins have been found in more than 90% of post-mortem brain samples from Alzheimer’s patients.
Furthermore, studies using animal models have shown that the presence of gingipains can trigger Alzheimer’s pathology, prompting researchers to investigate COR388 as a treatment for the disease.
The GAIN trial seeks to recruit 573 patients from the ages of 55 to 80 with a confirmed diagnosis of mild to moderate Alzheimer’s, at several testing centers across the U.S. and Europe. The trial is testing the efficacy, safety, and tolerability of two oral doses (80 mg or 40 mg pills, twice a day) of COR388 versus placebo.
Researchers will perform magnetic resonance imaging (MRI) brain scans and collect cerebrospinal fluid, saliva, and blood samples at the onset of treatment, at 24 weeks, and at 48 weeks.
The samples will be analyzed for Alzheimer’s biomarkers, neuroinflammation, and levels of P. gingivalis.
Patients will also be evaluated for changes in clinical status, including the severity of cognitive symptoms of dementia, after the 48-week treatment period. Eligible participants who complete one year in the study may enroll in a follow-up trial where all patients will receive the candidate therapy.
Patients in Australian Trials of Anavex 2-73 May Continue Using Therapy, Agency Says
People in Australia with Alzheimer’s disease who have finished five years of treatment with Anavex 2-73 (blarcamesine) in Phase 2 clinical trials may continue to use Anavex Life Sciences‘ investigational oral therapy at their doctor’s request.
Under a special access scheme, the Therapeutic Goods Administration (TGA) — a part of the Australian Government Department of Health — allowed for compassionate use based on safety findings and early evidence of benefit in these clinical studies.
A larger Phase 3 trial in early Alzheimer’s patients is now underway and enrolling in Australia and parts of Europe. Canada is expected to open sites as well.
Anavex 2-73 is an investigational oral therapy that is believed to reduce inflammation, lessen cellular stress, and prevent the accumulation of toxic proteins in the brain. It works by binding to sigma-1, a receptor protein present in neurons.
The Phase 2a clinical trial ANAVEX 2-73-002 (NCT02244541), which ran for 57 weeks in Australia, aimed to find the optimum dose for Anavex 2-73 in about 32 people with Alzheimer’s. Those who completed this trial could enroll in its 208-week open-label extension study, ANAVEX 2-73-003 (NCT02756858), which is set to conclude in November.
Results have been positive, suggesting that the investigational therapy is generally safe and well-tolerated, and preliminary data indicated that the medication may slow cognitive decline.
Anavex 2-73 is also being tested in a larger and placebo-controlled Phase 2b/3 clinical trial, called ANAVEX 2-73-AD-004 (NCT03790709). This trial’s primary goal is to determine treatment effectiveness in aiding cognition and daily life activities in up to 450 adults, ages 60 to 85, with mild cognitive impairment or mild dementia due to Alzheimer’s.
The ANAVEX 2-73-AD-004 trial is currently recruiting in Australia and the Netherlands, and Anavex recently received approvals to begin enrolling patients in Canada and the U.K. Additional trial and contact information can be found here.
Predicting resistance to amyloid-beta deposition and cognitive resilience in the oldest-old
The objective of this study was to explore long-term predictors of avoiding β-amyloid (Aβ) deposition and maintaining unimpaired cognition as outcomes in the oldest old.
In a longitudinal observational cohort study, 100 former participants of the Ginkgo Evaluation of Memory Study (GEMS; 2000–2008) completed biannual Pittsburgh compound B-PET imaging and annual clinical-cognitive evaluations beginning in 2010. Most recent Aβ status and cognitive status were selected for each participant. Longitudinal outcomes included change in serial Aβ and cognitive tests. Baseline predictors from GEMS included neuropsychological tests, daily functioning, APOE genotype, lifestyle variables, occupational measures, health history, sleep, subjective memory, physical and cognitive activities, depressive symptoms, and physical performance and health indices, among others.
The APOE*2 allele predicted last Aβ status (n = 34 Aβ negative vs n = 66 Aβ positive). Baseline cognition predicted cognitive status (n = 30 unimpaired vs n = 70 impaired). Predictors of cognitive status among Aβ-positive participants only (n = 14 normal cognition vs n = 52 impaired) were baseline cognitive test scores and smoking history. Baseline pulse pressure predicted longitudinal Aβ increase; paid work engagement and life satisfaction predicted less cognitive decline.
Conclusions The APOE*2 allele and lower pulse pressure predict resistance to Aβ deposition in advanced aging. Cognitive test scores 14 years prior, likely reflecting premorbid abilities, predict cognitive status and maintenance of unimpaired cognition in the presence of Aβ. Several lifestyle factors appear protective.
Association of baseline semantic fluency and progression to mild cognitive impairment in middle-aged men
The objective of the study was to test the hypothesis that individual differences in episodic memory and verbal fluency in cognitively normal middle-aged adults will predict progression to amnestic mild cognitive impairment (MCI) after 6 years.
The cohort analyzed included 842 male twins who were cognitively normal at baseline (mean 56 years) and completed measures of episodic memory and verbal fluency at baseline and again 6 years later (mean 62 years).
Conclusions Among individuals who were cognitively normal at wave 1, episodic memory moderately to strongly predicted progression to MCI at average age 62, emphasizing the fact that there is still meaningful variability even among cognitively normal individuals. Episodic memory, which is typically a primary focus for Alzheimer disease (AD) risk, declined earlier and more quickly than fluency. However, semantic fluency at average age 56 predicted 6-year change in memory as well as progression to amnestic MCI even after accounting for baseline memory performance. These findings emphasize the utility of memory and fluency measures in early identification of AD risk.
Adherence to a Healthy Diet Reduces Non-motor Symptoms Found in Parkinson’s Disease
Following a healthy diet may lower the occurrence of non-motor symptoms that precede Parkinson's disease (PD), according to a pooled analysis published online on August 19 in Neurology.
The researchers found that increased Alternative Healthy Eating Index (AHEI) and the alternate Mediterranean diet (aMED) diet pattern scores were inversely related with odds of three or more prodromal PD features like excessive daytime sleepiness, depressive symptoms and constipation, reported Samantha Molsberry, PhD, of Harvard University in Cambridge, Massachusetts, and colleagues.
Notably, people with PD who eat healthier foods like nuts and vegetables and consume moderate amounts of alcohol were inversely related with the odds of at least three prodromal features, they added.
In the pooled analysis of the two large cohort studies, increased adherence to both the aMED and AHEI diet patterns were inversely associated with the odds of three or more prodromal features, specifically with constipation, excessive daytime sleepiness, and depressive symptoms.
Limitations of the study include the homogeneity of the study populations which may limit the generalizability of the results. In addition, the researchers acknowledged that although they did assess prodromal symptoms, having these symptoms does not mean the participants will develop PD. Finally, the prodromal features of PD were not evaluated at baseline.
Blood Tests for Tau in Alzheimer's Disease Appear Promising in Several New Trials
Several new studies suggest that a blood test for phosphoro-tau can discriminate Alzheimer's disease from other neurodegenerative disorders.
A series of new studies point to the promise of phosphorylated tau in the blood for detecting Alzheimer's disease (AD) reliably and early, researchers said at the virtual Alzheimer's Association International Conference.
The trend of the findings pointed to the superiority of plasma phosphorylated tau 217 (p-tau217) for reliably identifying AD. In one study, simultaneously published online in JAMA on July 28, researchers looked at an Arizona-based neuropathology cohort; a Swedish cohort ranging from those who were cognitively unimpaired to those with AD and non-AD dementia; and a Colombian kindred group—some of whom were carriers of a genetic mutation associated with early-onset AD and some of whom were not carriers. In all, there were 1,438 participants, said Oskar Hansson, MD, PhD, professor of neurology at Lund University in Sweden.
They found, looking at the Arizona cohort, that p-tau217 could differentiate between those with an intermediate or high likelihood of having AD and those without AD, with an area under the curve of 0.89. This was significantly better than the performance of p-tau181 in this regard (p< 0.05). It also performed better than neurofilament light chain and amyloid-beta 42/40, researchers found.
In the Swedish cohort, the accuracy in discriminating between those with AD and those with other neurodegenerative diseases was significantly higher for plasma p-tau217 (AUC = 0.96) than it was for plasma p-tau81, plasma neurofilament light chain, AB 42/40 and MRI (p< 0.001).
In the Colombian cohort, researchers found that plasma levels of p-tau217 were significantly greater for carriers of the PSEN1 E280A mutation than it was for non-carriers, from the age of about 25 and older, which is 20 years before expected arrival of mild cognitive impairment symptoms.
Researchers also found that p-tau217 in the plasma could tell the difference between a normal and abnormal tau PET scan with significantly more accuracy than plasma p-tau181, plasma neurofilament light chain and MRI. The only measure that p-tau217 didn't outperform in this regard was p-tau217 in the CSF.
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