Background: Clinical benefits have been reported with a specific multinutrient intervention (Souvenaid) in Alzheimer's disease and mild cognitive impairment due to Alzheimer's disease. The effects of Souvenaid in age-related cognitive decline are not established.
Objective: To assess the feasibility of using virtual assessments to study the effects of a multinutrient on cognitive ageing.
Design: This is a randomized, double-blind, placebo-controlled, parallel group virtual pilot trial performed over 6 months in a single-centre. Participants are randomly allocated (1:1) to receive the specific multinutrient (Souvenaid) or an isocaloric, same tasting, placebo.
Setting: Trial visits are done virtually using secure online video communication.
Participants: English or Spanish speaking people aged 55-89 years from all ethnic groups and considered to have age-related cognitive decline are eligible.
Measurements: Neuropyschological tests are done at baseline and after 6 months of intervention. Participants are contacted monthly by telephone to monitor safety, assess motivation and promote compliance. The primary outcome is feasibility determined by assessing recruitment rate, recruitment time, adherence rate and retention rate. A comprehensive set of neuropyschological measures will provide a broad assessment of cognitive function, including verbal memory, processing speed, and attention and executive function. Self-reported questionnaires are used to assess quality of life.
Conclusions: This pilot trial will provide data to guide inform selection of participants and outcome measures in future studies in age-related cognitive decline.
Background: S-adenosyl methionine (SAMe) is a pivotal metabolite in multiple pathways required for neuronal homeostasis, several of which are compromised in Alzheimer's disease (AD). Correction of the SAMe deficiency that is characteristic of the AD brain may attenuate or prevent pathological processes driving AD-associated neurodegeneration including aberrant tau hyperphosphorylation and DNA hypomethylation.
Objectives: The primary aim is to test the hypothesis that daily treatment with 400 mg oral SAMe for 180 days will lead to a greater reduction from baseline in plasma levels of p-tau181 compared to placebo in patients with mild cognitive impairment or dementia due to AD.
Design, setting, participants: This is a phase II, randomized, multi-center, double-blind, placebo-controlled trial among 60 participants with mild cognitive impairment or dementia due to AD. Participants will be randomized in a 1:1 ratio to receive either SAMe or matching placebo, to be taken as an adjunct to their AD standard of care.
Measurements and results: The primary outcome is change in plasma p-tau181 concentration between baseline and following 180 days of treatment, which will be compared between the active and placebo group. Secondary outcomes are the safety of SAMe administration (incidence of serious adverse events), change from baseline in cognitive performance (as measured by the Repeatable Battery for the Assessment of Neuropsychological Status), and epigenetic changes in DNA methylation.
Conclusion: Demonstration of effective and safe lowering of plasma p-tau181 with SAMe in this phase II trial would pave the way for an exciting field of translational research and a larger phase III trial.
Introduction: Lower blood levels of the omega-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) are correlated with worse cognitive functions, particularly among APOE ε4 carriers. Whether DHA supplementation in APOE ε4 carriers with limited DHA consumption and dementia risk factors can delay or slow down disease progression when started before the onset of clinical dementia is not known.
Methods: PreventE4 is a double-blind, single site, randomized, placebo-controlled trial in cognitively unimpaired individuals with limited omega-3 consumption and dementia risk factors (n=368). Its objectives are to determine (1) whether carrying the APOE ε4 allele is associated with lower delivery of DHA to the brain; and (2) whether high dose DHA supplementation affects brain imaging biomarkers of AD and cognitive function.
Results: 365 cognitively unimpaired individuals between 55 and 80 (mean age 66) were randomized to 2 grams of DHA per day or identically appearing placebo for a period of 2 years. Half the participants were asked to complete lumbar punctures at baseline and 6-month visits to obtain cerebrospinal fluid (CSF). The primary trial outcome measure is the change in CSF DHA to arachidonic acid ratio after 6 months of the intervention (n=181). Secondary trial outcomes include the change in functional and structural connectivity using resting state functional MRI at 24 months (n=365). Exploratory outcomes include the change in Repeatable Battery of the Assessment of Neuropsychological Status at 24 months (n=365).
Conclusions: Findings from PreventE4 will clarify the brain delivery of DHA in individuals carrying the APOE ε4 allele with implications for dementia prevention strategies. Trial was registered as NCT03613844.
Background: Multimer detection system-oligomeric amyloid-β (MDS-OAβ) measure plasma OAβ level, which is associated with earlier Alzheimer's disease (AD) pathology. However, no study has investigated MDS-OAβ differences in cognitive normal older adults (CN) with or without cerebral Aβ burden and its correlation with Aβ deposition and white matter (WM) integrity.
Objective: To investigate associations among cerebral Aβ burden, MDS-OAβ, and WM integrity in CN.
Design: This is a single center, cross-sectional study which used data from Catholic Aging Brain Imaging (CABI) database.
Setting: CABI database contains brain scans of patients who visited the outpatient clinic at Catholic Brain Health Center, Yeouido St. Mary's Hospital, The Catholic University of Korea, between 2017 and 2022.
Participants: A total 34 amyloid-PET negative CN and 23 amyloid-PET positive CN were included.
Measurements: Plasma Aβ level using MDS-OAβ, cerebral Aβ deposition level using global standardized uptake value ratio (SUVR) values, WM integrity using fractional anisotropy (FA) and mean diffusivity (MD), and cortical thickness from structural MRI were utilized.
Restuls: The amyloid-PET positive group showed higher MDS-OAβ level than the amyloid-PET negative group (0.997 ± 0.19 vs. 0.79 ± 0.28, P <0.005), but they did not differ in WM integrity or cortical thickness. The MDS-OAβ positive group showed higher global cerebral Aβ deposition or mean global SUVR values (0.609 ± 0.135 vs. 0.533 ± 0.121 vs. P <0.05), lower regional FA of left forceps minor and the right superior longitudinal fasciculus (family-wise error rate, p <0.05), and lower cortical thickness of left fusiform (p <0.05, Monte Carlo simulation) than the MDS-OAβ negative group. MDS-OAβ was positively associated with global cerebral Aβ deposition (r=0.278, P <0.05) and negatively associated (r = - 0.324, P < 0.05) with regional WM integrity.
Conclusions: In this study, MDS-OAβ value demonstrated earlier and different AD pathology than cerebral Aβ retention according to amyloid-PET. Longitudinal studies are needed to elucidate the causal relationships of plasma OAβ and cerebral Aβ with WM integrity disturbance and cortical atrophy during the AD trajectory.
Background: The 523 poly-T length polymorphism (rs10524523) in TOMM40 has been reported to influence longitudinal cognitive test performance within APOE ε3/3 carriers. The results from prior studies are inconsistent. It is also unclear whether specific APOE and TOMM40 genotypes contribute to heterogeneity in longitudinal cognitive performance during the preclinical stages of AD.
Objectives: To determine the effects of these genes on longitudinal cognitive change in early preclinical stages of AD, we used the clinical trial data from the recently concluded TOMMORROW study to examine the effects of APOE and TOMM40 genotypes on neuropsychological test performance.
Design: A phase 3, double-blind, placebo-controlled, randomized clinical trial.
Setting: Academic affiliated and private research clinics in Australia, Germany, Switzerland, the UK, and the USA.
Participants: Cognitively normal older adults aged 65 to 83.
Intervention: Pioglitazone tablet.
Measurements: Participants from the TOMMORROW trial were stratified based on APOE genotype (APOE ε3/3, APOE ε3/4, APOE ε4/4). APOE ε3/3 carriers were further stratified by TOMM40'523 genotype. The final analysis dataset consists of 1,330 APOE ε3/3 carriers and 7,001 visits. Linear mixed models were used to compare the rates of decline in cognition across APOE groups and the APOE ε3/3 carriers with different TOMM40'523 genotypes.
Results: APOE ε3/4 and APOE ε4/4 genotypes compared with the APOE ε3/3 genotype were associated with worse performance on measures of global cognition, episodic memory, and expressive language. Further, over the four years of observation, the APOE ε3/3 carriers with the TOMM40'523-S/S genotype showed better global cognition and accelerated rates of cognitive decline on tests of global cognition, executive function, and attentional processing compared to APOE ε3/3 carriers with TOMM40'523-S/VL and VL/VL genotypes and compared to the APOE ε3/4 and APOE ε4/4 carriers.
Conclusions: We suggest that both APOE and TOMM40 genotypes may independently contribute to cognitive heterogeneity in the pre-MCI stages of AD. Controlling for this genetic variability will be important in clinical trials designed to slow the rate of cognitive decline and/or prevent symptom onset in preclinical AD.
Background: Social determinants of health (SDOH) may influence health in people living with dementia. Little is known about SDOH differences in urban compared to rural dwelling people living with dementia.
Objectives: To explore urban-rural differences in SDOH in people living with mild cognitive impairment (MCI) and dementia.
Design: Descriptive study.
Setting/participants: People ≥55 years with MCI or dementia empaneled to Community Internal Medicine at Mayo Clinic (Rochester, MN, USA) who completed SDOH questions between June 1, 2019 and June 30, 2021 were included.
Measurements: SDOH questions addressed education, depression, alcohol use, financial strain, food insecurity, physical activity, social connections, stress and transportation. SDOH data were compared by location based on Rural-Urban Commuting Areas Codes.
Results: Of 3552 persons with MCI (n=1495) or dementia (n=2057), 62% lived in urban areas, 19% in large rural, 10% in small rural and 9% in isolated areas. Approximately 60% were physically inactive, 20% socially isolated and 30% had stress concerns. Rural patients experienced greater financial strain (p=0.003).
Conclusion: Social isolation, stress and physical inactivity are common in people living with MCI and dementia across urban and rural areas. Targeted interventions to improve physical and psychosocial health could have great impact in this population.
Background: Alzheimer's disease (AD) disproportionately affects Black/African American and Hispanic/Latino adults, yet they are underrepresented in AD studies. Recruitment challenges for these populations limit generalizability of findings.
Objectives: This study explores barriers and facilitators to signing up for an AD participant recruitment registry website intended to optimize recruitment of these adults. The registry is geared toward recruitment on smartphones and tablets (mobile devices), as research suggests that mobile-first approaches may be more successful within these populations.
Design: In 2020, we conducted four focus groups (n = 39) and an online survey (n = 1010) with Black/African American and Hispanic/Latino adults. The survey also included Whites as a comparison group.
Setting: Focus groups were in-person at research facilities in New Orleans, Louisiana, and Los Angeles, California. The online survey was distributed by a survey panel company to participants nationwide.
Participants: Black/African American (n = 360), Hispanic/Latino (n = 359), or White (n = 330) individuals, 45-75 years old, who self-reported not having mild cognitive impairment (MCI), dementia, or AD.
Measurements: Barriers and facilitators explored in the focus groups and survey were related to health and AD (e.g., AD-related concerns and past participation/willingness to participate in health or AD studies); current use of mobile devices (e.g., comfort using devices and receptivity to the AD recruitment registry); and participant characteristics and beliefs (e.g., demographics, health literacy level, and trust in government and the scientific community).
Results: The focus groups and survey revealed similar findings. Participants commonly use mobile devices to go online and perform health-related activities. They were aware of AD, expressed concerns with developing it, and were willing to participate in AD-related studies (motivated by personal connection to AD, altruism, and compensation). When presented with the AD recruitment registry, most provided positive feedback (e.g., easy to use and informative) and shared an interest in joining. Barriers to joining the registry with a mobile device included complex or multistep enrollment processes, beliefs that studies are primarily for those with a specific disease, and confusion about how studies can prevent AD among those low-risk for AD. The focus groups also revealed that Black/African American participants expressed more hesitation than Hispanic/Latinos in joining the registry due to greater distrust in the government and scientific community.
Conclusions: Recruiting more Black/African American and Hispanic/Latino participants into AD studies is vitally important. This mixed methods study suggests that adults in these underrepres
Aducanumab is the first FDA-approved amyloid-lowering immunotherapy for Alzheimer's disease. There is little real-world data to guide management of amyloid-related imaging abnormalities (ARIA), a potentially serious side-effect which requires surveillance with magnetic resonance imaging. We report our experiences in managing ARIA in patients receiving aducanumab at the Butler Hospital Memory and Aging Program during the year following FDA approval. We followed the Appropriate Use Recommendations for aducanumab to guide patient selection, detection, and management of ARIA (1). ARIA-E occurred in 6 out of 24 participants treated; all APOE-ε4 carriers. Treatment was discontinued in 4 cases of moderate-severe ARIA-E, temporarily held in 1 moderate case, and dosed through in 1 mild case (mean duration = 3 months, range, 1-6 months). No participants required hospitalization or high dose corticosteroids. Participants on anticoagulation were excluded and no macrohemorrhages occurred. These data support the measured approaches to treatment outlined in the Appropriate Use Recommendations.
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