Sub-cortical vascular ischaemia is the second most common etiology contributing to cognitive impairment in older adults, and is frequently under-diagnosed and under-treated. Although evidence is ...mounting that exercise has benefits for cognitive function among seniors, very few randomized controlled trials of exercise have been conducted in populations at high-risk for progression to dementia. Aerobic-based exercise training may be of specific benefit in delaying the progression of cognitive decline among seniors with vascular cognitive impairment by reducing key vascular risk factors associated with metabolic syndrome. Thus, we aim to carry out a proof-of-concept single-blinded randomized controlled trial primarily designed to provide preliminary evidence of efficacy aerobic-based exercise training program on cognitive and everyday function among older adults with mild sub-cortical ischaemic vascular cognitive impairment.
A proof-of-concept single-blinded randomized trial comparing a six-month, thrice-weekly, aerobic-based exercise training group with usual care on cognitive and everyday function. Seventy older adults who meet the diagnostic criteria for sub-cortical ischaemic vascular cognitive impairment as outlined by Erkinjuntti and colleagues will be recruited from a memory clinic of a metropolitan hospital. The aerobic-based exercise training will last for 6 months. Participants will be followed for an additional six months after the cessation of exercise training.
This research will be an important first step in quantifying the effect of an exercise intervention on cognitive and daily function among seniors with sub-cortical ischaemic vascular cognitive impairment, a recognized risk state for progression to dementia. Exercise has the potential to be an effective, inexpensive, and accessible intervention strategy with minimal adverse effects. Reducing the rate of cognitive decline among seniors with sub-cortical ischaemic vascular cognitive impairment could preserve independent functioning and health related quality of life in this population. This, in turn, could lead to reduced health care resource utilization costs and avoidance of early institutional care.
Mutations in the progranulin gene (GRN) are a common cause of familial frontotemporal dementia. We used a comprehensive neuropsychological battery to investigate whether early cognitive changes could ...be detected in GRN mutation carriers before dementia onset. Twenty-four at-risk members from six families with known GRN mutations underwent detailed neuropsychological testing. Group differences were investigated by domains of attention, language, visuospatial function, verbal memory, non-verbal memory, working memory and executive function. There was a trend for mutation carriers (n=8) to perform more poorly than non-carriers (n=16) across neuropsychological domains, with significant between group differences for visuospatial function (p<.04; d=0.92) and working memory function (p<.02; d=1.10). Measurable cognitive differences exist before the development of frontotemporal dementia in subjects with GRN mutations. The neuropsychological profile of mutation carriers suggests early asymmetric, right hemisphere brain dysfunction that is consistent with recent functional imaging data from our research group and the broader literature.
Comorbid depression is a leading neuropsychiatric complication in the Alzheimer's disease (AD) syndrome. In 2011, diagnostic criteria for AD were revised to include neuropsychiatric symptoms. It has ...been proposed that adding an antidepressant to existing treatment for AD could provide relief for not only depressive but also cognitive symptoms.
The aim was to quantitatively review published studies to examine the efficacy of selective serotonin reuptake inhibitor (SSRI)/serotonin-noradrenaline (norepinephrine) reuptake inhibitor (SNRI) therapy for alleviation of comorbid, diagnosed depression as well as cognitive decline in AD.
A search of electronic databases was performed. Studies were retained for analysis if SSRI/SNRI antidepressant therapy was compared with placebo among AD patients with comorbid depression. Effect-size (ES) estimates (Hedges' g) were calculated using Comprehensive Meta-Analysis software.
From 598 examined studies, 12 SSRI studies met the inclusion criteria, and from these, only six met all criteria, among which five reported sufficient and consistent data to be included in the meta-analysis. Within a random effect model, ES estimates of the first and second nested global analyses were non-significant, non-heterogeneous and small to null at the endpoint for depression, favouring SSRIs, -0.06 and -0.10, respectively (p > 0.05). The ES for global cognition as measured by the Mini-Mental State Examination was negligible (ES = 0.001).
Current evidence does not support the efficacy of SSRI treatment for symptoms of comorbid depression in AD. However, studies differed in terms of criteria for diagnosis of depression, the compound tested and outcome measures for depression. These factors could account for the lack of a clear benefit for depression.
To estimate the prevalence of mild cognitive impairment (MCI) and its subtypes, taking into account education and health status.
This is the first report of our Study on Aging and Dementia in Mexico. ...This study included 2,944 elderly individuals 60 years old or more with in-home assessment for cognitive impairment. The prevalence of MCI was based on Petersen criteria. MCI was classified as amnestic of single domain (a-MCI-s) or multiple domain (a-MCI-md) or nonamnestic of single domain (na-MCI-s) or multiple domain (na-MCI-md). In addition to a battery of neuropsychological measures, a self-report depression measure and a medical history including history of stroke, heart disease and other health conditions were recorded.
The global estimated prevalence of MCI in the Mexican population was 6.45%. Of these subjects, 2.41% met criteria for a-MCI-s, 2.56% for a-MCI-md, 1.18% for na-MCI-s and 0.30% for na-MCl-md. Women showed a higher prevalence of MCI than men (63.7 vs. 36.3%, respectively). The analysis showed that heart disease odds ratio (OR) 1.5, stroke (OR 1.2) and depression (OR 2.1) were associated with an increased risk of MCI.
The prevalence of MCI in Mexico is similar to that in other countries. The results suggest that stroke, heart disease and depression may have an important role in the etiology of MCI.
Abstract Repeat expansions in chromosome 9 open reading frame 72 ( C9ORF72 ) are an important cause of both motor neuron disease (MND) and frontotemporal dementia (FTD). Currently, little is known ...about factors that could account for the phenotypic heterogeneity detected in C9ORF72 expansion carriers. In this study, we investigated 4 genes that could represent genetic modifiers: ataxin-2 ( ATXN2 ), non-imprinted in Prader-Willi/Angelman syndrome 1 ( NIPA1 ), survival motor neuron 1 ( SMN1 ), and survival motor neuron 2 ( SMN2 ). Assessment of these genes, in a unique cohort of 331 C9ORF72 expansion carriers and 376 control subjects, revealed that intermediate repeat lengths in ATXN2 possibly act as disease modifier in C9ORF72 expansion carriers; no evidence was provided for a potential role of NIPA1 , SMN1 , or SMN2 . The effects of intermediate ATXN2 repeats were most profound in probands with MND or FTD/MND (2.1% vs. 0% in control subjects, p = 0.013), whereas the frequency in probands with FTD was identical to control subjects. Though intermediate ATXN2 repeats were already known to be associated with MND risk, previous reports did not focus on individuals with clear pathogenic mutations, such as repeat expansions in C9ORF72 . Based on our present findings, we postulate that intermediate ATXN2 repeat lengths may render C9ORF72 expansion carriers more susceptible to the development of MND; further studies are needed, however, to validate our findings.
Our aim was to investigate the patterns and trajectories of white matter (WM) diffusion abnormalities in microtubule-associated protein tau (MAPT) mutations carriers. We studied 22 MAPT mutation ...carriers (12 asymptomatic, 10 symptomatic) and 20 noncarriers from 8 families, who underwent diffusion tensor imaging (DTI) and a subset (10 asymptomatic, 6 symptomatic MAPT mutation carriers, and 10 noncarriers) were followed annually (median = 4 years). Cross-sectional and longitudinal changes in mean diffusivity (MD) and fractional anisotropy were analyzed. Asymptomatic MAPT mutation carriers had higher MD in entorhinal WM, which propagated to the limbic tracts and frontotemporal projections in the symptomatic stage compared with noncarriers. Reduced fractional anisotropy and increased MD in the entorhinal WM were associated with the proximity to estimated and actual age of symptom onset. The annualized change of entorhinal MD on serial DTI was accelerated in MAPT mutation carriers compared with noncarriers. Entorhinal WM diffusion abnormalities precede the symptom onset and track with disease progression in MAPT mutation carriers. Our cross-sectional and longitudinal data showed a potential clinical utility for DTI to track neurodegenerative disease progression for MAPT mutation carriers in clinical trials.
•Elevated mean diffusivity (MD) in the entorhinal white matter (WM) is present in asymptomatic MAPT mutation carriers.•Higher MD and lower fractional anisotropy in the entorhinal WM are associated with the proximity to symptom onset.•Longitudinal increase of MD in the entorhinal WM accelerates with aging in MAPT mutation carriers.
To identify potential genetic modifiers contributing to the phenotypic variability that is detected in patients with repeat expansions in chromosome 9 open reading frame 72 (C9ORF72), we investigated ...the frequency of these expansions in a cohort of 334 subjects previously found to carry mutations in genes known to be associated with a spectrum of neurodegenerative diseases.
A 2-step protocol, with a fluorescent PCR and a repeat-primed PCR, was used to determine the presence of hexanucleotide expansions in C9ORF72. For one double mutant, we performed Southern blots to assess expansion sizes, and immunohistochemistry to characterize neuropathology.
We detected C9ORF72 repeat expansions in 4 of 334 subjects (1.2% or 1.8% of 217 families). All these subjects had behavioral phenotypes and also harbored well-known pathogenic mutations in either progranulin (GRN: p.C466LfsX46, p.R493X, p.C31LfsX35) or microtubule-associated protein tau (MAPT: p.P301L). Southern blotting of one double mutant with a p.C466LfsX46 GRN mutation demonstrated a long repeat expansion in brain (>3,000 repeats), and immunohistochemistry showed mixed neuropathology with characteristics of both C9ORF72 expansions and GRN mutations.
Our findings indicate that co-occurrence of 2 evidently pathogenic mutations could contribute to the pleiotropy that is detected in patients with C9ORF72 repeat expansions. These findings suggest that patients with known mutations should not be excluded from further studies, and that genetic counselors should be aware of this phenomenon when advising patients and their family members.
INTRODUCTION
Clinical research in Alzheimer's disease (AD) lacks cohort diversity despite being a global health crisis. The Asian Cohort for Alzheimer's Disease (ACAD) was formed to address ...underrepresentation of Asians in research, and limited understanding of how genetics and non‐genetic/lifestyle factors impact this multi‐ethnic population.
METHODS
The ACAD started fully recruiting in October 2021 with one central coordination site, eight recruitment sites, and two analysis sites. We developed a comprehensive study protocol for outreach and recruitment, an extensive data collection packet, and a centralized data management system, in English, Chinese, Korean, and Vietnamese.
RESULTS
ACAD has recruited 606 participants with an additional 900 expressing interest in enrollment since program inception.
DISCUSSION
ACAD's traction indicates the feasibility of recruiting Asians for clinical research to enhance understanding of AD risk factors. ACAD will recruit > 5000 participants to identify genetic and non‐genetic/lifestyle AD risk factors, establish blood biomarker levels for AD diagnosis, and facilitate clinical trial readiness.
HIGHLIGHTS
The Asian Cohort for Alzheimer's Disease (ACAD) promotes awareness of under‐investment in clinical research for Asians.
We are recruiting Asian Americans and Canadians for novel insights into Alzheimer's disease.
We describe culturally appropriate recruitment strategies and data collection protocol.
ACAD addresses challenges of recruitment from heterogeneous Asian subcommunities.
We aim to implement a successful recruitment program that enrolls across three Asian subcommunities.
Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9ORF72) are causative for frontotemporal dementia (FTD) and motor neuron disease (MND). Substantial phenotypic heterogeneity ...has been described in patients with these expansions. We set out to identify genetic modifiers of disease risk, age at onset, and survival after onset that may contribute to this clinical variability.
We examined a cohort of 330 C9ORF72 expansion carriers and 374 controls. In these individuals, we assessed variants previously implicated in FTD and/or MND; 36 variants were included in our analysis. After adjustment for multiple testing, our analysis revealed three variants significantly associated with age at onset (rs7018487 UBAP1; p-value = 0.003, rs6052771 PRNP; p-value = 0.003, and rs7403881 MT-Ie; p-value = 0.003), and six variants significantly associated with survival after onset (rs5848 GRN; p-value = 0.001, rs7403881 MT-Ie; p-value = 0.001, rs13268953 ELP3; p-value = 0.003, the epsilon 4 allele APOE; p-value = 0.004, rs12608932 UNC13A; p-value = 0.003, and rs1800435 ALAD; p-value = 0.003).
Variants identified through this study were previously reported to be involved in FTD and/or MND, but we are the first to describe their effects as potential disease modifiers in the presence of a clear pathogenic mutation (i.e. C9ORF72 repeat expansion). Although validation of our findings is necessary, these variants highlight the importance of protein degradation, antioxidant defense and RNA-processing pathways, and additionally, they are promising targets for the development of therapeutic strategies and prognostic tests.
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