Jpad-Journal of Prevention of Alzheimers Disease最新文献

Background: Epidemiological evidence has demonstrated a clear association between diabetes mellitus and increased risk of Alzheimer's disease (AD). Cerebral accumulation of phosphorylated tau aggregates, a cardinal neuropathological feature of AD, is associated with neurodegeneration and cognitive decline. Clinical and experimental studies indicate that diabetes mellitus affects the development of tau pathology; however, the underlying molecular mechanisms remain unknown.

Objective: In the present study, we used a unique diabetic AD mouse model to investigate the changes in tau phosphorylation patterns occurring in the diabetic brain.

Design: Tau-transgenic mice were fed a high-fat diet (n = 24) to model diabetes mellitus. These mice developed prominent obesity, severe insulin resistance, and mild hyperglycemia, which led to early-onset neurodegeneration and behavioral impairment associated with the accumulation of hyperphosphorylated tau aggregates.

Results: Comprehensive phosphoproteomic analysis revealed a unique tau phosphorylation signature in the brains of mice with diabetic AD. Bioinformatic analysis of the phosphoproteomics data revealed putative tau-related kinases and cell signaling pathways involved in the interaction between diabetes mellitus and AD.

Conclusion: These findings offer potential novel targets that can be used to develop tau-based therapies and biomarkers for use in AD.

Disclosing Alzheimer's disease (AD) biomarkers to research participants is a growing practice. Here, we aim to synthesize the experiences of clinicians leading preclinical AD biomarker disclosure. Semi-structured interviews were conducted individually with each of the four clinicians conducting biomarker disclosure as a part of a longitudinal, observational AD cohort study. Study clinicians emphasized the importance of participant education, having adequate time available for the disclosure visit, and forms to facilitate disclosure. To train and support future clinicians conducting AD biomarker disclosure, our study clinicians highlighted providing information about AD and biomarkers, shadowing a disclosure visit, having team debriefing sessions, and collating a frequently asked questions document. To date, this is the first characterization of clinician reflections on disclosing AD biomarker result to cognitively unimpaired research participants. As more clinicians in research or clinical settings seek to disclose AD biomarker results, best practices for training clinicians to lead disclosure are necessary.

Background: Computerized cognitive training (CCT) has emerged as a potential treatment option for mild cognitive impairment (MCI). It remains unclear whether CCT's effect is driven in part by expectancy of improvement.

Objectives: This study aimed to determine factors associated with therapeutic expectancy and the influence of therapeutic expectancy on treatment effects in a randomized clinical trial of CCT versus crossword puzzle training (CPT) for older adults with MCI.

Design: Randomized clinical trial of CCT vs CPT with 78-week follow-up.

Setting: Two-site study - New York State Psychiatric Institute and Duke University Medical Center.

Participants: 107 patients with MCI.

Intervention: 12 weeks of intensive training with CCT or CPT with follow-up booster training over 78 weeks.

Measurements: Patients rated their expectancies for CCT and CPT prior to randomization.

Results: Patients reported greater expectancy for CCT than CPT. Lower patient expectancy was associated with lower global cognition at baseline and older age. Expectancy did not differ by sex or race. There was no association between expectancy and measures of everyday functioning, hippocampus volume, or apolipoprotein E genotype. Expectancy was not associated with change in measures of global cognition, everyday functioning, and hippocampus volume from baseline to week 78, nor did expectancy interact with treatment condition.

Conclusions: While greater cognitive impairment and increased age was associated with low expectancy of improvement, expectancy was not associated with the likelihood of response to treatment with CPT or CCT.

Background: The utility of neuropsychological measurements as forerunners of Alzheimer's Disease Dementia (AD) in individuals with normal cognition or mild cognitive impairment (MCI) is undeniable.

Objectives: To assess the differential prognostic value of cognitive performance in older men versus women.

Design: Longitudinal analysis of data acquired from the National Alzheimer's Coordinating Center Uniform Data Set.

Settings: Data on older adults (≥60 years) were derived from 43 National Institute on Aging - funded Alzheimer's Disease Research Centers.

Participants: 10,073 cognitively unimpaired (CU) older adults followed for 5.5±3.8 years and 3,925 participants with amnestic MCI monitored for 3.5±2.8 years.

Measurements: The domains of episodic memory, verbal fluency, naming, attention, processing speed and executive function were assessed. Cox proportional hazards models examined associations between individual cognitive domains and AD incidence separately for each participant set. CU and MCI. These predictive models featured individual neuropsychological measures, sex, neuropsychological measure by sex interactions, as well as a number of crucial covariates.

Results: Episodic memory and verbal fluency were differentially related to future AD among CU individuals, explaining a larger proportion of risk variance in women compared to men. On the other hand, naming, attention and executive function were differentially related to future AD among participants with MCI, accounting for a greater fraction of risk variance in men than women.

Conclusion: Cognitive performance is differentially related to risk of progressing to AD in men versus women without dementia.

Background: The understanding of Alzheimer's disease (AD) has been dominated by the amyloid hypothesis. However, therapies targeting beta-amyloid have largely failed, generating interest in other potential pathogenic factors including energy metabolism.

Objectives: To interrogate canonical energy metabolism pathways from human prefrontal cortical tissue samples obtained from necropsy comparing AD and control.

Design, setting, and participants: Postmortem pre-frontal cortical tissue from 10 subjects histologically diagnosed with AD and 10 control (CTRL) subjects was subjected to untargeted metabolomics to interrogate energy metabolism pathways. The samples were matched by age, sex, and post-mortem interval. Metabolite Measurements: Untargeted metabolomics analyses were via Metabolon®.

Results: Glucose-derived energy metabolites in the glycolytic and pentose phosphate pathway and the ketone body β-hydroxybutyrate were uniformly decreased in AD brain vs. CTRL brain.

Conclusion: This pilot study aimed to identify energy metabolism abnormalities using untargeted brain metabolomics in two independent subject cohorts. Our study revealed a pattern of global energy deficit in AD brain, supporting a growing body of evidence of deficient energy metabolism in AD.

Background: A disease-modifying Alzheimer's treatment could provide budgetary savings to Canadian provinces from a reduction in long-term care home use, yet we do not know the magnitude of those potential savings.

Objective: We project savings to each Canadian province's budget from 2023 to 2043.

Design: Annual savings are projected using a Markov model. We account for reduction in long-term care home use and in use of Alternative Level of Care (ALC) beds, which are hospital beds occupied by care home-eligible patients on the wait list for admission.

Results: A treatment that delays disease progression by 40% is projected to avoid 142,507 long-term care home and ALC years, resulting in $17.2 billion cumulative savings across all Canadian provinces, a 21% relative reduction among treatment eligible patients. Average per capita savings were $1,132, ranging from $734 (Alberta) to $2,895 (Prince Edward Island). Cumulative savings could increase to $22.7 billion with enhanced triage of patients in primary care stages and to $25.6 billion if all capacity constraints for diagnosis and treatment were removed.

Conclusion: A disease-modifying treatment could create budgetary savings from lower long-term care home use, offsetting part of the treatment cost. With the increasing demand for long-term care home beds and the high rates of patients being held in hospitals while wait-listed, such a treatment could additionally provide relief to the overburdened long-term care system in Canada.

Background: Identifying individuals before the onset of overt symptoms is key in the prevention of Alzheimer's disease (AD).

Objectives: Investigate the use of miRNA as early blood-biomarker of cognitive decline in older adults.

Design: Cross-sectional.

Setting: Two observational cohorts (CHARIOT-PRO, Alzheimer's Disease Neuroimaging Initiative (ADNI)).

Participants: 830 individuals without overt clinical symptoms from CHARIOT-PRO and 812 individuals from ADNI.

Measurements: qPCR analysis of a prioritised set of 38 miRNAs in the blood of individuals from CHARIOT-PRO, followed by a brain-specific functional enrichment analysis for the significant miRNAs. In ADNI, genetic association analysis for polymorphisms within the significant miRNAs' genes and CSF levels of phosphorylated-tau, total-tau, amyloid-β42, soluble-TREM2 and BACE1 activity using whole genome sequencing data. Post-hoc analysis using multi-omics datasets.

Results: Six miRNAs (hsa-miR-128-3p, hsa-miR-144-5p, hsa-miR-146a-5p, hsa-miR-26a-5p, hsa-miR-29c-3p and hsa-miR-363-3p) were downregulated in the blood of individuals with low cognitive performance on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). The pathway enrichment analysis indicated involvement of apoptosis and inflammation, relevant in early AD stages. Polymorphisms within genes encoding for hsa-miR-29c-3p and hsa-miR-146a-5p were associated with CSF levels of amyloid-β42, soluble-TREM2 and BACE1 activity, and 21 variants were eQTL for hippocampal MIR29C expression.

Conclusions: six miRNAs may serve as potential blood biomarker of subclinical cognitive deficits in AD. Polymorphisms within these miRNAs suggest a possible interplay between the amyloid cascade and microglial activation at preclinical stages of AD.

Background: African Americans with MCI may be at increased risk for dementia compared to Caucasians. The effect of race on the efficacy of cognitive training in MCI is unclear.

Methods: We used data from a two-site, 78-week randomized trial of MCI comparing intensive, home-based, computerized training with Web-based cognitive games or Web-based crossword puzzles to examine the effect of race on outcomes. The study outcomes were changes from baseline in cognitive and functional scales as well as MRI-measured changes in hippocampal volume and cortical thickness. Analyses used linear models adjusted for baseline scores. This was an exploratory study.

Results: A total of 105 subjects were included comprising 81 whites (77.1%) and 24 African Americans (22.8%). The effect of race on the change from baseline in ADAS-Cog-11 was not significant. The effect of race on change from baseline to week 78 in the Functional Activities Questionnaire (FAQ) was significant with African American participants' FAQ scores showing greater improvements at weeks 52 and 78 (P = 0.009, P = 0.0002, respectively) than white subjects. Within the CCT cohort, FAQ scores for African American participants showed greater improvement between baseline and week 78, compared to white participants randomized to CCT (P = 0.006). There was no effect of race on the UPSA. There was no effect of race on hippocampal or cortical thickness outcomes.

Conclusions: Our preliminary findings suggest that web-based cognitive training programs may benefit African Americans with MCI at least as much as Caucasians, and highlight the need to further study underrepresented minorities in AD prevention trials. (Supported by the National Institutes of Health, National Institute on Aging; ClinicalTrials.gov number, NCT03205709.).

Background: Alzheimer's disease (AD) is the most common neurodegenerative disease worldwide, and an updated quantification of its impact on morbidity, disability, and mortality is warranted. We conducted a systematic literature review, focusing on the past decade, to characterize AD and assess its impact on affected individuals.

Methods: Searches of Embase, MEDLINE, and the Cochrane Library were conducted on August 7, 2020 and updated on November 10, 2021. Observational studies from any country reporting incidence, prevalence, comorbidities, and/or outcomes related to disability and mortality/life expectancy, in people with mild cognitive impairment (MCI) due to AD, or mild, moderate, or severe AD dementia, were considered relevant.

Results: Data were extracted from 88 studies (46 incidence/prevalence; 44 comorbidities; 25 mortality-/disability-related outcomes), mostly from Europe, the USA, and Asia. AD dementia diagnosis was confirmed using biomarkers in only 6 studies. Estimated 5-year mortality in AD was 35%, and comorbidity prevalence estimates varied widely (hypertension: 30.2-73.9%; diabetes: 6.0-24.3%; stroke: 2.7-13.7%). Overall, people with AD dementia were more likely to have cardiovascular disease or diabetes than controls, and 5-year mortality in people with AD dementia was double that in the age- and year-matched general population (115.0 vs 60.6 per 1,000 person-years).

Conclusions: AD is associated with excess morbidity and mortality. Future longitudinal studies of population aging, incorporating biomarker assessment to confirm AD diagnoses, are needed to better characterize the course of MCI due to AD and AD dementia.

Dementia is forecast to become increasingly prevalent, particularly in low- and middle-income countries, and is associated with high human and economic costs. Primary prevention of dementia -preventing risk factors leading to disease development - is an emerging global public health priority. Primary prevention can be achieved in two ways: individual-level or population-level. In this rapid review, we quantify the proportion of contributing interventional evidence to the dementia primary prevention literature that is concerned with either approach. We searched Medline, the National Institute for Health and Care Excellence, Cochrane, the World Health Organization, and Google to identify systematic reviews that described primary prevention interventions for dementia. We used search terms related to dementia risk reduction, intervention/policy, and review. We analysed reference lists of included dementia prevention reviews to identify contributing primary prevention evidence, and categorised these as either individual-level or population-level. Additionally, we examined search strategies to investigate the likelihood of reviews identifying available population-level interventions. We included twelve of the 527 articles retrieved. Population-level evidence was summarised by only two reviews. In these two reviews, <2.5% of the interventions described where population-level interventions. Most search strategies were weighted towards identifying individual-level evidence. Existing systematic reviews of dementia primary prevention interventions include almost no population-level evidence. Correction of this imbalance is needed to ensure that dementia prevention policies can achieve meaningful reductions in the prevalence of, and inequalities in, dementia.