Alzheimer''s and Dementia: Diagnosis, Assessment and Disease Monitoring最新文献

Introduction: Identification of cognitive decline is critical in older adults at risk for dementia. In a 2020 study reported in Archives of Clinical Neuropsychology, Kiselica and colleagues developed standardized regression-based (SRB) change formulae for the Uniform Data Set 3.0 Neuropsychological Battery in cognitively unimpaired older adults. However, validation of their applicability in impaired individuals is needed.

Methods: Using longitudinal data on 5974 participants (cognitively unimpaired, mild cognitive impairment, dementia) from the National Alzheimer's Coordinating Center, SRB change scores were calculated for each individual and compared across groups.

Results: Across 6 to 24 months, minimal cognitive change was observed in cognitively unimpaired participants. Modest declines were seen in those with mild cognitive impairment and substantial declines in those with dementia. Change scores were negatively correlated with the Clinical Dementia Rating scale. In impaired individuals, SRB scores indicated more decline in those with positive amyloid scans.

Discussion: Validation of SRB scores affords greater confidence in employing them in clinical and research settings.

Highlights: Validation of regression-based cognitive change scores in impaired samples.Clear differences on change scores across three groups (intact, MCI, dementia).Largely stable scores in intact participants, but notable decline in MCI and dementia.Moderate to strong relationship between change scores and the Clinical Dementia Rating scale sum of boxes.

Introduction: This study investigated whether epigenetic age acceleration (AA) is associated with the change in cognitive function and the risk of incident dementia over 9 years, separately in males and females.

Methods: Six epigenetic AA measures, including GrimAge, were estimated in baseline blood samples from 560 Australians aged ≥70 years (50.7% female). Cognitive assessments included global function, episodic memory, executive function, and psychomotor speed. Composite cognitive scores were also generated. Dementia (Diagnostic and Statistical Manual for Mental Disorders - IV [DSM-IV] criteria) was adjudicated by international experts.

Results: Associations between epigenetic AA and cognitive performance over-time varied by sex. In females only, GrimAA/Grim2AA was associated with worse delayed recall, composite cognition, and composite memory (adjusted-beta ranged from -0.1372 to -0.2034). In males only, GrimAA/Grim2AA was associated with slower processing speed (adjusted-beta, -0.3049) and increased dementia risk (adjusted hazard ratios [HRs], 1.78 and 2.00, respectively).

Discussion: Epigenetic AA is associated with cognitive deterioration in later life but with evidence of sex-specific associations.

Highlights: Epigenetic age acceleration was associated with cognitive deterioration over time.However, these associations differed by sex.In females, accelerated GrimAge appeared to be a better marker of decline in memory.In males, accelerated GrimAge was associated with slower processing speed over time.Association between accelerated GrimAge and dementia risk was found only in males.

Introduction: Alzheimer's disease (AD), the most prevalent neurodegenerative disorder globally, has emerged as a significant health concern. Recently it has been revealed that extracellular vesicles (EVs) play a critical role in AD pathogenesis and progression. Their stability and presence in various biofluids, such as blood, offer a minimally invasive window for monitoring AD-related changes.

Methods: We analyzed plasma EV-derived messenger RNA (mRNA) from 82 human subjects, including individuals with AD, mild cognitive impairment (MCI), and healthy controls. With next-generation sequencing, we profiled differentially expressed genes (DEGs), identifying those associated with AD.

Results: Based on DEGs identified in both the MCI and AD groups, a diagnostic model was established based on machine learning, demonstrating an average diagnostic accuracy of over 98% and showed a strong correlation with different AD stages.

Discussion: mRNA derived from plasma EVs shows significant promise as a non-invasive biomarker for the early detection and continuous monitoring of AD.

Highlights: The study conducted next-generation sequencing (NGS) of mRNA derived from human plasma extracellular vesicles (EVs) to assess Alzheimer's disease (AD).Profiling of plasma EV-derived mRNA shows a significantly enriched AD pathway, indicating its potential for AD-related studies.The AD-prediction model achieved a receiver-operating characteristic area under the curve (ROC-AUC) of more than 0.98, with strong correlation to the established Clinical Dementia Rating (CDR).

Introduction: The influence of hippocampal connectivity on memory performance is well established in individuals with high educational attainment. However, the role of hippocampal connectivity in illiterate populations remains poorly understood.

Methods: Thirty-five illiterate adults were administered a literacy assessment (Test of Functional Health Literacy in Adults [TOFHLA]), structural and resting state functional magnetic resonance imaging, and an episodic memory test (Free and Cued Selective Reminding Test). Illiteracy was defined as a TOFHLA score < 53. We evaluated the correlation between hippocampal connectivity at rest and both free recall and literacy scores.

Results: Participants were mostly female (57.1%) and self-declared as being Black individuals (84.8%), with a median age of 50 years. The median TOFHLA literacy score was 28.0 [21.0; 42.5] out of 100 points and the median free recall score was 30.0 [26.2; 35] out of 48 points. The median gray matter volume of both the left and right hippocampi was 2.3 [2.1; 2.4] cm³. We observed a significant connectivity between both hippocampi and the precuneus and the ventral medial prefrontal cortex. The right hippocampal connectivity positively correlated with the literacy scores (β = 0.58, P = 0.008). There was no significant association between episodic memory and hippocampal connectivity. Neither memory nor literacy scores correlated with hippocampal gray matter volume.

Discussion: Low literacy levels correlated with hippocampal connectivity in illiterate adults. The lack of association with memory scores might be associated with low brain reserve in this sample.

Highlights: A significant link was found between health literacy and hippocampal connectivity.Enhanced hippocampus- ventromedial prefrontal cortex connectivity suggests potential cognitive reserve improvement.Higher cognitive reserve may protect against hippocampal atrophy and neurodegeneration.Health literacy improvements could help prevent cognitive impairment in illiterate populations.Study highlights importance of considering structural racism in brain connectivity research.

Introduction: In a 5-year follow-up study, we investigated the enduring effects of cognitive training on older adults with mild cognitive impairment (MCI).

Methods: A randomized controlled single-blind trial involved 145 older adults with MCI, assigned to cognitive training (MEMO+), an active control psychosocial intervention, or a no-contact condition. Five-year effects were measured on immediate and delayed memory recall, the Montreal Cognitive Assessment screening test (MoCA), self-reported strategy use, and daily living difficulties.

Results: At follow-up, participants who received cognitive training showed a smaller decline in delayed memory and maintained MoCA scores, contrasting with greater declines in the control groups. Cognitive training participants outperformed controls in both delayed memory and MoCA scores at the 5-year time point. No significant group differences were observed in self-reported strategy use or difficulties in daily living.

Discussion: Cognitive training provides long-term benefits by mitigating memory decline and slowing clinical symptom progression in older adults with MCI.

Highlights: Cognitive training reduced the 5-year memory decline of persons with MCI.Cognitive training also reduced decline on the Montreal Cognitive Assessment (MoCA).No intervention effect was found on strategy use or activities of daily living.

Introduction: We aimed to assess the knowledge of social norms in patients with behavioral variant frontotemporal dementia (bvFTD) with the Dutch version of the Social Norms Questionnaire (SNQ-NL).

Methods: The SNQ-NL was administered in 34 patients with bvFTD, 20 prodromal mutation carriers, 76 presymptomatic mutation carriers, and 56 controls. Group differences and correlations with other neuropsychological tests and gray matter volume were examined.

Results: Patients with bvFTD had lower total SNQ-NL scores and more over-adherence errors than presymptomatic mutation carriers and controls (P < 0.001). SNQ-NL performance correlated with tests for executive functioning and social cognition, and with gray matter volume in bilateral frontal and unilateral temporal regions.

Discussion: The SNQ-NL can identify impairments in knowledge of social norms in bvFTD, highlighting its significance in clinical diagnosis and upcoming clinical trials. The SNQ-NL currently fails to differentiate presymptomatic mutation carriers from controls; to this end, larger sample sizes from larger cohorts and longitudinal follow-up are warranted.

Highlights: The Dutch version of the Social Norms Questionnaire (SNQ-NL) is able to detect impairment in social cognition in symptomatic bvFTD patients.A trend towards a lower performance in prodromal mutation carriers was found.Performance on the SNQ-NL is related to other measures of social cognition, executive functioning, and language.Lower SNQ-NL performance is related to gray matter volume loss in bilateral frontal and temporal regions.The SNQ-NL provides insight into the underlying cause of deficits in social cognition in bvFTD.

Training studies typically investigate the cumulative rather than the analytically challenging immediate effect of exercise on cognitive outcomes. We investigated the dynamic interplay between single-session exercise intensity and time-locked recognition speed-accuracy scores in older adults with Alzheimer's dementia (N = 17) undergoing a 24-week dual-task regime. We specified a state-of-the-art hierarchical Bayesian continuous-time dynamic model with fully connected state variables to analyze the bi-directional effects between physical and recognition scores over time. Higher physical performance was dynamically linked to improved recognition (-1.335, SD = 0.201, 95% Bayesian credible interval [BCI] [-1.725, -0.954]). The effect was short-term, lasting up to 5 days (-0.368, SD = 0.05, 95% BCI [-0.479, -0.266]). Clinical scores supported the validity of the model and observed temporal dynamics. Higher physical performance predicted improved recognition speed accuracy in a day-by-day manner, providing a proof-of-concept for the feasibility of linking exercise training and recognition in patients with Alzheimer's dementia.

Highlights: Hierarchical Bayesian continuous-time dynamic modeling approachA total of 72 repeated physical exercise (PP) and integrated recognition speed-accuracy (IRSA) measurementsPP is dynamically linked to session-to-session variability of IRSAHigher PP improved IRSA in subsequent sessions in subjects with Alzheimer's dementiaShort-term effect: lasting up to 4 days after training session.

Introduction: We examined the relationship between sedentary behavior (SB), moderate-to-vigorous physical activity (MVPA), and white matter hyperintensity (WMH) volumes, a common magnetic resonance imaging (MRI) marker associated with risk of neurodegenerative disease in middle-aged to older adults.

Methods: We used data from the UK Biobank (n = 14,415; 45 to 81 years) that included accelerometer-derived measures of SB and MVPA, and WMH volumes from MRI.

Results: Both MVPA and SB were associated with WMH volumes (β_MVPA = -0.03 [-0.04, -0.01], p < 0.001; β_SB = 0.02 [0.01, 0.03], p = 0.007). There was a significant interaction between SB and MVPA on WMH volumes (β_SB×MVPA = -0.015 [-0.028, -0.001], p _SB×MVPA = 0.03) where SB was positively associated with WMHs at low MVPA, and MVPA was negatively associated with WMHs at high SB.

Discussion: While this study cannot establish causality, the results highlight the potential importance of considering both MVPA and SB in strategies aimed at reducing the accumulation of WMH volumes in middle-aged to older adults.

Highlights: SB is associated with greater WMH volumes and MVPA is associated with lower WMH volumes.Relationships between SB and WMH are strongest at low levels of MVPA.Associations between MVPA and WMH are strongest at high levels of SB.Considering both SB and MVPA may be effective strategies for reducing WMHs.

Introduction: Neuropsychiatric symptoms (NPS) are highly prevalent in Alzheimer's disease (AD). There are no effective treatments targeting these symptoms.

Methods: To facilitate identification of causative mechanistic pathways, we initiated an effort (NIH: U01AG079850) to collate, harmonize, and analyze all available NPS data (≈ 100,000 samples) of diverse ancestries with whole-genome sequencing data from the Alzheimer's Disease Sequencing Project (ADSP).

Results: This study will generate a genomic resource for Alzheimer's disease with both harmonized whole-genome sequencing and NPS phenotype data that will be publicly available through NIAGADS. Primary analyses will (1) identify novel genetic risk factors associated with NPS in AD, (2) characterize the shared genetic architecture of NPS in AD and primary psychiatric disorders, and (3) assess the role of ancestry effects in the etiology of NPS in AD.

Discussion: Expansion of the ADSP to harmonize and refine NPS phenotypes coupled with the proposed core analyses will lay the foundation to disentangle the molecular mechanisms underlying these detrimental symptoms in AD in diverse populations.

Highlights: Neuropsychiatric symptoms (NPS) are highly prevalent in Alzheimer's disease (AD).There are no effective treatments targeting NPS in AD.The current effort aims to collate, harmonize, and analyze all NPS data from the Alzheimer's Disease Sequencing Project.Core analyses will identify underlying genetic factors and mechanistic pathways.The harmonized genomic and phenotypic data from this initiative will be available through National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site.

Introduction: We aimed to determine the effect of years of schooling (YoS) and age on the Mexican adaptation of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD-MX) scores in preclinical carriers group (PCG) and non-carriers group (NCG) of the APP _V717I mutation.

Methods: We included 39 first-degree Mexican relatives of APP _V717I carriers (PCG = 15; NCG = 24). We report eight CERAD-MX tasks: Mini-Mental State Examination (MMSE), Word List Learning (WLL), Delayed Recall (WLD) and Recognition (WLR), Constructional Praxis Copy (CPC) and Recall (CPR), Semantic Verbal Fluency (SVF), and Verbal Boston Naming (VBN), comparing both groups' performance and simulating new samples' random vectors by inverse transform sampling.

Results: PCG and NCG performed similarly on CERAD-MX. In both groups, YoS and age influence all z scores. A positive age effect resulted for PCG on CPC and SVF; for the NCG on MMSE, SVF, and VBN.

Discussion: All tasks are influenced by YoS. Higher YoS/younger age or YoS/older age interactions affected different tasks, suggesting that YoS confounds outcomes.

Highlights: Years of schooling (YoS) and age affect the Mexican adaptation of the Consortium to Establish a Registry for Alzheimer's Disease scores of APP _V717I preclinical carriers.Preclinical carriers underperformed non-carriers on Constructional Praxis Recall.Fewer YoS emerges as a confounding variable when detecting cognitive failures.Younger participants in both groups overperformed the older ones in the Memory tasks.Randomized data simulation increases statistical power when analyzing rare diseases.