Journal of Alzheimer's Disease最新文献

BackgroundMotoric cognitive risk (MCR) syndrome is characterized by subjective cognitive complaints and slow gait and confers a higher risk of dementia. Cerebral small vessel disease (CSVD) is associated with poor cognitive, functional, and survival outcomes in aging. Markers of CSVD seen on magnetic resonance imaging (MRI) include white matter hyperintensities (WMHs) and lacunes.ObjectiveTo examine associations between imaging markers of CSVD and the MCR syndrome.MethodsCross-sectional data from 4 cohorts in 4 countries were examined. WMHs and lacunes were quantified from brain MRIs manually, using a standardized grading scale. Regression models examined the associations between WMH and lacunes and MCR, gait speed, slow gait, and cognitive complaints. We also compared the prevalence of the outcomes of interest between participants with "confluent or diffuse" or "no or mild" WMH. Statistical models were adjusted for age, sex, study site, and vascular risk factors.ResultsData from 1772 participants (M Age = 71.1 years, 49.9% female) was analyzed. Higher global WMH scores were associated with MCR (aOR = 1.07, p = 0.015). Frontal and basal ganglia WMH scores were associated with MCR (aOR = 1.23, p = 0.007, aOR = 1.31, p = 0.023, respectively). Participants with "confluent-diffuse" WMH had significantly higher prevalence of MCR (30.2% versus 19.2%, p = 0.003). Basal ganglia lacunes were associated with MCR (aOR = 1.57, p = 0.018).ConclusionsIn this multi-cohort study of older adults without cognitive impairment, we show that WMH and lacunes independently predict increased risk of MCR, after adjusting for key confounders. Our findings, based on a large multi-ethnic cohort, reveal region-specific CSVD patterns linked to MCR and related outcomes.

BackgroundVarious functional impairments in eye movements have been observed in Alzheimer's disease (AD) and other neurodegenerative disorders. Detecting abnormal eye movements may help identify individuals at risk of memory diseases even when evident clinical symptoms are absent.ObjectiveTo investigate the earliest possible stage at which the risk of memory impairment can be detected using computer-based eye-tracking (ET) analysis of King-Devick (KD) test performance.MethodsWe recruited a total of 34 healthy controls and 33 participants with a Clinical Dementia Rating-Sum of Boxes (CDR-SOB) score of 0.5 or higher. They all underwent a neurological examination, the Consortium to Establish a Registry for Alzheimer's Disease neuropsychological test battery (CERAD-NB), and a CDR interview. The KD reading test was performed using computer-based ET. We analyzed fixation durations, saccade durations, and saccade amplitudes. For this study, test results were analyzed in relation to CDR-SOB.ResultsThe mean duration of saccades was significantly shorter in the CDR-SOB 0.5 group compared to healthy controls (p = 0.001), and this difference remained significant across groups with CDR-SOB >0.5. The mean amplitude of saccades was significantly lower in individuals with CDR-SOB scores ranging from 1 to 4, as well as those with scores exceeding 4.5, in comparison to healthy controls (p = 0.007).ConclusionsThese findings suggest that ET analysis of the KD test may help detect individuals with very early cognitive problems. Therefore, this method shows promise as a supportive or potentially indicative biomarker for future studies aimed at developing user-friendly tools to identify individuals at risk for AD or other memory diseases.

BackgroundNeuropsychiatric symptoms (NPS) are increasingly recognized as core features of Alzheimer's disease (AD), often emerging preclinically. Adults with Down syndrome (DS) represent a genetically determined population at high risk for AD (DS-associated AD, DSAD), yet their neuropsychiatric profiles remain undercharacterized and seldom compared with sporadic AD (sAD).ObjectiveTo delineate and compare NPS profiles across the AD continuum in adults with and without DS, examining their relationships with amyloid-tau (AT) biomarker status, neuroimaging, and neurophysiological markers.MethodsWe conducted a cross-sectional study of 293 adults (138 with DS, ≥ 18 years; 155 non-DS, ≥ 50 years) stratified by cognitive stage. NPS were assessed via Neuropsychiatric Inventory (NPI). A subset underwent cerebrospinal fluid biomarker analysis, MRI, and EEG. Linear models explored NPI associations with AT status, MRI/EEG findings, sex, and psychotropic medication use.ResultsNPS severity increased with cognitive decline in both cohorts; affective and behavioral domains were most prevalent. Individuals with DS showed significantly higher NPI total scores across all stages, particularly disinhibition and aberrant motor behaviors during dementia. Positive AT biomarker status and abnormal EEG/MRI findings independently associated with greater NPI burden, including in cognitively unimpaired individuals. Polypharmacy and female sex were additional predictors in DS. Caregiver distress paralleled NPI severity.ConclusionsThis study identifies shared and syndrome-specific NPS trajectories in DSAD and sAD, with clear associations to AD biomarkers and neurophysiological dysfunction. Findings support NPS as early indicators of AD pathology and underscore the importance of personalized, developmentally informed behavioral assessment and care.

BackgroundLecanemab and donanemab are anti-amyloid-β monoclonal antibodies recently approved in the United States and Europe for the treatment of early Alzheimer's disease (AD). Their modest clinical benefit, safety profile, and cost raise debate about real-world applicability. Fortasyn Connect (Souvenaid^TM), a multi-nutrient intervention, has shown potential clinical benefits in prodromal AD.ObjectiveTo compare the clinical effect sizes (Cohen's d) and estimated months of preserved independence in instrumental activities of daily living (IADLs) for lecanemab, donanemab, and Souvenaid™, based on published pivotal clinical trial data.MethodsCohen's d on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) was computed using standardized mean differences and 95% confidence intervals (CIs) derived from published trials. Times of functional independence were estimated using the Hartz approach.ResultsPoint estimates of Cohen's d effect sizes on CDR-SB were -0.34, -0.33, and -0.52 for lecanemab, donanemab, and Souvenaid™, respectively, with no statistically significant differences between drugs. Estimated gains in IADL independence were 10 months for lecanemab, 8 months for donanemab, and 27 months for Souvenaid™.ConclusionsDespite differences in study designs, Souvenaid^TM demonstrated comparable clinical efficacy with superior safety, accessibility, and cost profile. These findings support further evaluation of Souvenaid^TM as a non-invasive, scalable option in early AD management.

BackgroundPredementia, encompassing subjective cognitive decline (SCD) and mild cognitive impairment (MCI), represents an early phase of neurodegeneration with a heightened risk of progression to dementia. This stage offers a critical window for intervention. Virtual reality (VR) enhances neuroplasticity in predementia via multisensory stimulation, addressing research gaps.​​ObjectiveTo assess the impact of VR-based interventions on cognitive abilities, emotional well-being, and instrumental activities of daily living (IADL) in individuals with predementia conditions.MethodsA search of seven databases identified studies involving seniors aged ≥65 with SCD or MCI. Eligible studies compared conventional cognitive training or usual care as controls. Quality was assessed using the Cochrane Risk of Bias Tool, and evidence certainty was graded using the GRADE framework.ResultsTwelve randomized controlled trials were included. The meta-analysis revealed that, in comparison to control groups, VR-based cognitive interventions had superior effects on subjective cognitive complaints (SMD = -4.06, 95% CI [-4.86, -3.25]), learning and memory (SMD = 0.41, 95% CI [0.02, 0.80]), working memory (SMD = -0.06, 95% CI [-0.08, -0.03]), verbal fluency (SMD = 0.49, 95% CI [0.03, 0.94]), spatial cognition (SMD = 1.43, 95% CI [0.77, 2.10]), and IADL (SMD = 0.77, 95% CI [0.14, 1.40]).ConclusionsVR-based cognitive interventions could improve objective cognitive performance, subjective cognitive complaints, and IADL in predementia. Future research should prioritize optimizing the intervention protocols and enhancing the geriatric-specific VR-based cognitive intervention.

Recent epidemiological evidence showed that mutations to the HFE-63 allele of this hemochromatosis-associated iron-assimilation protein improve chances of avoiding Alzheimer's disease (AD). This is unexpected since increased brain ferroptosis in gray-matter increases the risk for vascular dementia and AD. However, diffusion tensor imaging from a key Alzheimer's Disease Neuroimaging Initiative biomarker study showed that the hemochromatosis H63D allele protected white matter tracts and improved cognitive performance in individuals when APOE4 accelerates AD. H63D-carrying individuals exhibit elevated serum ferritin levels. We suggest coordinate increased levels of H-ferritin in iron-rich oligodendrocytes in H63D carriers generates sufficient neuroprotection to enhance myelin sheath integrity in white matter axons.

BackgroundEpisodic memory tests in Alzheimer's disease (AD) often depend on verbal recall or drawing.ObjectiveTo develop Visual Image Simple Recognition Test (VISRET) and evaluate its psychometric and clinical performance.MethodsWe studied 149 individuals (healthy participants [HP] = 62; AD = 53; patients with aphasia [AP] = 34). We assessed reliability (split-half Spearman-Brown [SB]), known-groups validity with age-adjusted models and age-stratified analyses, and a Bayesian logistic model (AD versus HP). A Bayesian linear model produced a composite Memory Score and highest posterior density (HPD)-based cut-offs using HP alone, subsequently evaluated by five-fold cross-validation. Convergent and discriminant validity were assessed by correlating VISRET with established neuropsychological tests in non-aphasic AD.ResultsInternal consistency was good in AD (SB = 0.87) and acceptable when pooled within-group (SB = 0.84). AD-HP discrimination was large, persisting after age adjustment, within age strata, and following aphasic AD exclusion. The Bayesian model showed excellent discrimination (posterior-mean AUC = 0.99, 95% HPD = 0.97-0.99). AP differed from HP but with trivial absolute differences (total 39.6 versus 39.4; false recognitions 0.1 versus 0.3). In non-aphasic AD, VISRET total correlated with an established episodic memory test (ρ=0.60) but demonstrated weak or near-zero correlations with non-memory domains (e.g., nonverbal reasoning, ρ=0.02). Cross-validated, HP-derived Memory-Score cut-offs achieved mean AUC = 0.98; at the 95%-HPD threshold, sensitivity = 0.87 and specificity = 0.95; at 99%-HPD, sensitivity = 0.74 and specificity = 0.98.ConclusionsVISRET is a brief, language-minimized recognition test facilitating AD-related memory impairment detection, with minimal practical impact of aphasia. The HP-derived Memory Score and cut-offs demonstrated stable cross-validation, suggesting potential clinical utility pending replication and external validation.

BackgroundType 2 diabetes (T2DM) is an independent risk factor for accelerated cognitive decline, creating a need for non-invasive biomarkers to diagnose T2DM-related mild cognitive impairment (T2DM-MCI). Circular RNAs (circRNAs), known to regulate T2DM pathophysiology, represent promising candidate biomarkers.ObjectiveWe aimed to assess the relationship between circRNAs levels and cognitive decline in T2DM patients.MethodThis study included 64 patients with T2DM-MCI and 75 patients with T2DM and normal cognition (T2DM-NC). All T2DM-MCI participants completed a 1.5-year follow-up period. Neuropsychological assessments were performed for all participants. Blood levels of circRNA were quantified using real-time quantitative polymerase chain reaction.Results(1) Whole-blood expression of hsa_circ_0015335 was significantly reduced in T2DM-MCI patients compared to T2DM-NC controls. (2) Receiver operating characteristic (ROC) curve analysis demonstrated that hsa_circ_0015335 could differentiate T2DM-MCI from T2DM-NC with an Area Under ROC Curve of 0.722. (3) Lower hsa_circ_0015335 levels showed significant negative correlations with global cognitive function, episodic memory, and executive function scores in T2DM-MCI patients. (4) A significant interaction was observed between reduced hsa_circ_0015335 expression and elevated triglyceride glucose (TyG) index, collectively contributing to global cognitive impairment in T2DM-MCI patients. (5) Mediation analysis revealed that the TyG index significantly mediated the association between baseline hsa_circ_0015335 levels and the rate of global cognitive decline during follow-up.ConclusionsPeripheral blood hsa_circ_0015335 shows potential as a biomarker for T2DM-MCI identification and cognitive decline progression in affected patients. This circRNA may contribute to cognitive impairment pathogenesis in T2DM, potentially through mechanisms involving glucose metabolism dysregulation.

BackgroundMemory loss is a core feature of typical Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI). Standard memory tests such as word lists assess verbal episodic memory with delayed recall and recognition. However, actual memory fidelity is likely variable, continuous, and has a subjective component.ObjectiveWe investigated dual-processing models of episodic memory (recollection versus familiarity) using confidence ratings in a "judgment of knowing" paradigm (JOK).MethodsThis paradigm was applied to the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) memory test as part of neuropsychological evaluation at University of Pittsburgh Alzheimer's Disease Research Center (ADRC), to generate novel indices of memory function to improve sensitivity to early memory problems and provide a memory awareness metric. On recognition testing, participants rated how sure they were of their yes/no responses to each item. We derived novel variables related to memory and metacognition, including an Accuracy-Certainty Index and the Relative Certainty Index.ResultsIn this sample of 347 participants (185 with AD, 55 with MCI, 111 cognitively unimpaired), CERAD Delayed Recall was the best single variable for discriminating groups, although multiple certainty variables also discriminated groups well.ConclusionsThe addition of certainty indices to a standard verbal memory task increased discriminative power between groups, particularly between cognitively normal controls and MCI or AD.

BackgroundIncreasing evidence suggests that the trajectory of Alzheimer's disease (AD) pathologies, such as amyloid and tau, differ between the sexes.ObjectiveGiven the higher susceptibility of females to dementia, we aimed to investigate the sex differences in the primary accumulation of tau and its subsequent spread to later cortical brain regions.MethodsWe included 315 participants in this study: 221 cognitively unimpaired individuals with normal amyloid (n = 140, A- CU) or abnormal amyloid (n = 81, A+ CU), and 94 cognitively impaired individuals with abnormal amyloid (A+ CI). Each individual received two to six tau positron emission tomography (PET) scans using the [18F]-Flortaucipir (FTP) tracer. Linear regression analyses were performed to assess sex-specific tau spreading throughout the Braak stages among three clinical groups.ResultsThe median (interquartile range) age of all samples was 73.5 (68 to 78.2) years. In total, 170 participants (54%) were female. In the A+ CU group, females exhibited higher tau-PET SUVR levels in all Braak I, III-IV, and V-VI. We found that the spreading pattern of tau may vary by sex and AD stages. In the A+ CI individuals, there was an observed interaction between the female sex and baseline tau SUVRs in Braak stages III-IV (p < 0.0001 and Bonferroni-corrected p < 0.0023), affecting longitudinal accumulation of tau in later Braak stages V-VI.ConclusionsOur findings found a sex-specific pattern of tau spreading from Braak stages III-IV to V-VI in A+ CI older adults. This disadvantage may indicate that females might experience faster tau spreading and quicker disease progression when the condition develops to more advanced disease stages.