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

Abstract: Plasma pTau181, a marker of amyloid and tau burden, was evaluated as a prognostic predictor of clinical decline and Alzheimer's disease (AD) progression of amyloid-positive (Aβ+) patients with mild cognitive impairment (MCI). The training cohort for constructing the Bayesian prediction models comprised 135 Aβ+ MCI clinical trial placebo subjects. Performance was evaluated in two validation cohorts. An 18-month ≥1 increase in the Clinical Dementia Rating Sum of Boxes was the clinical decline criterion. Baseline plasma pTau181 concentration matched clinical assessments' prediction performance. Adding pTau181 to clinical assessments significantly improved the prediction of an 18-month clinical decline and the 36-month progression from Aβ+ MCI to AD. The area under the receiver operating characteristic curve for the latter increased from 71.8% to 79%, and the hazard ratio for time-to-progression improved from 2.26 to 3.11 (p < 0.0001). Baseline plasma pTau181 has the potential for identifying Aβ+ MCI subjects with faster clinical decline over time.

Highlights: This study assessed pTau181 as a prognostic predictor of 18-month clinical decline and extended progression to Alzheimer's disease (AD) in amyloid-positive patients with mild cognitive impairment (Aβ+ MCI).The research findings underscore the promise of baseline plasma pTau181 as a screening tool for identifying Aβ+ MCI individuals with accelerated clinical decline within a standard 18-month clinical trial period. The predictive accuracy is notably enhanced when combined with clinical assessments.Similar positive outcomes were noted in forecasting the extended progression of Aβ+ MCI subjects to AD.

Introduction: Alzheimer's disease (AD) neuropathological changes present with amnestic and nonamnestic (atypical) syndromes. The contribution of comorbid neuropathology as a substratum of atypical expression of AD remains under investigated.

Methods: We examined whether atypical AD exhibited increased comorbid neuropathology compared to typical AD and if such neuropathologies contributed to the accelerated clinical decline in atypical AD.

Results: We examined 60 atypical and 101 typical AD clinicopathological cases. The number of comorbid pathologies was similar between the groups (p = 0.09). Argyrophilic grain disease was associated with atypical presentation (p = 0.008) after accounting for sex, age of onset, and disease duration. Vascular brain injury was more common in typical AD (p = 0.022). Atypical cases had a steeper Mini-Mental Status Examination (MMSE) decline over time (p = 0.033).

Discussion: Comorbid neuropathological changes are unlikely to contribute to atypical AD presentation and the steeper cognitive decline seen in this cohort.

Highlights: Autopsy cohort of 60 atypical and 101 typical AD; does comorbid pathology explain atypical presentation?Atypical versus Typical AD: No significant differences in comorbid neuropathologies were found (p = 0.09).Argyrophilic Grain Disease Association: significantly correlates with atypical AD presentations, suggesting a unique neuropathological pattern (p = 0.008).Vascular Brain Injury Prevalence: Vascular brain injury is more common in typical AD than in atypical AD (p = 0.022).Cognitive Decline in Atypical AD: Atypical AD patients experience a steeper cognitive decline measured by MMSE than those with typical AD despite lacking more comorbid neuropathology, highlighting the severity of atypical AD pathogenesis (p = 0.033).

Introduction: This study investigates the relationship between cognitive functioning and 59 modifiable and intrinsic factors at the cusp of midlife.

Methods: We analyzed data from 1221 participants in the Colorado Adoption/Twin Study of Lifespan behavioral development and cognitive aging (CATSLife; M_age = 33.20, %Female = 52.74). We assessed the impact of 59 factors on cognitive functioning using regularized regression and co-twin control models, controlling for earlier-life cognitive functioning and gray matter volume.

Results: Eight robust factors were identified, including education attainment, cognitive complexity, purpose-in-life, and smoking status. Twins reporting higher levels of cognitive complexity and purpose-in-life showed better cognitive performance than their cotwin, while smoking was negatively associated. Using meta-analytically derived effect size threshold, we additionally identified that twins experiencing more financial difficulty tend to perform less well compared with their cotwin.

Discussion: The findings highlight the early midlife link between cognitive functioning and lifestyle/psychological factors, beyond prior cognitive performance, brain status, genetic and familial confounders. Our results further highlight the potential of established adulthood as a crucial window for dementia prevention interventions targeting lifestyle and psychosocial factors.

Highlights: Cog complexity(+), purpose-in-life(+) were associated with cognition in early midlife.Smoking(-) was also associated with cognition in early midlife.Results were consistent controlling for genetic and environmental confounds.Association between EA and cognition might be mostly genetic and familial confounded.

The Hispanic/Latino population is one of the largest and most diverse ethnoracial groups in the United States at high risk for dementia. We examined cognitive constructs and associations with subsequent hippocampal volume (HV) and white matter hyperintensity volume (WMHV). Participants were from the Hispanic Community Health Study/Study of Latinos-Magnetic Resonance Imaging Study (n = 2029). We examined confirmatory factor analysis and longitudinal invariance using neurocognitive scores at Visits 1 (2008-2011) and 2 (2014-2018) and path analyses. We obtained a longitudinally invariant two-factor episodic memory (EM) and working memory (WM) construct. Lower EM profile at both visits was associated with greater WMHV and smaller HV at Visit 2. Lower WM profile at both visits was associated with larger WMHV and smaller HV at Visit 2. Neurocognitive profiles were associated with subsequent neurodegeneration in a sample of Hispanics/Latinos. Identifying neurocognitive risk profiles may lead to early detection and intervention, and significantly impact the course of neurodegeneration.

Highlights: Cognitive profiles predict brain integrity up to 10 years later.We observed two-factor latent memory constructs and longitudinal invariance.These findings were observed in a Hispanic/Latino cohort.

Introduction: Commercially available plasma p-tau217 biomarker tests are not well studied in ethnically diverse samples.

Methods: We evaluated associations between ALZPath plasma p-tau217 and amyloid-beta positron emission tomography (Aβ-PET) in Hispanic/Latino (88% of Cuban or South American ancestry) and non-Hispanic/Latino older adults. One- and two-cutoff ranges were derived and evaluated to assess agreement with Aβ-PET.

Results: A total of 239 participants underwent blood draw and Aβ-PET (age 70.8 ± 7.8, 55.2% female, education 15.6 ± 3.4 years, 48.9% Hispanic/Latino, 94.9% white). Plasma p-tau217 showed excellent discrimination of Aβ-PET positive and negative participants (visual read: AUC = 0.91 [0.87-0.95], p < 0.001; Centiloids quantification: AUC = 0.90 [0.86-0.94]). There was a greater percent agreement between low p-tau217 and negative Aβ-PET (95.8%) than high p-tau217 and positive Aβ-PET (86.3%). Analyses within ethnicity-specific subgroups suggested similar p-tau217 performance.

Discussion: Plasma p-tau217 (ALZPath) relates to brain Aβ in Hispanic/Latino and non-Hispanic/Latino older adults. Independent validation and replication are necessary to establish reference ranges and inform appropriate contexts of use across ethno-racially diverse populations.

Highlights: Plasma p-tau217 (ALZPath) and Aβ-PET were measured in Hispanic/Latino and non-Hispanic/Latino older adults.Plasma p-tau217 accurately discriminated Aβ-PET positive and negative participants.Applying a two-cutoff "intermediate" plasma p-tau217 approach could reduce need for more invasive and costly testing.Plasma p-tau217 associations with Aβ-PET were strong within both Hispanic/Latino and non-Hispanic/Latino groups.

Introduction: Subjective hearing and memory problems are detectable earlier than objective measures of sensory loss and cognitive decline, which are known to be related to an increased risk of dementia in later life.

Methods: Using a population-representative cohort of 6006 individuals (aged 50-75) we examined whether participants who self-reported hearing and short-term memory issues showed greater rates of dementia within 17 years of follow-up. A sub-cohort was tested for audiometric threshold and cognition after 14 years.

Results: Hearing and memory problems were associated with a greater risk of dementia (hazard ratios [HRs] = 1.42 [95% confidence interval: 1.11-1.81], 1.57 [1.30-1.90]), and poorer cognition 14 years later. The risk was greatest in those reporting both problems (HR = 1.99 [1.42-2.80]). At follow-up, the level of hearing loss was associated with lower cognitive scores.

Discussion: Self-reports of hearing and short-term memory problems are associated with poorer cognitive performance and a greater risk of dementia. Subjective assessments may have predictive power over more than a decade.

Highlights: In a sample of older adults subjective hearing and memory problems were associated with dementia risk.Cross-sectionally, the audiometric screening threshold was associated with cognitive test scores.Subjective sensory and memory loss questions are easy to implement and show good predictive power.

Introduction: Neuropsychiatric symptoms (NPS) are nearly universal in dementia; some cross-sectional studies of NPS in dementia have found racial/ethnic differences, though it is unknown if NPS prevalence differs among racial/ethnic groups before and after dementia diagnosis.

Methods: Participants were followed annually at Alzheimer's Disease Centers and were assessed on the Neuropsychiatric Inventory-Questionnaire (NPI-Q) with at least one follow-up visit at which they were diagnosed with dementia. Descriptive statistics were generated by race/ethnicity. NPS were modeled over time as a function of race/ethnicity and with diagnosis date as the baseline.

Results: NPS were present in 95% in at least one time point. After adjusting for covariates, there were no statistically significant differences in NPI-Q total scores among racial/ethnic groups at the time of and after dementia diagnosis.

Discussion: Findings from our prospective cohort study suggest that when individuals are matched at the time of conversion to dementia, there are no racial/ethnic differences in NPS.

Highlights: Neuropsychiatric symptoms of dementia are frequent and increase caregiver burden.Prior studies reported more neuropsychiatric symptoms (NPS) in Black compared to White individuals with dementia.National Alzheimer's Coordinating Center Black, White, and Hispanic participants did not differ in NPS at the time of dementia diagnosis.

Introduction: Brain glucose hypometabolism is a preclinical feature of Alzheimer's disease (AD). Dietary omega-3 fatty acids promote brain glucose metabolism, but clinical research is incipient. Circulating omega-3s objectively reflect their dietary intake.

Methods: This was a cross-sectional study in 320 cognitively unimpaired participants at increased risk of AD dementia. Using lipidomics, we determined blood docosahexaenoic (DHA) and alpha-linolenic (ALA) acid levels (omega-3s from marine and plant origin, respectively). We assessed brain glucose metabolism using [18-F]-fluorodeoxyglucose (FDG) positron emission tomography (PET).

Results: Blood ALA directly related to FDG uptake in brain areas known to be affected in AD. Stronger associations were observed in apolipoprotein E ε4 carriers and homozygotes. For DHA, significant direct associations were restricted to amyloid beta-positive tau-positive participants.

Discussion: Blood omega-3 directly relate to preserved glucose metabolism in AD-vulnerable brain regions in individuals at increased risk of AD dementia. This adds to the benefits of omega-3 supplementation in the preclinical stage of AD dementia.

Highlights: Blood omega-3s were related to brain glucose uptake in participants at risk of Alzheimer's disease (AD) dementia.Complementary associations were observed for omega-3 from marine and plant sources.Foods rich in omega-3 might be useful in early features of AD.

Introduction: Alzheimer's disease (AD) is often misclassified in electronic health records (EHRs) when relying solely on diagnosis codes. This study aimed to develop a more accurate, computable phenotype (CP) for identifying AD patients using structured and unstructured EHR data.

Methods: We used EHRs from the University of Florida Health (UFHealth) system and created rule-based CPs iteratively through manual chart reviews. The CPs were then validated using data from the University of Texas Health Science Center at Houston (UTHealth) and the University of Minnesota (UMN).

Results: Our best-performing CP was "patient has at least 2 AD diagnoses and AD-related keywords in AD encounters," with an F1-score of 0.817 at UF, 0.961 at UTHealth, and 0.623 at UMN, respectively.

Discussion: We developed and validated rule-based CPs for AD identification with good performance, which will be crucial for studies that aim to use real-world data like EHRs.

Highlights: Developed a computable phenotype (CP) to identify Alzheimer's disease (AD) patients using EHR data.Utilized both structured and unstructured EHR data to enhance CP accuracy.Achieved a high F1-score of 0.817 at UFHealth, and 0.961 and 0.623 at UTHealth and UMN.Validated the CP across different demographics, ensuring robustness and fairness.

Introduction: Alzheimer's disease (AD) blood biomarkers show promise for clinical diagnosis but their reliability in chronic kidney disease (CKD) is debated. This study investigates the impact of kidney transplant (KT) on AD biomarkers in CKD.

Methods: We assessed AD biomarkers in 46 CKD patients pre-KT, at 12 weeks and 12 months post-KT, with baseline measures from 13 non-CKD controls. Using linear mixed models, we examined associations with participant groups, estimated glomerular filtration rate (eGFR) and cognition.

Results: CKD patients showed elevated levels of neurofilament light (117 ± 72 vs. 11 ± 5 pg/mL), phosphorylated tau 181 (75 ± 42 vs. 13 ± 8 pg/mL), glial fibrillary acidic protein (193 ± 127 vs. 94 ± 39 pg/mL), amyloid β 42 (17 ± 5 vs. 5 ± 1 pg/mL), and amyloid β 40 (259 ± 96 vs. 72 ± 17 pg/mL) compared to controls. Post-KT, biomarker levels approached normal with improved eGFR, paralleled by enhanced cognitive function.

Discussion: AD blood biomarker elevations in CKD are reversible with improved kidney function through KT.

Highlights: AD biomarker levels are extremely high in severe CKD.AD biomarker levels are higher in patients with kidney failure on dialysis when compared to CKD patients not on dialysis.These elevations in AD biomarker levels in kidney failure are reversable and decrease dramatically after kidney transplantation.The change in biomarker levels after transplantation align with changes in kidney function.The change in biomarker levels after transplantation align with changes in cognitive function.