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

Introduction: We examined whether the Performance Assessment of Self-Care Skills (PASS) and Everyday Cognition Scale-12 (ECog-12) dichotomized cognitive groups in a sample of predominantly Black adults.

Methods: Two hundred forty-six community-dwelling adults (95% Black, age 50+) completed cognitive testing, the PASS, and the ECog. Cognitive groups (probable vs unlikely cognitive impairment) were determined by performance on the Modified Mini-Mental State Examination. We examined the predictive validity of the PASS shopping, medication management, and information retrieval subtests and the ECog-12 to dichotomize cognitive groups.

Results: Performance on all PASS subtests (all p's < .05) differed between cognitive groups, but not ECog-12 (p = 0.17). Only the PASS shopping and medication management had good reliability for determining cognitive group (areas under the curve (AUCs) of .74 each).

Discussion: PASS shopping and medication management exhibited adequate predictive validity when distinguished between cognitive status groups, whereas the PASS information retrieval and ECog-12 did not.

Highlights: Mild functional decline is a core diagnostic criterion for cognitive impairment.Performance-based assessments are a valuable tool for assessing functional decline.Most performance-based measures were developed using homogenous samples.Few studies have validated these measures in other racial and ethnic populations.

Introduction: Chronic kidney disease (CKD) is associated with cognitive decline and changes in brain structure. However, their associations remain unclear, particularly the selective vulnerability characteristics that make some brain regions more vulnerable.

Methods: We investigated the baseline association between estimated glomerular filtration rates (eGFR) and cognitive function in 15,897 individuals from the CARTaGENE cohort. We performed vertex-based magnetic resonance imaging (MRI) analyses between eGFR and longitudinal cortical thickness in the 1397 participants who underwent brain MRI after 6 years. Imaging transcriptomics was used to characterize the gene expression and neurodegenerative features associated with this association.

Results: Lower eGFR correlated with reduced cognitive performance and brain structure. Brain regions associated with eGFR were enriched for mitochondrial and inflammatory-related genes. These associations occurred independently from age, sex, education, and body mass index (BMI), Framingham risk score, and white matter lesion volume.

Discussion: This study highlights the link between reduced eGFR, cognitive impairment, and brain structure, revealing some of the kidney-brain axis mechanisms.

Highlights: Lower eGFR is associated with reduced cognitive abilities.Structural brain changes are mediated by eGFR levels.Specific gene expression patterns correlate with lower eGFR and brain changes.Mitochondrial and inflammation-related genes were enriched in these patterns.

Introduction: Growing interest centers on the association between circulating ketone bodies (KB) and cognitive function, notably in aging and neurodegenerative diseases.

Methods: Associations of plasma KB with incident dementia and cognitive performances were examined among Multi-Ethnic Study of Atherosclerosis (MESA) participants. KB were measured using plasma samples collected following an overnight fasting at Exam 1 (2000-02) and detailed cognitive testing at Exam 5 (2010-2012, N = 4392), Exam 6 (2016-2018, N = 1838), and in MESA-MIND (2019-2021, N = 2060).

Results: Over 16.7 years, a doubling of total KB was associated with a greater risk of incident dementia (hazard ratio [HR]: 1.14 [1.04-1.29]). Higher total KB was associated with worse cognitive performance in the Digit Span test at exam 5 [β: -0.30 (-0.47, -0.14)]. We also found that a higher KB was associated with greater functional impairment and a higher Quick Dementia Rating Scale (QDRS) score.

Discussion: In a diverse, cardiovascular disease-free population, elevated KB levels were associated with incident dementia and impaired cognitive performance in specific domains.

Highlights: A study of ketone bodies (KB) and cognitive performance and incident dementia.Nuclear magnetic resonance (NMR) spectroscopy was used to measure plasma KB at baseline.Doubling of baseline total KB was associated with higher incident dementia.Higher KB was also associated with worse performance on a test of working memory.

Introduction: Plasma phosphorylated tau-217 (p-tau217) and neurofilament light (NfL) can differentiate between different dementias in selected cohorts. We aim to test the discrimination potential of these markers in a real-world cohort.

Methods: We measured p-tau217 (ALZpath) and NfL (Quanterix) in 415 (unselected) consecutive memory clinic patients. Biomarker levels were dichotomized as low/high to create four biomarker profiles based on p-tau217 and NfL levels.

Results: p-Tau217 levels were highest in patients with Alzheimer's disease (AD) dementia, whereas NfL levels were highest in patients with frontotemporal dementia (FTD). Low p-tau217/low NfL was associated mostly with non-neurological diagnoses (79%), and high p-tau217/low NfL indicated AD pathology at any stage (84%). Low p-tau217/high NfL indicated FTD (38%) and high p-tau217/high NfL indicated AD dementia (87%).

Discussion: p-Tau217 can identify AD pathology at any disease stage. NfL can differentiate FTD from other diagnoses (e.g., AD dementia). Plasma p-tau217 and NfL can support clinical decision-making, and we suggest using them as complements to standard clinical assessment.

Highlights: Phosphorylated tau-2017 (p-tau217) can detect Alzheimer's disease (AD) across the clinical continuum.Neurofilament light (NfL) can differentiate frontotemporal dementia (FTD) from other diagnoses (AD dementia, dementia with Lewy bodies [DLB], and Psychiatry).p-Tau217 may detect AD co-pathology in other diseases or dementia types (e.g., DLB).p-Tau217 and NfL show potential for clinical implementation.

Introduction: Olfactory dysfunction can be an early sign of Alzheimer's disease (AD). We used tau positron emission tomography-magnetic resonance (PET-MR) to analyze a key region of the olfactory circuit, the piriform cortex, in comparison to the adjacent medial temporal lobe.

Methods: Using co-registered magnetic resonance imaging (MRI) and ¹⁸F-PI-2620 tau PET-MR scans in 94 older adults, we computed tau uptake in the piriform-periamygdaloid cortex, amygdala, entorhinal-perirhinal cortices, and hippocampus.

Results: We found an ordinal cross-sectional increase in piriform cortex tau uptake with increasing disease severity (amyloid-negative controls, amyloid-positive controls, mild cognitive impairment [MCI] and AD), comparable to entorhinal-perirhinal cortex. Amyloid-positive controls showed significantly greater tau uptake than amyloid-negative controls. Negative correlations were present between memory performance and piriform uptake. Piriform uptake was not elevated in cognitively unimpaired Parkinson's disease.

Discussion: Cross-sectionally, there is an early increase in tau uptake in the piriform cortex in AD but not in Parkinson's disease.

Highlights: Positron emission tomography-magnetic resonance (PET-MR) analysis of the piriform cortex sheds light on its role as a potential early region affected by neurodegenerative disorders underlying olfactory dysfunction.Uptake of tau tracer was elevated in the piriform cortex in Alzheimer's disease (AD) and mild cognitive impairment (MCI) but not in Parkinson's disease (PD).Memory performance was worse with greater piriform uptake.

Introduction: Characterizing pathological changes in the brain that underlie cognitive impairment, including Alzheimer's disease and related disorders, is central to clinical concerns of prevention, diagnosis, and treatment.

Methods: We describe the properties of a brain gray matter region ("Union Signature") that is derived from four behavior-specific, data-driven signatures in a discovery cohort.

Results: In a separate validation set, the Union Signature demonstrates clinically relevant properties. Its associations with episodic memory, executive function, and Clinical Dementia Rating Sum of Boxes are stronger than those of several standardly accepted brain measures (e.g., hippocampal volume, cortical gray matter) and other previously developed brain signatures. The ability of the Union Signature to classify clinical syndromes among normal, mild cognitive impairment, and dementia exceeds that of the other measures.

Discussion: The Union Signature is a powerful, multipurpose correlate of clinically relevant outcomes and a strong classifier of clinical syndromes.

Highlights: Data-driven brain signatures are potentially valuable in models of cognitive aging.In previous work, we outlined rigorous validation of signatures for memory.This work demonstrates a signature predicting multiple clinical measures.This could be useful in models of interventions for brain support of cognition.

Introduction: The geroscience hypothesis proposes systemic biological aging is a root cause of cognitive decline.

Methods: We analyzed Framingham Heart Study Offspring Cohort data (n = 2296; 46% male; baseline age M = 62, SD = 9, range = 25-101 y). We measured cognitive decline across two decades of neuropsychological-testing follow-up. We measured pace of aging using the DunedinPACE epigenetic clock. Analysis tested if participants with faster DunedinPACE values experienced more rapid cognitive decline compared with those with slower DunedinPACE values.

Results: Participants with faster DunedinPACE had poorer cognitive functioning at baseline and experienced more rapid cognitive decline over follow-up. Results were robust to confounders and consistent across population strata. Findings were similar for the PhenoAge and GrimAge epigenetic clocks.

Discussion: Faster pace of aging is a risk factor for preclinical cognitive decline. Metrics of biological aging may inform risk stratification in clinical trials and prognosis in patient care.

Highlights: Faster DunedinPACE is associated with preclinical cognitive aging.Higher baseline cognition was protective of DunedinPACE-associated cognitive decline.The DunedinPACE association with cognitive decline explained a fourth of dementia risk.

Introduction: Genetics of cerebral amyloid angiopathy (CAA) remains understudied.

Methods: We assessed variants in Alzheimer's disease (AD) risk factor genes and differential diagnosis genes by performing exome sequencing among 78 patients with early-onset definite or probable CAA, after negative screening for APP mutation or duplication.

Results: Among 14 genes involved in non-Aβ CAA, or vascular leukoencephalopathies, we detected pathogenic NOTCH3 variants in two patients, who exhibited lobar hematomas at the ages of 58 and 65, leading to a diagnosis redirection toward CADASIL. Of the remaining 76 patients, 23.1% carried at least one apolipoprotein E (APOE) ε2 allele and 43.6% carried at least one APOE ε4 allele, known as CAA risk factors. A total of 15 out of 76 (19.7%) carried either a loss-of-function or a rare predicted damaging missense or known AD risk variant in SORL1, TREM2, ABCA7, ABCA1, and ATP8B4.

Discussion: Exome sequencing allowed the redirection toward CADASIL in two patients and suggested shared genetic factors between AD and CAA, beyond the APOE gene.

Highlights: The genetic component of cerebral amyloid angiopathy (CAA) remains understudied.Rare differential diagnoses such as CADASIL should be considered, even in cases of cerebral hemorrhage.Our study suggests shared genetic factors between AD and CAA, beyond the APOE gene.Rare variants in SORL1, TREM2, ABCA7, ABCA1 and ATP8B4 might be susceptibility factors in early-onset CAA.

Introduction: Both micro- and macrostructural white matter (WM) abnormalities, particularly those related to axonal degeneration, are associated with cognitive decline in adults with Down syndrome (DS) prior to a diagnosis of Alzheimer disease. Neurofilament light chain (NfL) is a support protein within myelinated axons released into blood following axonal damage. In this study we investigated cross-sectional relationships between WM microstructural changes as measured by diffusion tensor imaging (DTI) and plasma NfL concentration in adults with DS without dementia.

Methods: Thirty cognitively stable (CS) adults with DS underwent diffusion-weighted MRI scanning and plasma NfL measurement. DTI measures of select WM tracts were derived using automatic fiber tracking, and associations with plasma NfL were assessed using Spearman correlation coefficients.

Results: Higher Plasma NfL was associated with greater altered diffusion measures of select tracts.

Discussion: Early increases in plasma NfL may reflect early white matter microstructural changes prior to dementia in DS.

Highlights: The onset of such WM changes in DS has not yet been widely studied.WM microstructural properties correlated with plasma neurofilament light chain (NfL).NfL may reflect early, selective WM changes in adults with DS at high risk of developing AD.

Introduction: We evaluated short versions of a 16-item odor identification (OID) test, with regard to their ability to identify individuals at high dementia risk.

Methods: Participants from the population-based SNAC-K study (n = 2418) were followed across 12 years. We formed 13 abbreviated clusters based on the identifiability and perceptual characteristics of the Sniffin' Sticks Test (SST) items, and pre-existing test versions. Dementia hazard was estimated with Cox regressions.

Results: Lower OID scores were associated with an increased dementia hazard across all odor clusters. Lower performance in the high identifiability cluster showed the strongest association with dementia (hazard ratio = 1.39, 95% confidence interval [1.28-1.51]). Moreover, the high-intensity odor cluster showed a stronger association with dementia than the low-intensity cluster (P = 0.02).

Discussion: The findings suggest that the SST items differ with regard to their association with dementia and support using a reduced set size for clinical practice.

Highlights: Odor identification (OID) items differ in their association with future dementia.Reduced OID set sizes render hazard ratios comparable to larger set sizes.Identifiability and perceptual characteristics of odors should be considered when designing dementia screening instruments.