Alzheimer's & Dementia最新文献

INTRODUCTION

The molecular mechanisms underlying early-onset Alzheimer's disease (EOAD) and late-onset Alzheimer's disease (LOAD) remain incompletely understood, particularly in Asian populations.

METHODS

RNA-sequencing was carried out on blood samples from 248 participants in the Seoul National University Bundang Hospital cohort to perform differential gene expression (DGE) and weighted gene co-expression network analysis. Findings were replicated in an independent Korean cohort (N = 275).

RESULTS

DGE analysis identified 18 and 88 dysregulated genes in EOAD and LOAD, respectively. Network analysis identified a LOAD-associated module showing a significant enrichment in pathways related to mitophagy, 5′ adenosine monophosphate-activated protein kinase signaling, and ubiquitin-mediated proteolysis. In the replication cohort, downregulation of SMOX and PLVAP in LOAD was replicated, and the LOAD-associated module was highly preserved. In addition, SMOX and PLVAP were associated with brain amyloid beta deposition.

DISCUSSION

Our findings suggest distinct molecular signatures for EOAD and LOAD in a Korean population, providing deeper understanding of their diagnostic potential and molecular mechanisms.

Highlights

INTRODUCTION

Chinese women experience higher dementia rates than men, yet sex-specific risk factors are understudied. We examined how menopause age affects cognitive function and decline in aging Chinese women.

METHODS

Data were from 7419 postmenopausal women 45–101 years of age at baseline in the China Health and Retirement Longitudinal Study (CHARLS; 2011–2018). Menopause age was categorized using clinical cutoffs (<40, 40–44, 45–49, 50–55, >55 years). Cognitive function was assessed with neuropsychological tests up to four times over 7 years, and associations were analyzed using multivariable-adjusted linear mixed-effects regression.

RESULTS

Compared to menopause at 50–55 years (3661/7419; 49.3%), premature (<40; 235/7419; 3.2%), early (40–44; 623/7419; 8.4%), and late menopause (>55; 366/7419; 4.9%) were associated with lower baseline cognitive scores. Although the rate of cognitive decline did not differ significantly across menopause age groups, late menopause showed a trend toward faster decline.

DISCUSSION

Cognitive health interventions should consider extreme menopausal age as a risk factor.

Highlights

INTRODUCTION

Tau pathology impacts neurodegeneration and cognitive decline in Alzheimer's disease (AD), with the dorsal raphe nucleus (DRN) being among the brain regions showing the earliest tau pathology. As a serotonergic hub, DRN activity is altered by selective serotonin reuptake inhibitors (SSRIs), which also have variable effects on cognitive decline and pathology in AD.

METHODS

We examined N = 191 subjects with baseline ¹⁸F-fluorodeoxyglucose positron emission tomography and plasma biomarker data to study the effects of SSRIs on tau pathology, cognitive decline, and DRN metabolism.

RESULTS

Plasma phosphorylated tau 181 (p-tau181) was lower with SSRI use. The effect of SSRIs on cognition varied by cognitive assessment. The DRN was hypometabolic in AD patients relative to healthy controls; however, SSRI use restored the metabolic activity of this region in AD patients.

DISCUSSION

Long-term SSRI use may reduce the pathological presentation of AD but has variable effects on cognitive performance.

Highlights

The characteristic events in neurodegenerative diseases (NDDs) encompass protein misfolding, aggregation, accumulation, and their related cellular dysfunction, synaptic function loss. While distinct proteins are implicated in the pathological processes of different NDDs, the process of protein misfolding and aggregation remains notably similar across various conditions. Specifically, proteins undergo misfolding into beta-folded (β-folded) conformation, resulting in the formation of insoluble amyloid proteins. Despite advancements in comprehending protein aggregation, certain facets of this intricate process remain incompletely elucidated. In recent years, the concept that long non-coding RNAs (lncRNAs) contribute to protein aggregation has gained recognition. LncRNAs influence the formation of protein aggregates by facilitating protein overexpression through the regulation of gene transcription and translation, inhibiting protein degradation via lysosomal and autophagic pathways, and targeting aberrant modifications and phase transitions of proteins. A better understanding of the relationship between lncRNAs and aberrant protein aggregation is an important step in dissecting the underlying molecular mechanisms and will contribute to the discovery of new therapeutic targets and strategies.

Highlights

INTRODUCTION

Modeling the survival rate in syndromes associated with frontotemporal lobar degeneration (FTLD) is essential to assess disease trajectories.

METHODS

In 262 patients with FTLD, we considered plasma neurofilament light chain (NfL), glial fibrillary acidic protein, brain-derived tau, phosphorylated tau217 and amyloid beta (Aβ42/Aβ40). The FTLD Survival Score (FTLD-SS) was calculated by the β coefficients of the variables independently associated with survival rate.

RESULTS

Increased plasma NfL levels (p < 0.001), older age at evaluation (p = 0.002), positive family history (p = 0.04), and motor phenotypes (p < 0.001) were associated with reduced survival. The predictive validity of FTLD-SS was 0.75 (95% confidence interval, 0.59–0.91) at 1 year.

DISCUSSION

Survival rate in FTLD is shaped by intensity of neurodegeneration (using plasma NfL as proxy) together with certain clinical variables. The FTLD-SS may serve as a simple tool for survival rate estimation and for patient stratification in clinical trials.

Highlights

BACKGROUND

Alzheimer's disease-related biomarkers detect pathology years before symptoms emerge, when disease-modifying therapies might be most beneficial. Remote cognitive testing provides a means of assessing early cognitive changes. We explored the relationship between neurodegenerative biomarkers and cognition in cognitively normal individuals.

METHODS

We remotely deployed 13 computerized Cognitron tasks in 255 Insight 46 participants. We generated amyloid load and positivity, white matter hyperintensity volume (WMHV), whole brain and hippocampal volumes at age 73, plus rates of change over 2 years. We examined the relationship between Cognitron, biomarkers, and standard neuropsychological tests.

RESULTS

Slower response time on a delayed recognition task predicted amyloid positivity (odds ratio [OR] = 1.79, confidence interval [CI]: 1.15, 2.95), and WMHV (1.23, CI: 1.00, 1.56). Brain and hippocampal atrophy rates correlated with poorer visuospatial performance (b = -0.42, CI: -0.80, -0.05) and accuracy on immediate recognition (b = -0.01, CI: -0.012, -0.001), respectively. Standard tests correlated with Cognitron composites (rho = 0.50, p < 0.001).

DISCUSSION

Remote computerized testing correlates with standard supervised assessments and holds potential for studying early cognitive changes associated with neurodegeneration.

Highlights

BACKGROUND

Despite significant astrocytic involvement in Parkinson's disease (PD), the knowledge regarding the role of reactive astrogliosis is still at the surface level; largely due to lack of specific biomarkers to track these processes. Novel astroglial PET-tracers BU99008 and Deprenyl, hold immense potential for visualizing reactive astrogliosis in PD.  However, they have not been thoroughly investigated in PD.

METHODS

We employed a multi-marker approach and performed in vitro radioligand binding and autoradiography studies with ³H-BU99008 and ³H-Deprenyl together with astrocytic immunofluorescence and morphometric analyses in the frontal cortex, temporal cortex, caudate and putamen brain regions of PD (n = 4) and control (n = 7) cases.

RESULTS AND DISCUSSION

³H-BU99008 and ³H-Deprenyl showed distinct binding behavior and displayed a diverse array of binding sites (single or multiple) in PD and control brains. Importantly, ³H-BU99008 and ³H-Deprenyl autoradiography studies captured pronounced reactive astrogliosis in PD brain regions, corroborated by marked changes in astrocytic markers, morphology, and cellular processes.

Highlights

INTRODUCTION

One of the pathological hallmarks of Alzheimer's disease (AD) is the accumulation of amyloid beta 42 (Aβ42). Decreased venous drainage may enhance Aβ42 accumulation. We aimed to compare venous cross-sectional area (CSA) of AD patients to cognitively healthy controls.

METHODS

All patients underwent neurocognitive evaluation and brain magnetic resonance imaging, including time-of-flight sequence. Venous CSA was measured at the jugular foramen level.

RESULTS

Thirty-nine AD/mild cognitive impairment patients and 20 cognitively healthy controls were included. Total venous CSA was smaller in the cognitively impaired group (mean CSA 139.77 mm² [SD: 32.22] vs 166.55 mm² [SD: 33.1], p = 0.004]. When divided, both internal jugular and non-jugular systems were smaller within cognitively impaired patients; statistical significance was achieved only for the non-jugular system (mean CSA 41.21 mm² [SD: 21.52] vs 54.5 mm² [SD: 27.31], p = 0.045).

DISCUSSION

There is an association between smaller venous systems and cognitive impairment, most prominently in the non-jugular system. Venous narrowing may cause impaired venous drainage, leading to an accumulation of Aβ42.

Highlights

Understanding of the biology of Alzheimer's disease (AD) has long been fragmented, with various investigators concentrating on amyloid beta (Aβ) or tau, inflammation, cell death pathways, misfolded proteins, glia, and more. Yet data from multiple authors has repeatedly shown altered expression of myriad genes related to these seemingly disparate phenomena. In 2022, Morgan et al. organized the massive data on changes in AD in a meticulous survey of the literature and related these changes to Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Their data showed that 91% of the known KEGG pathways are involved in AD and that many of these pathways are represented by the known cellular/molecular phenomena of AD. Such data then raise the fundamental question: What mechanism(s) may be responsible for such widespread changes in gene expression? We review evidence for a unifying model based on sequestrations in stress granules and alteration of nucleocytoplasmic transport in AD.

Highlights