Total Tau Protein Mediates the Association of Ischemic Cerebrovascular Disease with Cognitive Decline.

Background: Patients with transient ischemic attack (TIA) or ischemic stroke demonstrate an increased risk of cognitive dysfunction. Accumulating evidence indicates that ischemic cerebrovascular disease (ICVD) may interact with the amyloid/tau/neurodegeneration (AT[N]) biomarkers to promote dementia. However, the precise pathological mechanisms remain to be fully characterized. Objective: To elucidate the interrelationships among ICVD, ATN biomarkers in cerebrospinal fluid (CSF), and cognition. Methods: A total of 2524 participants were recruited from the CABLE study. ICVD referred to TIA/ischemic stroke. Cognitive performance was assessed by China Modified Mini-Mental State Examination (CM-MMSE) and Montreal Cognitive Assessment-b (MoCA-b). Multivariate linear regression analyses were performed to evaluate the associations of ICVD with CSF ATN biomarkers and cognition. Causal mediation analyses were used to identify whether the association was mediated by ATN biomarkers. Results: ICVD was associated with higher total-tau (t-tau) (p = 2.828×10-2) and poorer cognition (CM-MMSE: p = 1.539×10-5, MoCA-b: p = 4.552×10-6). Additionally, no discernible correlation surfaced between ICVD and amyloid-ß (Aß) 42 (p = 6.910×10-1) or phosphorylated tau (p-tau) (p = 4.324×10-1). The influence of ICVD on cognitive function was partially mediated by CSF t-tau (CM-MMSE: proportion: 2.74%, MoCA-b: proportion: 2.51%). Subgroup analyses revealed the influences of t-tau were especially evident in male (CM-MMSE: proportion: 5.45%, MoCA-b: proportion: 5.38%) and mid-life group (CM-MMSE: proportion: 9.83%, MoCA-b: proportion: 5.31%). Conclusions: These results delineated t-tau as a potential mediator for the influence of ICVD on cognition. Targeting brain ischemia and alleviating neuronal injury induced by ischemia may be a promising approach for preventing cognitive decline.

Associations of Frailty with Neuropsychiatric Symptoms of Alzheimer's Disease: A Longitudinal Study.

Background: Frailty is a vulnerability state increasing the risk of many adverse health outcomes, but little is known about the effects of frailty on neuropsychiatric health. Objective: To explore the associations between frailty and the risk of neuropsychiatric symptoms (NPSs) in Alzheimer's disease (AD), especially in its different clinical stages. Methods: We included 2,155 individuals assessed using modified frailty index-11 (mFI-11), Neuropsychiatric Inventory (NPI) and Neuropsychiatric Inventory Questionnaire (NPI-Q) in the Alzheimer's Disease Neuroimaging Initiative (ADNI). The relationships between frailty and NPSs were explored with logistic regression models and Cox proportional hazard regression models. Causal mediation analyses were conducted to explore the mediation factors between frailty and NPSs. Results: Among mild cognitive impairment (MCI) participants, frailty was cross-sectionally associated with an increased risk of apathy, and longitudinally associated with increased risk of depression and apathy. Among AD participants, frailty was cross-sectionally associated with increased risk of depression and anxiety, and longitudinally associated with an increased risk of apathy. Among participants with cognitive progression, frailty was associated with increased risk of depression and apathy. In MCI participants, the influence of frailty on NPSs was partially mediated by hippocampus volume, whole brain volume, and monocytes, with mediating proportions ranging from 8.40% to 9.29%. Conclusions: Frailty was associated with NPSs such as depression, anxiety, and apathy among MCI, AD, and cognitive progression participants. Atrophy of the hippocampus and whole brain, as well as peripheral immunity may be involved in the potential mechanisms underlying the above associations.

Genetic susceptibility modifies the association of long-term air pollution exposure on Parkinson's disease.

Inconsistent findings exist regarding the potential association between polluted air and Parkinson's disease (PD), with unclear insights into the role of inherited sensitivity. This study sought to explore the potential link between various air pollutants and PD risk, investigating whether genetic susceptibility modulates these associations. The population-based study involved 312,009 initially PD-free participants with complete genotyping data. Annual mean concentrations of PM2.5, PM10, NO2, and NOx were estimated, and a polygenic risk score (PRS) was computed to assess individual genetic risks for PD. Cox proportional risk models were employed to calculate hazard ratios (HR) and 95% confidence intervals (CI) for the associations between ambient air pollutants, genetic risk, and incident PD. Over a median 12.07-year follow-up, 2356 PD cases (0.76%) were observed. Compared to the lowest quartile of air pollution, the highest quartiles of NO2 and PM10 pollution showed HRs and 95% CIs of 1.247 (1.089-1.427) and 1.201 (1.052-1.373) for PD incidence, respectively. Each 10 µg/m3 increase in NO2 and PM10 yielded elevated HRs and 95% CIs for PD of 1.089 (1.026-1.155) and 1.363 (1.043-1.782), respectively. Individuals with significant genetic and PM10 exposure risks had the highest PD development risk (HR: 2.748, 95% CI: 2.145-3.520). Similarly, those with substantial genetic and NO2 exposure risks were over twice as likely to develop PD compared to minimal-risk counterparts (HR: 2.414, 95% CI: 1.912-3.048). Findings suggest that exposure to air contaminants heightens PD risk, particularly in individuals genetically predisposed to high susceptibility.