Although hypertension is the leading modifiable risk factor for cerebrovascular disease, less is known about the relation of late-life change in blood pressure (BP) and cerebrovascular pathology beyond brain infarcts. Our previous work found sex-specific associations between declining systolic BP (SBP) and cognitive decline in late-life, suggesting that cerebrovascular pathology may be an upstream contributor to these sex differences. However, postmortem studies have not examined whether BP change differentially relates to vascular brain pathology in men and women, despite well-established sex differences in BP trajectories and cerebrovascular pathology. We examined associations between change in late-life BP and postmortem cerebrovascular (arteriolosclerosis, atherosclerosis, and cerebral amyloid angiopathy) pathology from 2033 community-dwelling older adults (mean baseline age = 79.7 [SD = 7.1] years; 69
The A152T point mutation is a rare genetic variant in the tau gene (MAPT) that is linked to risk of Alzheimer’s disease (AD) and frontotemporal dementia spectrum disorders, including progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). To uncover mechanisms through which the A152T variant contributes to risk of tauopathy, we performed single-nucleus RNA sequencing (snRNA-seq) on postmortem brain tissue collected from A152T carriers and pathology-matched non-carriers with either AD or PSP, along with age-matched controls. These efforts revealed that despite similar cell type composition across groups, A152T carriers exhibited distinct cell type-specific transcriptional changes in both AD and PSP. Differential expression analysis identified excitatory neurons, oligodendrocytes, and astrocytes as the most affected cell populations in AD and PSP, and these same cell types showed the strongest A152T-specific changes. These findings identify transcriptional alterations that differentiate sporadic AD and sporadic PSP from AD-A152T and PSP-A152T, as well as shared molecular signatures unique to A152T carriers in both PSP and AD. Donor-level pseudo-bulk analyses showed broad directional support with the single-nucleus findings although the proportion of donor-supported genes varied across cell type and comparison. Importantly, merging sporadic and A152T cases into a single disease group was found to mask transcriptional differences in several cell types in both AD and PSP, indicating divergence in transcriptional signature and highlighting the importance of screening for genetic risk variants like A152T in snRNA-seq data from human cohorts.
Cerebral small vessel disease (cSVD) is a leading cause of stroke and vascular cognitive impairment, yet the cellular mechanisms underlying microvascular dysfunction in human disease remain incompletely understood. In particular, the relationship between pericyte alterations and endothelial activation, two key features of blood–brain barrier dysfunction, remains unresolved. Here, we performed a quantitative single-vessel analysis of the human cortical microvasculature across increasing cSVD severity and ageing. Using multiplex immunohistochemistry combined with spectral unmixing and automated image analysis, we analysed 11,409 microvascular fragments from post-mortem brain tissue derived from 20 cases. Endothelial cells, pericytes, and endothelial activation were assessed using PECAM-1, PDGFRβ, and VCAM-1, respectively. Microvascular density and diameter differed between cortical grey matter and the underlying white matter, with white matter vessels being less dense and wider in controls. While vessel diameter remained stable across cSVD severity groups, microvascular density increased with cSVD severity and age in the white matter. At the molecular level, PDGFRβ signal decreased markedly with increasing cSVD severity, consistent with reduced pericyte coverage. This reduction was observed in both grey and white matter and correlated with disease severity and age. Notably, intermediate severity groups displayed marked heterogeneity, with vessels exhibiting either preserved or markedly reduced PDGFRβ signal. In parallel, endothelial markers PECAM-1 and VCAM-1 increased significantly with disease severity, reflecting endothelial activation. Unsupervised Gaussian mixture clustering of marker expression identified three vascular states characterised by (i) preserved PDGFRβ signal with low endothelial activation, (ii) reduced PDGFRβ signal without endothelial activation, and (iii) reduced PDGFRβ signal combined with endothelial activation. These clusters broadly aligned with neuropathological severity but revealed heterogeneity not captured by post-mortem diagnosis alone. Together, these findings suggest that pericyte alterations and endothelial activation are partially dissociated processes in human cSVD and identify distinct microvascular phenotypes across disease severity. These cross-sectional observations provide a framework for future longitudinal and experimental studies to determine their temporal and mechanistic relationships.
