進行性白質脳症

BACKGROUND: Progressive cognitive impairment in vascular dementia (VaD) is increasingly linked to brain network disruption, or "disconnection syndrome." Although Compound Congrong Yizhi Capsule (CCYC), a marketed Chinese patent medicine approved in China for vascular cognitive disorders, has been studied in terms of therapeutic efficacy and molecular targets, these approaches do not directly explain how this multi-target intervention modulates brain functional organization. Resting-state functional magnetic resonance imaging (rs-fMRI) enables in vivo characterization of BOLD-based brain network functional phenotypes. Here, we used rs-fMRI to investigate the effects of CCYC in a rat model of VaD. METHODS: VaD was induced by permanent bilateral common carotid artery occlusion (BCCAO) in rats. CCYC was administered by gavage for 6 weeks. Spatial navigation and memory retention were assessed using the Morris water maze (MWM). Resting-state fMRI was acquired on a 9.4 T scanner and analyzed using regional activity metrics, behavioral correlations, functional connectivity, and graph theoretical analyses. RESULTS: VaD rats showed abnormal regional activity in the frontal cortex, retrosplenial cortex, and hippocampal system, which were associated with impaired MWM performance. They also exhibited disrupted connectivity within the fronto-retrosplenial-hippocampal memory circuit, particularly between prefrontal/cingulate and retrosplenial-hippocampal regions. CCYC treatment was associated with partial normalization of these regional and circuit-level abnormalities. Graph theoretical analyses further showed partial improvement in whole-brain topological organization and nodal properties after CCYC treatment. These findings do not establish anatomical restoration of the underlying white matter tracts. CONCLUSION: CCYC may ameliorate VaD by modulating a systems-level neuroimaging phenotype centered on the fronto-retrosplenial-hippocampal memory circuit.

Programmed cell death protein 1 (PD-1) is expressed by T cells during progressive multifocal leukoencephalopathy (PML), a life-threatening brain disease caused by the human-only JC polyomavirus (JCPyV). PD-1 checkpoint immunotherapy has benefited some PML patients, but reasons for its variable outcomes are unclear. Using mouse polyomavirus (MuPyV), we show that PD-1 loss acts in a brain-autonomous manner to increase the magnitude of brain-infiltrating CD4+ and CD8+ T cells and the function of virus-specific CD8+ T cells; in concert, brain virus levels decline and neuroinflammation increases. Deletion of PD-1 in CD4+ T cells, but not CD8+ T cells, recapitulates effects of global PD-1 loss. Single-cell RNA sequencing shows that PD-1-deficient CD8+ T cells cluster as effectors while transcripts associated with proliferation and function are upregulated with loss of PD-1. Thus, CD4+ T cell-intrinsic PD-1 signaling balances antiviral defense against neural injury during polyomavirus infection of the brain.

Vascular dementia (VaD) is the second most prevalent form of dementia after Alzheimer's disease and is primarily driven by chronic cerebral hypoperfusion and neurovascular dysfunction. Growing evidence indicates that immune dysregulation and neuroglial-vascular injury play critical roles in disease progression; however, the molecular regulators underlying these processes remain insufficiently characterized. This study aimed to delineate immune heterogeneity and neuroglial-vascular alterations in VaD and to identify key regulatory targets involved in disease pathogenesis. Bulk RNA sequencing data (GSE122063) and single-cell transcriptomic data (GSE282111) were retrieved from the Gene Expression Omnibus database and integratively analyzed to characterize immune infiltration patterns and cellular dysregulation. Immune profiling was performed using CIBERSORT and single-sample gene set enrichment analysis. Disease-associated cell subsets and hub genes were identified using Seurat, Scissor, and high-dimensional weighted gene co-expression network analysis (hdWGCNA). Pseudotime trajectory analysis and molecular docking were subsequently applied to investigate gene expression dynamics and potential therapeutic relevance. Bulk transcriptomic analysis revealed a pronounced pro-inflammatory shift in VaD brain tissue, characterized by increased infiltration of M1 macrophages, neutrophils, and activated dendritic cells, alongside reduced levels of M2 macrophages, resting CD4+ memory T cells, and regulatory T cells. Single-cell analysis demonstrated marked loss of oligodendrocytes, astrocytes, and endothelial cells in VaD. Scissor integration showed positive associations between VaD and oligodendrocytes, astrocytes, and endothelial cells, whereas microglia and oligodendrocyte progenitor cells were negatively associated. hdWGCNA identified 3 co-expression modules; intersection of the blue module with bulk differentially expressed genes highlighted DOCK3, ELF2, and Sin3A associated protein 25, with ELF2 uniquely co-expressed across relevant cell types. Pseudotime analysis indicated sustained downregulation of ELF2 during VaD-related cellular differentiation. Molecular docking analysis suggested strong binding affinities between ELF2 and nicergoline (-7.23 kcal/mol), nimodipine (-6.92 kcal/mol), and donepezil (-6.29 kcal/mol). This integrative transcriptomic study reveals disrupted immune balance and neuroglial-vascular cell homeostasis in vascular dementia, and prioritizes ELF2 as a candidate regulator associated with immune heterogeneity in VaD.