Changes in glial gene expression in the prefrontal cortex in relation to major depressive disorder, suicide and psychotic features

BACKGROUND: To establish whether major depressive disorder (MDD), suicidal behaviors and psychotic features contribute to glial alterations in the human prefrontal cortex. MATERIALS AND METHODS: We compared mRNA expression using real-time qPCR of 17 glia related genes in the dorsolateral prefrontal cortex (DLPFC) and the anterior cingulate cortex (ACC) between 24 patients with MDD and 12 well-matched controls without psychiatric or neurological diseases. The MDD group was subdivided into i) MDD who died of suicide (MDD-S) or natural causes (MDD-NS) and ii) MDD with or without psychotic features (MDD-P and MDD-NP). The results were followed up with confounder factor analysis. RESULTS: Astrocyte gene aldehyde dehydrogenase-1 L1 (ALDH1L1) showed an increased expression in the DLPFC of MDD-NS and the ACC of MDD-NP. S100 calcium-binding protein B (S100B) was upregulated in the DLPFC of MDD compared to the controls. Microglial markers CD11B and purinergic receptor 12 (P2RY12) both showed decreased expression in the ACC of MDD-NS. CD68 was increased in the DLPFC of MDD in both, MDD-S and MDD-P, compared to the controls. In addition, there was increased translocator protein (TSPO) expression in the DLPFC of MDD, especially MDD-NS. In the ACC, this gene had a lower expression in MDD-P than in MDD-NP. Myelin basic protein (MBP) mRNA in the DLPFC increased in MDD, in relation to psychotic features, but not to suicide. LIMITATIONS: Sample volumes are relatively small. CONCLUSIONS: Different glial functions in MDD were related to specific brain area, suicide or psychotic features

Identification of clinical disease trajectories in neurodegenerative disorders with natural language processing

Neurodegenerative disorders exhibit considerable clinical heterogeneity and are frequently misdiagnosed. This heterogeneity is often neglected and difficult to study. Therefore, innovative data-driven approaches utilizing substantial autopsy cohorts are needed to address this complexity and improve diagnosis, prognosis and fundamental research. We present clinical disease trajectories from 3,042 Netherlands Brain Bank donors, encompassing 84 neuropsychiatric signs and symptoms identified through natural language processing. This unique resource provides valuable new insights into neurodegenerative disorder symptomatology. To illustrate, we identified signs and symptoms that differed between frequently misdiagnosed disorders. In addition, we performed predictive modeling and identified clinical subtypes of various brain disorders, indicative of neural substructures being differently affected. Finally, integrating clinical diagnosis information revealed a substantial proportion of inaccurately diagnosed donors that masquerade as another disorder. The unique datasets allow researchers to study the clinical manifestation of signs and symptoms across neurodegenerative disorders, and identify associated molecular and cellular features

Conservation and divergence of myelin proteome and oligodendrocyte transcriptome profiles between humans and mice

Human myelin disorders are commonly studied in mouse models. Since both clades evolutionarily diverged approximately 85 million years ago, it is critical to know to what extent the myelin protein composition has remained similar. Here, we use quantitative proteomics to analyze myelin purified from human white matter and find that the relative abundance of the structural myelin proteins PLP, MBP, CNP, and SEPTIN8 correlates well with that in C57Bl/6N mice. Conversely, multiple other proteins were identified exclusively or predominantly in human or mouse myelin. This is exemplified by peripheral myelin protein 2 (PMP2), which was specific to human central nervous system myelin, while tetraspanin-2 (TSPAN2) and connexin-29 (CX29/GJC3) were confined to mouse myelin. Assessing published scRNA-seq-datasets, human and mouse oligodendrocytes display well-correlating transcriptome profiles but divergent expression of distinct genes, including Pmp2, Tspan2, and Gjc3. A searchable web interface is accessible via www.mpinat.mpg.de/myelin. Species-dependent diversity of oligodendroglial mRNA expression and myelin protein composition can be informative when translating from mouse models to humans

Tissue-resident memory T cells invade the brain parenchyma in multiple sclerosis white matter lesions

Multiple sclerosis is a chronic inflammatory, demyelinating disease, although it has been suggested that in the progressive late phase, inflammatory lesion activity declines. We recently showed in the Netherlands Brain Bank multiple sclerosis-autopsy cohort considerable ongoing inflammatory lesion activity also at the end stage of the disease, based on microglia/macrophage activity. We have now studied the role of T cells in this ongoing inflammatory lesion activity in chronic multiple sclerosis autopsy cases. We quantified T cells and perivascular T-cell cuffing at a standardized location in the medulla oblongata in 146 multiple sclerosis, 20 neurodegenerative control and 20 non-neurological control brain donors. In addition, we quantified CD3+, CD4+, and CD8+ T cells in 140 subcortical white matter lesions. The location of CD8+ T cells in either the perivascular space or the brain parenchyma was determined using CD8/laminin staining and confocal imaging. Finally, we analysed CD8+ T cells, isolated from fresh autopsy tissues from subcortical multiple sclerosis white matter lesions (n = 8), multiple sclerosis normal-ap

Absence of B Cells in Brainstem and White Matter Lesions Associates With Less Severe Disease and Absence of Oligoclonal Bands in MS

OBJECTIVE: To determine whether B-cell presence in brainstem and white matter (WM) lesions is associated with poorer pathological and clinical characteristics in advanced MS autopsy cases. METHODS: Autopsy tissue of 140 MS and 24 control cases and biopsy tissue of 24 patients with MS were examined for CD20+ B cells and CD138+ plasma cells. The presence of these cells was compared with pathological and clinical characteristics. In corresponding CSF and plasma, immunoglobulin (Ig) G ratio and oligoclonal band (OCB) patterns were determined. In a clinical cohort of 73 patients, the presence of OCBs was determined during follow-up and compared to status at diagnosis. RESULTS: In 34% of active and 71% of mixed active/inactive lesions, B cells were absent, which correlated with less pronounced meningeal B-cell infiltration (p < 0.0001). The absence of B cells and plasma cells in brainstem and WM lesions was associated with a longer disease duration (p = 0.001), less frequent secondary progressive MS compared with relapsing and primary progressive MS (p < 0.0001 and p = 0.046, respectively), a lower proportion of mixed active/inactive lesions (p = 0.01), and less often perivascular T-cell clustering (p < 0.0001). Moreover, a lower CSF IgG ratio (p = 0.006) and more frequent absence of OCBs (p < 0.0001) were not