Distinct transcriptional changes distinguish efficient and poor remyelination in multiple sclerosis.

Multiple sclerosis (MS) is a highly heterogeneous disease with varying remyelination potential across individuals and between lesions. However, the molecular mechanisms underlying the potential to remyelinate remain poorly understood. In this study, we aimed to take advantage of the intrinsic heterogeneity in remyelinating capacity between MS donors and lesions to uncover known and novel pro-remyelinating molecules for MS therapies.

Cortical CD200-CD200R and CD47-SIRPα expression is associated with multiple sclerosis pathology.

Control of microglia activity through CD200-CD200R and CD47-SIRPα interactions has been implicated in brain homeostasis. Here, we assessed CD200, CD47, CD200R and SIRPα expression with qPCR and immunohistochemistry in multiple sclerosis (MS) normal-appearing cortical grey matter (NAGM), normal-appearing white matter (NAWM), cortical grey matter (GM) lesions and perilesional GM, and compared this to control GM and white matter (WM), to investigate possible altered control of microglia in MS. In MS NAGM, CD200 expression is lower compared with control GM, specifically in cortical layers 1 and 2, and CD200 expression in NAGM negatively correlates with the cortical lesion rate.

Modification of T- and B-cell-associated immuno-pathologic mechanisms in multiple sclerosis by disease modifying therapies: Achievements and opportunities.

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS), which can clinically manifest as attacks of neurologic disability and new lesion formation, and a progression of sustained neurologic disability over time. In MS, activated B and T cells are recruited from outside the CNS, and contribute to inflammation, demyelination, and tissue damage inside the brain parenchyma. In the last decades, the treatment of MS has improved by the introduction of several disease-modifying therapies (DMTs).

Disentangling the heterogeneity of multiple sclerosis through identification of independent neuropathological dimensions.

Multiple sclerosis (MS) is a heterogeneous neurological disorder with regards to clinical presentation and pathophysiology. Here, we investigated the heterogeneity of MS by performing an exploratory factor analysis on quantitative and qualitative neuropathology data collected for 226 MS donors in the Netherlands Brain Bank autopsy cohort. Three promising dimensions were identified and subsequently validated with clinical, neuropathological, and genetic data.

Reporting Psychiatric Disease Characteristics in Post-Mortem- and Biological Research.

Inflammation is a prominent hypothesis in the neurobiology of depression. In our transcriptomic profiling study of microglia in chronic major depressive disorder (MDD), we revealed a distinct disease-associated microglia (DAM) transcriptomic profile exclusively found in cortical gray matter, that we have designated DepDAM. These DepDAM revealed an immune-suppressed state, with a possible upstream mechanism for microglial suppression, by upregulation of CD200 and CD47 ("don't eat me signals") located on synapses.

Gene-expression profiling of individuals resilient to Alzheimer's disease reveals higher expression of genes related to metallothionein and mitochondrial processes and no changes in the unfolded protein response.

Some individuals show a discrepancy between cognition and the amount of neuropathological changes characteristic for Alzheimer's disease (AD). This phenomenon has been referred to as 'resilience'. The molecular and cellular underpinnings of resilience remain poorly understood.

The concept of resilience to Alzheimer's Disease: current definitions and cellular and molecular mechanisms.

Some individuals are able to maintain their cognitive abilities despite the presence of significant Alzheimer's Disease (AD) neuropathological changes. This discrepancy between cognition and pathology has been labeled as resilience and has evolved into a widely debated concept. External factors such as cognitive stimulation are associated with resilience to AD, but the exact cellular and molecular underpinnings are not completely understood.

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.

Profiling of microglia nodules in multiple sclerosis reveals propensity for lesion formation.

Microglia nodules (HLA-DR cell clusters) are associated with brain pathology. In this post-mortem study, we investigated whether they represent the first stage of multiple sclerosis (MS) lesion formation. We show that microglia nodules are associated with more severe MS pathology.

Disease stage-dependent changes in brain levels and neuroprotective effects of neuroactive steroids in Parkinson's disease.

Neuroactive steroids are known neuroprotective agents and neurotransmitter regulators. We previously found that expression of the enzymes synthesizing 5α-dihydroprogesterone (5α-DHP), allopregnanolone (ALLO), and dehydroepiandrosterone sulfate (DHEAS) were reduced in the substantia nigra (SN) of Parkinson's Disease (PD) brain. Here, concentrations of a comprehensive panel of steroids were measured in human post-mortem brains of PD patients and controls.

Microglia Transcriptional Profiling in Major Depressive Disorder Shows Inhibition of Cortical Gray Matter Microglia.

Background: Microglia have been implicated in the pathophysiology of major depressive disorder (MDD), but information on biological mechanisms is limited. Therefore, we investigated the gene expression profile of microglial cells in relation to neuronal regulators of microglia activity in well-characterized MDD and control autopsy brains.

Methods: Pure, intact microglia were isolated at brain autopsy from occipital cortex gray matter (GM) and corpus callosum white matter of 13 donors with MDD and 10 age-matched control donors for RNA sequencing.

Osteopontin associates with brain T-cell transcriptome and compartmentalization in donors with and without multiple sclerosis.

The human brain is populated by perivascular T cells with a tissue-resident memory T (T)-cell phenotype, which in multiple sclerosis (MS) associate with lesions. We investigated the transcriptional and functional profile of freshly isolated T cells from white and gray matter. RNA sequencing of CD8 and CD4 CD69 T cells revealed T-cell signatures.

Ultrastructural Axon-Myelin Unit Alterations in Multiple Sclerosis Correlate with Inflammation.

Objective: Changes in the normal-appearing white matter (NAWM) in multiple sclerosis (MS) may contribute to disease progression. Here, we systematically quantified ultrastructural and subcellular characteristics of the axon-myelin unit in MS NAWM and determined how this correlates with low-grade inflammation.

Methods: Human brain tissue obtained with short postmortem delay and fixation at autopsy enables systematic quantification of ultrastructural characteristics.

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.

Tissue donations for multiple sclerosis research: current state and suggestions for improvement.

Although major progress in multiple sclerosis research has been made during the last decades, key questions related to the cause and the mechanisms of brain and spinal cord pathology remain unresolved. These cover a broad range of topics, including disease aetiology, antigenic triggers of the immune response inside and/or outside the CNS and mechanisms of inflammation, demyelination neurodegeneration and tissue repair. Most of these questions can be addressed with novel molecular technologies in the injured CNS.

Common Microscale and Macroscale Principles of Connectivity in the Human Brain.

The brain requires efficient information transfer between neurons and large-scale brain regions. Brain connectivity follows predictable organizational principles. At the cellular level, larger supragranular pyramidal neurons have larger, more branched dendritic trees, more synapses, and perform more complex computations; at the macroscale, region-to-region connections display a diverse architecture with highly connected hub areas facilitating complex information integration and computation.

Neurofilament Light Chain Levels in Multiple Sclerosis Correlate With Lesions Containing Foamy Macrophages and With Acute Axonal Damage.

Background And Objectives: To investigate whether white matter lesion activity, acute axonal damage, and axonal density in MS associate with CSF neurofilament light chain (NfL) levels.

Methods: Of 101 brain donors with MS (n = 92 progressive MS, n = 9 relapsing-remitting MS), ventricular CSF was collected, and NfL levels were measured. White matter lesions were classified as active, mixed, inactive, or remyelinated, and microglia/macrophage morphology in active and mixed lesions was classified as ramified, ameboid, or foamy.

Accumulation of meningeal lymphocytes correlates with white matter lesion activity in progressive multiple sclerosis.

Subpial cortical demyelination is an important component of multiple sclerosis (MS) pathology contributing to disease progression, yet mechanism(s) underlying its development remain unclear. Compartmentalized inflammation involving the meninges may drive this type of injury. Given recent findings identifying substantial white matter (WM) lesion activity in patients with progressive MS, elucidating whether and how WM lesional activity relates to meningeal inflammation and subpial cortical injury is of interest.

The stress-axis in multiple sclerosis: Clinical, cellular, and molecular aspects.

Altered activity of the hypothalamus-pituitary-adrenal (HPA) stress-axis has been implicated in the pathogenesis and progression of multiple sclerosis (MS) and linked to the development of specific symptoms and comorbidities such as mood disorders, fatigue, or cognitive dysfunction. Overall the HPA-axis is activated or hyperresponsive in MS, though a hyporesponsive HPA-axis has been observed in a subgroup of MS patients that has a more severe course of the disease. Here we provide an overview of the possible causes of HPA-axis activation, sex- and subtype dependent differences, pathological, cellular, and molecular effects, and the clinical correlates of HPA-axis activity in MS.

Complement-associated loss of CA2 inhibitory synapses in the demyelinated hippocampus impairs memory.

The complement system is implicated in synapse loss in the MS hippocampus, but the functional consequences of synapse loss remain poorly understood. Here, in post-mortem MS hippocampi with demyelination we find that deposits of the complement component C1q are enriched in the CA2 subfield, are linked to loss of inhibitory synapses and are significantly higher in MS patients with cognitive impairments compared to those with preserved cognitive functions. Using the cuprizone mouse model of demyelination, we corroborated that C1q deposits are highest within the demyelinated dorsal hippocampal CA2 pyramidal layer and co-localized with inhibitory synapses engulfed by microglia/macrophages.

GPCRomics of Homeostatic and Disease-Associated Human Microglia.

G-protein-coupled receptors (GPCRs) are critical sensors affecting the state of eukaryotic cells. To get systematic insight into the GPCRome of microglia, we analyzed publicly available RNA-sequencing data of bulk and single cells obtained from human and mouse brains. We identified 17 rhodopsin and adhesion family GPCRs robustly expressed in microglia from human brains, including the homeostasis-associated genes , , , , , and .

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.