New views on the complex interplay between degeneration and autoimmunity in multiple sclerosis.

Multiple sclerosis (MS) is a frequently disabling neurological disorder characterized by symptoms, clinical signs and imaging abnormalities that typically fluctuate over time, affecting any level of the CNS. Prominent lymphocytic inflammation, many genetic susceptibility variants involving immune pathways, as well as potent responses of the neuroinflammatory component to immunomodulating drugs, have led to the natural conclusion that this disease is driven by a primary autoimmune process. In this Hypothesis and Theory article, we discuss emerging data that cast doubt on this assumption.

Micro-diffusely abnormal white matter: An early multiple sclerosis lesion phase with intensified myelin blistering.

Objective: Multiple sclerosis (MS) is a chronic central nervous system disease whose white matter lesion origin remains debated. Recently, we reported subtle changes in the MS normal appearing white matter (NAWM), presenting with an increase in myelin blisters and myelin protein citrullination, which may recapitulate some of the prodromal degenerative processes involved in MS pathogenesis. Here, to clarify the relevance of these changes for subsequent MS myelin degeneration we explored their prevalence in WM regions characterized by subtly reduced myelination (dubbed as micro-diffusely abnormal white matter, mDAWM).

Longitudinal fibre-specific white matter damage predicts cognitive decline in multiple sclerosis.

During the course of multiple sclerosis, many patients experience cognitive deficits which are not simply driven by lesion number or location. By considering the full complexity of white matter structure at macro- and microstructural levels, our understanding of cognitive impairment in multiple sclerosis may increase substantially. Accordingly, this study aimed to investigate specific patterns of white matter degeneration, the evolution over time, the manifestation across different stages of the disease and their role in cognitive impairment using a novel fixel-based approach.

Isolated cognitive impairment in people with multiple sclerosis: frequency, MRI patterns and its development over time.

Objectives: To study the frequency of isolated (i.e., single-domain) cognitive impairments, domain specific MRI correlates, and its longitudinal development in people with multiple sclerosis (PwMS).

Cognitive performance in multiple sclerosis: what is the role of the gamma-aminobutyric acid system?

Cognitive impairment occurs in 40-65% of persons with multiple sclerosis and may be related to alterations in glutamatergic and GABAergic neurotransmission. Therefore, the aim of this study was to determine how glutamatergic and GABAergic changes relate to cognitive functioning in multiple sclerosis . Sixty persons with multiple sclerosis (mean age 45.

A multimodal marker for cognitive functioning in multiple sclerosis: the role of NfL, GFAP and conventional MRI in predicting cognitive functioning in a prospective clinical cohort.

Background: Cognitive impairment in people with MS (PwMS) has primarily been investigated using conventional imaging markers or fluid biomarkers of neurodegeneration separately. However, the single use of these markers do only partially explain the large heterogeneity found in PwMS.

Objective: To investigate the use of multimodal (bio)markers: i.

The longitudinal relation between executive functioning and multilayer network topology in glioma patients.

Many patients with glioma, primary brain tumors, suffer from poorly understood executive functioning deficits before and/or after tumor resection. We aimed to test whether frontoparietal network centrality of multilayer networks, allowing for integration across multiple frequencies, relates to and predicts executive functioning in glioma. Patients with glioma (n = 37) underwent resting-state magnetoencephalography and neuropsychological tests assessing word fluency, inhibition, and set shifting before (T1) and one year after tumor resection (T2).

Investigating Functional Network Abnormalities and Associations With Disability in Multiple Sclerosis.

Background And Objectives: In multiple sclerosis (MS), functional networks undergo continuous reconfiguration and topography changes over the disease course. In this study, we aimed to investigate functional network to pography abnormalities in MS and their association with disease phenotype, clinical and cognitive disability, and structural MRI damage.

Methods: This is a multicenter cross-sectional study.

The network collapse in multiple sclerosis: An overview of novel concepts to address disease dynamics.

Multiple sclerosis is a neuroinflammatory and neurodegenerative disorder of the central nervous system that can be considered a network disorder. In MS, lesional pathology continuously disconnects structural pathways in the brain, forming a disconnection syndrome. Complex functional network changes then occur that are poorly understood but closely follow clinical status.

Structure-function coupling as a correlate and potential biomarker of cognitive impairment in multiple sclerosis.

Multiple sclerosis (MS) features extensive connectivity changes, but how structural and functional connectivity relate, and whether this relation could be a useful biomarker for cognitive impairment in MS is unclear. This study included 79 MS patients and 40 healthy controls (HCs). Patients were classified as cognitively impaired (CI) or cognitively preserved (CP).

Task- and resting-state fMRI studies in multiple sclerosis: From regions to systems and time-varying analysis. Current status and future perspective.

Multiple sclerosis (MS) is a neurological disorder affecting the central nervous system and features extensive functional brain changes that are poorly understood but relate strongly to clinical impairments. Functional magnetic resonance imaging (fMRI) is a non-invasive, powerful technique able to map activity of brain regions and to assess how such regions interact for an efficient brain network. FMRI has been widely applied to study functional brain changes in MS, allowing to investigate functional plasticity consequent to disease-related structural injury.

A more unstable resting-state functional network in cognitively declining multiple sclerosis.

Cognitive impairment is common in people with multiple sclerosis and strongly affects their daily functioning. Reports have linked disturbed cognitive functioning in multiple sclerosis to changes in the organization of the functional network. In a healthy brain, communication between brain regions and which network a region belongs to is continuously and dynamically adapted to enable adequate cognitive function.

Distinct gene expression in demyelinated white and grey matter areas of patients with multiple sclerosis.

Demyelination of the central nervous system is a prominent pathological hallmark of multiple sclerosis and affects both white and grey matter. However, demyelinated white and grey matter exhibit clear pathological differences, most notably the presence or absence of inflammation and activated glial cells in white and grey matter, respectively. In order to gain more insight into the differential pathology of demyelinated white and grey matter areas, we micro-dissected neighbouring white and grey matter demyelinated areas as well as normal-appearing matter from leucocortical lesions of human post-mortem material and used these samples for RNA sequencing.

Artificial double inversion recovery images can substitute conventionally acquired images: an MRI-histology study.

Cortical multiple sclerosis lesions are disease-specific, yet inconspicuous on magnetic resonance images (MRI). Double inversion recovery (DIR) images are sensitive, but often unavailable in clinical routine and clinical trials. Artificially generated images can mitigate this issue, but lack histopathological validation.

Myelin Quantification in White Matter Pathology of Progressive Multiple Sclerosis Post-Mortem Brain Samples: A New Approach for Quantifying Remyelination.

Multiple sclerosis (MS) is a demyelinating and neurodegenerative disease of the central nervous system (CNS). Repair through remyelination can be extensive, but quantification of remyelination remains challenging. To date, no method for standardized digital quantification of remyelination of MS lesions exists.

Functional network dynamics and decreased conscientiousness in multiple sclerosis.

Background: Conscientiousness is a personality trait that declines in people with multiple sclerosis (PwMS) and its decline predicts worse clinical outcomes. This study aims to investigate the neural underpinnings of lower Conscientiousness in PwMS by examining MRI anomalies in functional network dynamics.

Methods: 70 PwMS and 50 healthy controls underwent personality assessment and resting-state MRI.

Cellular Substrates of Functional Network Integration and Memory in Temporal Lobe Epilepsy.

Temporal lobe epilepsy (TLE) patients are at risk of memory deficits, which have been linked to functional network disturbances, particularly of integration of the default mode network (DMN). However, the cellular substrates of functional network integration are unknown. We leverage a unique cross-scale dataset of drug-resistant TLE patients (n = 31), who underwent pseudo resting-state functional magnetic resonance imaging (fMRI), resting-state magnetoencephalography (MEG) and/or neuropsychological testing before neurosurgery.

Abnormalities in normal-appearing white matter from which multiple sclerosis lesions arise.

Normal-appearing white matter is far from normal in multiple sclerosis; little is known about the precise pathology or spatial pattern of this alteration and its relation to subsequent lesion formation. This study was undertaken to evaluate normal-appearing white matter abnormalities in brain areas where multiple sclerosis lesions subsequently form, and to investigate the spatial distribution of normal-appearing white matter abnormalities in persons with multiple sclerosis. Brain MRIs of pre-lesion normal-appearing white matter were analysed in participants with new T2 lesions, pooled from three clinical trials: SYNERGY (NCT01864148; = 85 with relapsing multiple sclerosis) was the test data set; ASCEND (NCT01416181; = 154 with secondary progressive multiple sclerosis) and ADVANCE (NCT00906399; = 261 with relapsing-remitting multiple sclerosis) were used as validation data sets.

Axonal loss in major sensorimotor tracts is associated with impaired motor performance in minimally disabled multiple sclerosis patients.

Multiple sclerosis is a neuroinflammatory disease of the CNS that is associated with significant irreversible neuro-axonal loss, leading to permanent disability. There is thus an urgent need for markers of axonal loss for use in patient monitoring or as end-points for trials of neuroprotective agents. Advanced diffusion MRI can provide markers of diffuse loss of axonal fibre density or atrophy within specific white matter pathways.

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.

Mechanistic underpinning of an inside-out concept for autoimmunity in multiple sclerosis.

The neuroinflammatory disease multiple sclerosis is driven by autoimmune pathology in the central nervous system. However, the trigger of the autoimmune pathogenic process is unknown. MS models in immunologically naïve, specific-pathogen-free bred rodents support an exogenous trigger, such as an infection.

The subcellular arrangement of alpha-synuclein proteoforms in the Parkinson's disease brain as revealed by multicolor STED microscopy.

Various post-translationally modified (PTM) proteoforms of alpha-synuclein (aSyn)-including C-terminally truncated (CTT) and Serine 129 phosphorylated (Ser129-p) aSyn-accumulate in Lewy bodies (LBs) in different regions of the Parkinson's disease (PD) brain. Insight into the distribution of these proteoforms within LBs and subcellular compartments may aid in understanding the orchestration of Lewy pathology in PD. We applied epitope-specific antibodies against CTT and Ser129-p aSyn proteoforms and different aSyn domains in immunohistochemical multiple labelings on post-mortem brain tissue from PD patients and non-neurological, aged controls, which were scanned using high-resolution 3D multicolor confocal and stimulated emission depletion (STED) microscopy.