Identification of neuropathology-based subgroups in multiple sclerosis using a data-driven approach

Multiple sclerosis (MS) is a heterogeneous disorder with regards to clinical presentation and pathophysiology. Stratification into biologically distinct subgroups could enhance prognostication and efficacious allocation to disease-modifying therapies. In this study, we identified MS subgroups by performing a clustering analysis on neuropathology data collected for MS donors in the Netherlands Brain Bank (NBB) autopsy cohort. The input dataset contained detailed information on white matter lesion load, the proportion of active, mixed active/inactive, inactive and remyelinating lesions, microglia morphology in these lesions, and the presence of microglial nodules, perivascular cuffs and cortical lesions for 228 donors. A factor analysis was performed to reduce noise and redundancy prior to hierarchical clustering with K-means consolidation. Four subgroups with distinct patterns of white matter lesions were identified. These were subsequently validated with additional clinical, neuropathological and genetic data. The subgroups differed with regards to disease progression and duration, the timing of motor, sensory and other relevant signs and symptoms, patterns of cortical lesions and the presence of B cells. Age at MS onset and sex, previously associated with milder forms of MS, did not differ between the subgroups; the subgroups could also not be distinguished based on the manifestation of clinical signs and symptoms. The available genetic data was used to calculate MS polygenic risk scores (PRSs) for donors included in the NBB cohort. The MS PRS did not differ between the subgroups, but was significantly correlated with the first and second dimension of the factor analysis, the latter lending genetic support to our subdivision. Taken together, these findings suggest a complex relationship between neuropathological subgroups and clinical characteristics, indicating that post-mortem cohort studies are critical to better stratify patients and understand underlying neuropathophysiological mechanisms, in order to ultimately achieve personalised medicine in MS

Therapeutically expanded human regulatory T-cells are super-suppressive due to HIF1A induced expression of CD73.

The adoptive transfer of regulatory T-cells (Tregs) is a promising therapeutic approach in transplantation and autoimmunity. However, because large cell numbers are needed to achieve a therapeutic effect, in vitro expansion is required. By comparing their function, phenotype and transcriptomic profile against ex vivo Tregs, we demonstrate that expanded human Tregs switch their metabolism to aerobic glycolysis and show enhanced suppressive function through hypoxia-inducible factor 1-alpha (HIF1A) driven acquisition of CD73 expression. In conjunction with CD39, CD73 expression enables expanded Tregs to convert ATP to immunosuppressive adenosine. We conclude that for maximum therapeutic benefit, Treg expansion protocols should be optimised for CD39/CD73 co-expression

Soundscape assessment: Towards a validated translation of perceptual attributes in different languages

The recently published ISO/TS 12913-2:2018 standard aims to provide researchers and practitioners around the world with a reliable questionnaire for soundscape characterization. The ISO Technical Specifications report protocols and attributes grounded in the soundscape literature, but only includes an English version. The applicability and reliability of these attributes in non-English speaking regions remains an open question, as research investigating translations of soundscape attributes is limited. To address this gap, an international collaboration was initiated with soundscape researchers from all over the world. Translation into 15 different languages, obtained through focus groups and panels of experts in soundscape studies, are proposed. The main challenges and outcomes of this preliminary exercise are discussed. The long-term objective is to validate the proposed translations using standardized listening experiments in different languages and geographical regions as a way to promote a widespread use of the soundscape attributes, both in academia and practice, across locations, populations and languages

Neural stem cells traffic functional mitochondria via extracellular vesicles.

Neural stem cell (NSC) transplantation induces recovery in animal models of central nervous system (CNS) diseases. Although the replacement of lost endogenous cells was originally proposed as the primary healing mechanism of NSC grafts, it is now clear that transplanted NSCs operate via multiple mechanisms, including the horizontal exchange of therapeutic cargoes to host cells via extracellular vesicles (EVs). EVs are membrane particles trafficking nucleic acids, proteins, metabolites and metabolic enzymes, lipids, and entire organelles. However, the function and the contribution of these cargoes to the broad therapeutic effects of NSCs are yet to be fully understood. Mitochondrial dysfunction is an established feature of several inflammatory and degenerative CNS disorders, most of which are potentially treatable with exogenous stem cell therapeutics. Herein, we investigated the hypothesis that NSCs release and traffic functional mitochondria via EVs to restore mitochondrial function in target cells. Untargeted proteomics revealed a significant enrichment of mitochondrial proteins spontaneously released by NSCs in EVs. Morphological and functional analyses confirmed the presence of ultrastructurally intact mitochondria within EVs with conserved membrane potential and respiration. We found that the transfer of these mitochondria from EVs to mtDNA-deficient L929 Rho0 cells rescued mitochondrial function and increased Rho0 cell survival. Furthermore, the incorporation of mitochondria from EVs into inflammatory mononuclear phagocytes restored normal mitochondrial dynamics and cellular metabolism and reduced the expression of pro-inflammatory markers in target cells. When transplanted in an animal model of multiple sclerosis, exogenous NSCs actively transferred mitochondria to mononuclear phagocytes and induced a significant amelioration of clinical deficits. Our data provide the first evidence that NSCs deliver functional mitochondria to target cells via EVs, paving the way for the development of novel (a)cellular approaches aimed at restoring mitochondrial dysfunction not only in multiple sclerosis, but also in degenerative neurological diseases

Soundscape assessment : towards a validated translation of perceptual attributes in different languages

The recently published ISO/TS 12913-2:2018 standard aims to provide researchers and practitioners around the world with a reliable questionnaire for soundscape characterization. The ISO Technical Specifications report protocols and attributes grounded in the soundscape literature, but only includes an English version. The applicability and reliability of these attributes in non-English speaking regions remains an open question, as research investigating translations of soundscape attributes is limited. To address this gap, an international collaboration was initiated with soundscape researchers from all over the world. Translation into 15 different languages, obtained through focus groups and panels of experts in soundscape studies, are proposed. The main challenges and outcomes of this preliminary exercise are discussed. The long-term objective is to validate the proposed translations using standardized listening experiments in different languages and geographical regions as a way to promote a widespread use of the soundscape attributes, both in academia and practice, across locations, populations and languages

Soundscape assessment:Towards a validated translation of perceptual attributes in different languages

The recently published ISO/TS 12913-2:2018 standard aims to provide researchers and practitioners around the world with a reliable questionnaire for soundscape characterization. The ISO Technical Specifications report protocols and attributes grounded in the soundscape literature, but only includes an English version. The applicability and reliability of these attributes in non-English speaking regions remains an open question, as research investigating translations of soundscape attributes is limited. To address this gap, an international collaboration was initiated with soundscape researchers from all over the world. Translation into 15 different languages, obtained through focus groups and panels of experts in soundscape studies, are proposed. The main challenges and outcomes of this preliminary exercise are discussed. The long-term objective is to validate the proposed translations using standardized listening experiments in different languages and geographical regions as a way to promote a widespread use of the soundscape attributes, both in academia and practice, across locations, populations and languages

Soundscape assessment: Towards a validated translation of perceptual attributes in different languages

The recently published ISO/TS 12913-2:2018 standard aims to provide researchers and practitioners around the world with a reliable questionnaire for soundscape characterization. The ISO Technical Specifications report protocols and attributes grounded in the soundscape literature, but only includes an English version. The applicability and reliability of these attributes in non-English speaking regions remains an open question, as research investigating translations of soundscape attributes is limited. To address this gap, an international collaboration was initiated with soundscape researchers from all over the world. Translation into 15 different languages, obtained through focus groups and panels of experts in soundscape studies, are proposed. The main challenges and outcomes of this preliminary exercise are discussed. The long-term objective is to validate the proposed translations using standardized listening experiments in different languages and geographical regions as a way to promote a widespread use of the soundscape attributes, both in academia and practice, across locations, populations and languages

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. In addition, axonal density and acute axonal damage were assessed using Bielschowsky and amyloid precursor protein (APP) (immune)histochemistry. RESULTS: CSF NfL measurements of donors with recent (<1 year) or clinically silent stroke were excluded. CSF NfL levels correlated negatively with disease duration (p = 6.9e-3, r = 0.31). In donors without atrophy, CSF NfL levels correlated positively with the proportion of active and mixed lesions containing foamy microglia/macrophages (p = 9.85e-10 and p = 1.75e-3, respectively), but not with those containing ramified microglia. CSF NfL correlated negatively with proportions of inactive (p = 5.66e-3) and remyelinated lesions (p = 0.03). In the normal appearing pyramid tract, axonal density negatively correlated with CSF NfL levels (Bielschowsky, p = 0.02, r = -0.31), and the presence of acute axonal damage in lesions was related to higher NfL levels (APP, p = 1.17e-6). The amount of acute axonal damage was higher in active lesions with foamy microglia/macrophages and in the rim of mixed lesions with foamy microglia/macrophages when compared with active lesions containing ramified microglia/macrophages (p = 4.6e-3 and p = 0.02, respectively), the center and border of mixed lesions containing ramified microglia/macrophages (center: p = 4.6e-3, border, p = 4.6e-3, and n.s., p = 4.6e-3, respectively), the center of mixed lesions containing foamy microglia/macrophages (p = 4.6e-3 and p = 0.02, respectively), inactive lesions (p = 4.6e-3 and p = 4.6e-3, respectively), and remyelinated lesions (p = 0.03 and p = 0.04, respectively). DISCUSSION: Our results demonstrated that active and mixed white matter MS lesions with foamy microglia show high acute axonal damage and correlate with elevated CSF NfL levels. Our data support the use of this biomarker to monitor inflammatory demyelinating lesion activity with axonal damage in MS