The aim of this study was to investigate the interplay between structural connectivity and cortical demyelination in early multiple sclerosis. About 27 multiple sclerosis patients and 18 age‐matched ...controls underwent two MRI scanning sessions. The first was done at 7T and involved acquiring quantitative T1 and T2* high‐resolution maps to estimate cortical myelination. The second was done on a Connectom scanner and consisted of acquiring high angular resolution diffusion‐weighted images to compute white matter structural connectivity metrics: strength, clustering and local efficiency. To further investigate the interplay between structural connectivity and cortical demyelination, patients were divided into four groups according to disease‐duration: 0–1 year, 1–2 years, 2–3 years, and >3 years. ANOVA and Spearman's correlations were used to highlight relations between metrics. ANOVA detected a significant effect between disease duration and both cortical myelin (p = 2 × 10−8) and connectivity metrics (p < 10−4). We observed significant cortical myelin loss in the shorter disease‐duration cohorts (0–1 year, p = .0015), and an increase in connectivity in the longer disease‐duration cohort (2–3 years, strength: p = .01, local efficiency: p = .002, clustering: p = .001). Moreover, significant covariations between myelin estimation and white matter connectivity metrics were observed: Spearman's Rho correlation coefficients of 0.52 (p = .0003), 0.55 (p = .0001), and 0.53 (p = .0001) for strength, local efficiency, and clustering, respectively. An association between cortical myelin loss and changes in white matter connectivity in early multiple sclerosis was detected. These changes in network organization might be the result of compensatory mechanisms in response to the ongoing cortical diffuse damage in the early stages of multiple sclerosis.
•When controlling for age, race, and MS therapy, those with endometriosis and MS experience more MS disability than those with only MS.•Patients with both endometriosis and MS require more monitoring ...and efficacious treatment than those with only MS.•Patients with both endometriosis and MS experience more anxiety and depression than those with MS alone.
Endometriosis (EMS) is pain syndrome in which endometrial tissue grows outside the uterus. EMS is associated with an increased risk of multiple sclerosis (MS), a demyelinating disease of the central nervous system.
To characterize clinical phenotypes of a cohort of patients with both EMS and MS compared to a cohort of matched controls with only MS.
We retrospectively identified patients with EMS and MS at Beth Israel Deaconess Medical Center (BIDMC). We collected data on EMS treatments and analyzed differences in histories of gynecological cancer, smoking, fatigue, anxiety, depression, headache, and neuropathic pain compared to matched controls. We used Wilcoxon signed rank tests for paired samples to compare Expanded Disability Status Scores (EDSS) and timed 25-foot walk values (T25FW).
Using a case-control methodology, we found significantly increased EDSS (p < 0.001) and T25FW (p = 0.01) in the EMS-MS group compared to the MS group. More patients in the EMS-MS group had histories of smoking, anxiety, depression, and headaches, while more patients in the MS group had histories of fatigue and neuropathic pain.
When controlling for age, race, and MS therapy, those with EMS-MS experience more MS disability than controls, suggesting this population requires more monitoring and efficacious treatment.
Compartmentalized meningeal inflammation is thought to represent one of the key players in the pathogenesis of cortical demyelination in multiple sclerosis. Positron emission tomography targeting the ...18 kDa mitochondrial Translocator Protein (TSPO) is a molecular-specific approach to quantify immune cell-mediated density in the cortico-meningeal tissue compartment in vivo. The aim of this study was to characterize cortical and meningeal TSPO expression in a heterogeneous cohort of multiple sclerosis cases using in vivo simultaneous MR-PET with 11C-PBR28, a second-generation TSPO radioligand, and ex vivo immunohistochemistry. Forty-nine multiple sclerosis patients (21 with secondary progressive and 28 with relapsing-remitting multiple sclerosis) with mixed or high affinity binding for 11C-PBR28 underwent 90-min 11C-PBR28 simultaneous MR-PET. Tracer binding was measured using 60-90 min normalized standardized uptake value ratio values sampled at mid-cortical depth and ∼3 mm above the pial surface. Data in multiple sclerosis patients were compared to 21 age-matched healthy controls. To characterize the nature of 11C-PBR28 PET uptake, the meningeal and cortical lesion cellular expression of TSPO was further described in post-mortem brain tissue from 20 cases with secondary progressive multiple sclerosis and five age-matched healthy donors. Relative to healthy controls, patients with multiple sclerosis exhibited abnormally increased TSPO signal in the cortex and meningeal tissue, diffusively in progressive disease and more localized in relapsing-remitting multiple sclerosis. In multiple sclerosis, increased meningeal TSPO levels were associated with increased Expanded Disability Status Scale scores (p = 0.007, by linear regression). Immunohistochemistry, validated using in-situ sequencing analysis, revealed increased TSPO expression in the meninges and adjacent subpial cortical lesions of post-mortem secondary progressive multiple sclerosis cases relative to control tissue. In these cases, increased TSPO expression was related to meningeal inflammation. Translocator Protein immunostaining was detected on meningeal major histocompatibility complex (MHC)-class II + macrophages and cortical activated MHC-class II + transmembrane protein (TMEM)119+ microglia. In vivo arterial blood data and neuropathology showed that endothelial binding did not significantly account for increased TSPO cortico-meningeal expression in multiple sclerosis. Our findings support the use of TSPO-PET in multiple sclerosis for imaging in vivo inflammation in the cortico-meningeal brain tissue compartment and provide in vivo evidence implicating meningeal inflammation in the pathogenesis of the disease.
Background:
Paramagnetic rim white matter (WM) lesions (PRL) are thought to be a main driver of non-relapsing multiple sclerosis (MS) progression. It is unknown whether cerebrospinal fluid ...(CSF)-soluble factors diffusing from the ventricles contribute to PRL formation.
Objective:
To investigate the distribution of PRL and non-rim brain WM lesions as a function of distance from ventricular CSF, their relationship with cortical lesions, the contribution of lesion phenotype, and localization to neurological disability.
Methods:
Lesion count and volume of PRL, non-rim WM, leukocortical lesion (LCL), and subpial/intracortical lesions were obtained at 7-T. The brain WM was divided into 1-mm-thick concentric rings radiating from the ventricles to extract PRL and non-rim WM lesion volume from each ring.
Results:
In total, 61 MS patients with ⩾1 PRL were included in the study. Both PRL and non-rim WM lesion volumes were the highest in the periventricular WM and declined with increasing distance from ventricles. A CSF distance-independent association was found between non-rim WM lesions, PRL, and LCL, but not subpial/intracortical lesions. Periventricular non-rim WM lesion volume was the strongest predictor of neurological disability.
Conclusions:
Non-rim and PRL share a gradient of distribution from the ventricles toward the cortex, suggesting that CSF proximity equally impacts the prevalence of both lesion phenotypes.
•Bariatric surgery is effective and safe with multiple sclerosis patients.•There was no significant change in neurologic function due to bariatric surgery.•Vitamin D levels increased ...post-surgery.•Those patients who failed to lose significant weight from surgery had chronic pain syndromes and were on gabapentin.
Obesity and lower vitamin D levels are associated with adverse outcomes in multiple sclerosis (MS). Bariatric surgery is a safe intervention in patients with MS, although it lowers vitamin D levels in the general population.
To investigate the effects of bariatric surgery on vitamin D levels and interrogate risk factors for unsuccessful post-operative weight loss in patients with MS.
We retrospectively identified patients with MS who underwent bariatric surgery from 2001 to 2023. Wilcoxon signed rank tests for paired samples were used to compare pre- and post-operative body mass index (BMI), expanded disability status scale (EDSS), timed 25-foot walk (T25FW), and median vitamin D values.
Following bariatric surgery, patients with MS had a decrease in BMI (mean percent total weight loss of 18.4 %, range 0–38 %, p < 0.001) and an increase in vitamin D values (mean increase of 23 ng/mL, range -4-32 ng/mL, p < 0.001), while no change in EDSS or T25FW was seen. Four out of 20 patients did not lose more than 5 % of their pre-operative BMI, all of whom had chronic pain syndromes and were on gabapentin.
Healthy vitamin D levels are attainable following bariatric surgery in patients with MS.
We have previously shown that myelin abnormalities characterize the normal aging process of the brain and that an age-associated reduction in Klotho is conserved across species. Predominantly ...generated in brain and kidney, Klotho overexpression extends life span, whereas loss of Klotho accelerates the development of aging-like phenotypes. Although the function of Klotho in brain is unknown, loss of Klotho expression leads to cognitive deficits. We found significant effects of Klotho on oligodendrocyte functions, including induced maturation of rat primary oligodendrocytic progenitor cells (OPCs) in vitro and myelination. Phosphoprotein analysis indicated that Klotho's downstream effects involve Akt and ERK signal pathways. Klotho increased OPC maturation, and inhibition of Akt or ERK function blocked this effect on OPCs. In vivo studies of Klotho knock-out mice and control littermates revealed that knock-out mice have a significant reduction in major myelin protein and gene expression. By immunohistochemistry, the number of total and mature oligodendrocytes was significantly lower in Klotho knock-out mice. Strikingly, at the ultrastructural level, Klotho knock-out mice exhibited significantly impaired myelination of the optic nerve and corpus callosum. These mice also displayed severe abnormalities at the nodes of Ranvier. To decipher the mechanisms by which Klotho affects oligodendrocytes, we used luciferase pathway reporters to identify the transcription factors involved. Together, these studies provide novel evidence for Klotho as a key player in myelin biology, which may thus be a useful therapeutic target in efforts to protect brain myelin against age-dependent changes and promote repair in multiple sclerosis.
Toll is a cell surface receptor with well described roles in the developmental patterning of invertebrates and innate immunity in adult Drosophila. Mammalian toll-like receptors represent a family of ...Toll orthologs that function in innate immunity by recognizing molecular motifs unique to pathogens or injured tissue. One member in this family of pattern recognition receptors, toll-like receptor 3 (TLR3), recognizes viral double-stranded RNA and host mRNA. We examined the expression and function of TLRs in the nervous system and found that TLR3 is expressed in the mouse central and peripheral nervous systems and is concentrated in the growth cones of neurons. Activation of TLR3 by the synthetic ligand polyinosine:polycytidylic acid (poly I:C) or by mRNA rapidly causes growth cone collapse and irreversibly inhibits neurite extension independent of nuclear factor kappaB. Mice lacking functional TLR3 were resistant to the neurodegenerative effects of poly I:C. Neonatal mice injected with poly I:C were found to have fewer axons exiting dorsal root ganglia and displayed related sensorimotor deficits. No effect of poly I:C was observed in mice lacking functional TLR3. Together, these findings provide evidence that an innate immune pattern recognition receptor functions autonomously in neurons to regulate axonal growth and advances a novel hypothesis that this class of receptors may contribute to injury and limited CNS regeneration.
Toll receptors in Drosophila melanogaster function in morphogenesis and host defense. Mammalian orthologues of Toll, the Toll-like receptors (TLRs), have been studied extensively for their essential ...functions in controlling innate and adaptive immune responses. We report that TLR8 is dynamically expressed during mouse brain development and localizes to neurons and axons. Agonist stimulation of TLR8 in cultured cortical neurons causes inhibition of neurite outgrowth and induces apoptosis in a dissociable manner. Our evidence indicates that such TLR8-mediated neuronal responses do not involve the canonical TLR-NF-κB signaling pathway. These findings reveal novel functions for TLR8 in the mammalian nervous system that are distinct from the classical role of TLRs in immunity.
Background:
Thalamic pathology is a marker for neurodegeneration and multiple sclerosis (MS) disease progression.
Objective:
To characterize (1) the morphology of thalamic lesions, (2) their relation ...to cortical and white matter (WM) lesions, and (3) clinical measures, and to assess (4) the imaging correlates of thalamic atrophy.
Methods:
A total of 90 MS patients and 44 healthy controls underwent acquisition of 7 Tesla images for lesion segmentation and 3 Tesla scans for atrophy evaluation. Thalamic lesions were classified according to the shape and the presence of a central venule. Regression analysis identified the predictors of (1) thalamic atrophy, (2) neurological disability, and (3) information processing speed.
Results:
Thalamic lesions were mostly ovoid than periventricular, and for the great majority (78%) displayed a central venule. Lesion volume in the thalamus, cortex, and WM did not correlate with each other. Thalamic atrophy was only associated with WM lesion volume (p = 0.002); subpial and WM lesion volumes were associated with neurological disability (p = 0.016; p < 0.001); and WM and thalamic lesion volumes were related with cognitive impairment (p < 0.001; p = 0.03).
Conclusion:
Thalamic lesions are unrelated to those in the cortex and WM, suggesting that they may not share common pathogenic mechanisms and do not contribute to thalamic atrophy. Combined WM, subpial, and thalamic lesion volumes at 7 Tesla contribute to the disease severity.
Background:
Thalamic degeneration impacts multiple sclerosis (MS) prognosis.
Objective:
To investigate heterogeneous thalamic pathology, its correlation with white matter (WM), cortical lesions and ...thickness, and as function of distance from cerebrospinal fluid (CSF).
Methods:
In 41 MS subjects and 17 controls, using 3 and 7 T imaging, we tested for (1) differences in thalamic volume and quantitative T2* (q-T2*) (2) globally and (3) within concentric bands originating from the CSF/thalamus interface; (4) the relation between thalamic, cortical, and WM metrics; and (5) the contribution of magnetic resonance imaging (MRI) metrics to clinical scores. We also assessed MS thalamic lesion distribution as a function of distance from CSF.
Results:
Thalamic lesions were mainly located next to the ventricles. Thalamic volume was decreased in MS versus controls (p < 10−2); global q-T2* was longer in secondary progressive multiple sclerosis (SPMS) only (p < 10−2), indicating myelin and/or iron loss. Thalamic atrophy and longer q-T2* correlated with WM lesion volume (p < 0.01). In relapsing-remitting MS, q-T2* thalamic abnormalities were located next to the WM (p < 0.01 (uncorrected), p = 0.09 (corrected)), while they were homogeneously distributed in SPMS. Cortical MRI metrics were the strongest predictors of clinical outcome.
Conclusion:
Heterogeneous pathological processes affect the thalamus in MS. While focal lesions are likely mainly driven by CSF-mediated factors, overall thalamic degeneration develops in association with WM lesions.
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