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Neurobiology of Disease Jun 2024Within the adult mouse subventricular zone (SVZ), neural stem cells (NSCs) produce neuroblasts and oligodendrocyte precursor cells (OPCs). T, the active thyroid hormone,...
Within the adult mouse subventricular zone (SVZ), neural stem cells (NSCs) produce neuroblasts and oligodendrocyte precursor cells (OPCs). T, the active thyroid hormone, influences renewal and commitment of SVZ progenitors. However, how regulators of T availability affect these processes is less understood. Using Mct8/Dio2 knockout mice, we investigated the role of MCT8, a TH transporter, and DIO2, the T-generating enzyme, in regulating adult SVZ-neurogliogenesis. Single-cell RNA-Seq revealed Mct8 expression in various SVZ cell types in WT mice, while Dio2 was enriched in neurons, astrocytes, and quiescent NSCs. The absence of both regulators in the knockout model dysregulated gene expression, increased the neuroblast/OPC ratio and hindered OPC differentiation. Immunostainings demonstrated compromised neuroblast migration reducing their supply to the olfactory bulbs, impairing interneuron differentiation and odor discrimination. These findings underscore the pivotal roles of MCT8 and DIO2 in neuro- and oligodendrogenesis, offering targets for therapeutic avenues in neurodegenerative and demyelinating diseases.
PubMed: 38901782
DOI: 10.1016/j.nbd.2024.106572 -
ELife Jun 2024Autoimmune diseases of the central nervous system (CNS) such as multiple sclerosis (MS) are only partially represented in current experimental models and the development...
Spontaneous human CD8 T cell and autoimmune encephalomyelitis-induced CD4/CD8 T cell lesions in the brain and spinal cord of HLA-DRB1*15-positive multiple sclerosis humanized immune system mice.
Autoimmune diseases of the central nervous system (CNS) such as multiple sclerosis (MS) are only partially represented in current experimental models and the development of humanized immune mice is crucial for better understanding of immunopathogenesis and testing of therapeutics. We describe a humanized mouse model with several key features of MS. Severely immunodeficient B2m-NOG mice were transplanted with peripheral blood mononuclear cells (PBMCs) from HLA-DRB1-typed MS and healthy (HI) donors and showed rapid engraftment by human T and B lymphocytes. Mice receiving cells from MS patients with recent/ongoing Epstein-Barr virus reactivation showed high B cell engraftment capacity. Both HLA-DRB1*15 (DR15) MS and DR15 HI mice, not HLA-DRB1*13 MS mice, developed human T cell infiltration of CNS borders and parenchyma. DR15 MS mice uniquely developed inflammatory lesions in brain and spinal cord gray matter, with spontaneous, hCD8 T cell lesions, and mixed hCD8/hCD4 T cell lesions in EAE immunized mice, with variation in localization and severity between different patient donors. Main limitations of this model for further development are poor monocyte engraftment and lack of demyelination, lymph node organization, and IgG responses. These results show that PBMC humanized mice represent promising research tools for investigating MS immunopathology in a patient-specific approach.
Topics: Animals; Humans; Multiple Sclerosis; Mice; HLA-DRB1 Chains; CD8-Positive T-Lymphocytes; Spinal Cord; Disease Models, Animal; Brain; Encephalomyelitis, Autoimmune, Experimental; CD4-Positive T-Lymphocytes; Female
PubMed: 38900149
DOI: 10.7554/eLife.88826 -
Brain and Behavior Jun 2024Gut microbiota alterations in multiple sclerosis (MS) patients have been reported in observational studies, but whether these associations are causal is unclear.
BACKGROUND
Gut microbiota alterations in multiple sclerosis (MS) patients have been reported in observational studies, but whether these associations are causal is unclear.
OBJECTIVE
We performed a Mendelian randomization study (MR) to assess the causal effects of gut microbiota on MS.
METHODS
Independent genetic variants associated with 211 gut microbiota phenotypes were selected as instrumental variables from the largest genome-wide association studies (GWAS) previously published by the MiBioGen study. GWAS data for MS were obtained from the International Multiple Sclerosis Genetics Consortium (IMSGC) for primary analysis and the FinnGen consortium for replication and collaborative analysis. Sensitivity analyses were conducted to evaluate heterogeneity and pleiotropy.
RESULTS
After inverse-variance-weighted and sensitivity analysis filtering, seven gut microbiota with potential causal effects on MS were identified from the IMSGC. Only five metabolites remained significant associations with MS when combined with the FinnGen consortium, including genus Anaerofilum id.2053 (odds ratio [OR] = 1.141, 95% confidence interval [CI]: 1.021-1.276, p = .021), Ruminococcus2 id.11374 (OR = 1.190, 95% CI: 1.007-1.406, p = .042), Ruminococcaceae UCG003 id.11361 (OR = 0.822, 95% CI: 0.688-0.982, p = .031), Ruminiclostridium5 id.11355 (OR = 0.724, 95% CI: 0.585-0.895, p = .003), Anaerotruncus id.2054 (OR = 0.772, 95% CI: 0.634-0.940, p = .010).
CONCLUSION
Our MR analysis reveals a potential causal relationship between gut microbiota and MS, offering promising avenues for advancing mechanistic understanding and clinical investigation of microbiota-mediated MS.
Topics: Humans; Mendelian Randomization Analysis; Multiple Sclerosis; Gastrointestinal Microbiome; Genome-Wide Association Study
PubMed: 38898610
DOI: 10.1002/brb3.3593 -
BMC Immunology Jun 2024For the past three years, the pandemic has had a major effect on global public health, mainly on those with underlying medical conditions, such as people living with...
BACKGROUND
For the past three years, the pandemic has had a major effect on global public health, mainly on those with underlying medical conditions, such as people living with Multiple Sclerosis. Vaccination among this group is of great importance, and the long-term impacts of vaccination and its safety on the health of these patients will continue to be revealed. Therefore, risks related to vaccination and immune response need to be assessed. The objective here was to characterize the immune response, short-term safety, and the effects of multiple variables on these factors after COVID-19 vaccination (mainly Sinopharm) among people with Multiple Sclerosis. We assessed the short-term safety and humoral SARS-COV-2 anti-RBD IgG response using a data collection form and Immunoassay, respectively.
RESULTS
No severe adverse events or MS relapse was observed. Myalgia/body pain (26.7%), low-grade fever (22.2%), and mild headache (15.6%) were the most common adverse events. The use and type of vaccine influenced the frequency of side effects with a p-value < 0.0001. Regarding immune response, patients on rituximab and fingolimod had a lower antibody titer compared to other medications. With a significant difference, hybrid immunity (p-value: 0.047) and type of DMTs (p-value: 0.017) affected the humoral response.
CONCLUSION
There is a low incidence of serious adverse effects, MS worsening or relapse after COVID-19 vaccination, and mainly, side effects are similar to that of the general population. It appears that treatment with various disease-modifying therapies does not induce or worsen the post-vaccination side effects, although some, including Rituximab and fingolimod, may affect the immunity induced after vaccination.
Topics: Humans; Immunity, Humoral; Multiple Sclerosis; COVID-19; SARS-CoV-2; Female; Antibodies, Viral; Male; COVID-19 Vaccines; Adult; Middle Aged; Rituximab; Immunoglobulin G; Vaccination; Immunosuppressive Agents
PubMed: 38898409
DOI: 10.1186/s12865-024-00628-w -
Nature Communications Jun 2024Retinal optical coherence tomography has been identified as biomarker for disease progression in relapsing-remitting multiple sclerosis (RRMS), while the dynamics of...
Retinal optical coherence tomography has been identified as biomarker for disease progression in relapsing-remitting multiple sclerosis (RRMS), while the dynamics of retinal atrophy in progressive MS are less clear. We investigated retinal layer thickness changes in RRMS, primary and secondary progressive MS (PPMS, SPMS), and their prognostic value for disease activity. Here, we analyzed 2651 OCT measurements of 195 RRMS, 87 SPMS, 125 PPMS patients, and 98 controls from five German MS centers after quality control. Peripapillary and macular retinal nerve fiber layer (pRNFL, mRNFL) thickness predicted future relapses in all MS and RRMS patients while mRNFL and ganglion cell-inner plexiform layer (GCIPL) thickness predicted future MRI activity in RRMS (mRNFL, GCIPL) and PPMS (GCIPL). mRNFL thickness predicted future disability progression in PPMS. However, thickness change rates were subject to considerable amounts of measurement variability. In conclusion, retinal degeneration, most pronounced of pRNFL and GCIPL, occurs in all subtypes. Using the current state of technology, longitudinal assessments of retinal thickness may not be suitable on a single patient level.
Topics: Humans; Retinal Degeneration; Male; Female; Tomography, Optical Coherence; Adult; Middle Aged; Disease Progression; Multiple Sclerosis, Relapsing-Remitting; Retina; Multiple Sclerosis, Chronic Progressive; Magnetic Resonance Imaging; Prognosis; Nerve Fibers; Retinal Ganglion Cells
PubMed: 38897994
DOI: 10.1038/s41467-024-49309-7 -
Neurology(R) Neuroimmunology &... Jul 2024A CSF-in gradient in cortical and thalamic gray matter (GM) damage has been found in multiple sclerosis (MS). We concomitantly explored the patterns of cortical,...
BACKGROUND AND OBJECTIVES
A CSF-in gradient in cortical and thalamic gray matter (GM) damage has been found in multiple sclerosis (MS). We concomitantly explored the patterns of cortical, thalamic, and caudate microstructural abnormalities at progressive distances from CSF using a multiparametric MRI approach.
METHODS
For this cross-sectional study, from 3T 3D T1-weighted scans, we sampled cortical layers at 25%-50%-75% depths from pial surface and thalamic and caudate bands at 2-3-4 voxels from the ventricular-GM interface. Using linear mixed models, we tested between-group comparisons of magnetization transfer ratio (MTR) and R2* layer-specific z-scores, CSF-in across-layer z-score changes, and their correlations with clinical (disease duration and disability) and structural (focal lesions, brain, and choroid plexus volume) MRI measures.
RESULTS
We enrolled 52 patients with MS (33 relapsing-remitting [RRMS], 19 progressive [PMS], mean age: 46.4 years, median disease duration: 15.1 years, median: EDSS 2.0) and 70 controls (mean age 41.5 ± 12.8). Compared with controls, RRMS showed lower MTR values in the outer and middle cortical layers (false-discovery rate [FDR]- ≤ 0.025) and lower R2* values in all 3 cortical layers (FDR- ≤ 0.016). PMS had lower MTR values in the outer and middle cortical (FDR- ≤ 0.016) and thalamic (FDR- ≤ 0.048) layers, and in the outer caudate layer (FDR- = 0.024). They showed lower R2* values in the outer cortical layer (FDR- = 0.003) and in the outer thalamic layer (FDR- = 0.046) and higher R2* values in all 3 caudate layers (FDR- ≤ 0.031). Both RRMS and PMS had a gradient of damage, with lower values closer to the CSF, for cortical (FDR- ≤ 0.002) and thalamic (FDR- ≤ 0.042) MTR. PMS showed a gradient of damage for cortical R2* (FDR- = 0.005), thalamic R2* (FDR- = 0.004), and caudate MTR (FDR- ≤ 0.013). Lower MTR and R2* of outer cortical, thalamic, and caudate layers and steeper gradient of damage toward the CSF were significantly associated with older age, higher T2-hyperintense white matter lesion volume, higher thalamic lesion volume, and lower brain volume (β ≥ 0.08, all FDR- ≤ 0.040). Lower MTR of outer caudate layer was associated with more severe disability (β = -0.26, FDR- = 0.040). No correlations with choroid plexus volume were found.
DISCUSSION
CSF-in damage gradients are heterogeneous among different GM regions and through MS course, possibly reflecting different dynamics of demyelination and iron loss/accumulation.
Topics: Humans; Middle Aged; Male; Female; Adult; Cross-Sectional Studies; Gray Matter; Cerebral Cortex; Thalamus; Multiple Sclerosis, Relapsing-Remitting; Multiple Sclerosis, Chronic Progressive; Magnetic Resonance Imaging; Multiparametric Magnetic Resonance Imaging; Multiple Sclerosis; Caudate Nucleus
PubMed: 38896808
DOI: 10.1212/NXI.0000000000200271 -
Human Brain Mapping Jun 2024Free water fraction (FWF) represents the amount of water per unit volume of brain parenchyma, which is not bound to macromolecules. Its excess in multiple sclerosis (MS)...
Free water fraction (FWF) represents the amount of water per unit volume of brain parenchyma, which is not bound to macromolecules. Its excess in multiple sclerosis (MS) is related to increased tissue loss. The use of mcDESPOT (multicomponent driven single pulse observation of T1 and T2), a 3D imaging method which exploits both the T1 and T2 contrasts, allows FWF to be derived in clinically feasible times. However, this method has not been used to quantify changes of FWF and their potential clinical impact in MS. The aim of this study is to investigate the changes in FWF in MS patients and their relationship with tissue damage and cognition, under the hypothesis that FWF is a proxy of clinically meaningful tissue loss. To this aim, we tested the relationship between FWF, MS lesion burden and information processing speed, evaluated via the Symbol Digit Modalities Test (SDMT). In addition to standard sequences, used for T1- and T2-weighted lesion delineation, the mcDESPOT sequence with 1.7 mm isotropic resolution and a diffusion weighted imaging protocol (b = 0, 1200 s/mm, 40 diffusion directions) were employed at 3 T. The fractional anisotropy map derived from diffusion data was used to define a subject-specific white matter (WM) atlas. Brain parenchyma segmentation returned masks of gray matter (GM) and WM, and normal-appearing WM (NAWM), in addition to the T1 and T2 lesion masks (T1L and T2L, respectively). Ninety-nine relapsing-remitting MS patients (age = 43.3 ± 9.9 years, disease duration 12.3 ± 7.7 years) were studied, together with twenty-five healthy controls (HC, age = 38.8 ± 11.0 years). FWF was higher in GM and NAWM of MS patients, compared to GM and WM of HC (both p < .001). In MS patients, FWF was the highest in the T1L and GM, followed by T2L and NAWM, respectively. FWF increased significantly with T1L and T2L volume (ρ ranging from 0.40 to 0.58, p < .001). FWF in T2L was strongly related to both T1L volume and the volume ratio T1L/T2L (ρ = 0.73, p < .001). MS patients performed worse than HC in the processing speed test (mean ± SD: 54.1 ± 10.3 for MS, 63.8 ± 10.8 for HC). FWF in GM, T2L, perilesional tissue and NAWM increased with SDMT score reduction (ρ = -0.30, -0.29, -0.33 respectively and r = -.30 for T2L, all with p < .005). A regional analysis, conducted to determine which NAWM regions were of particular importance to explain the relationship between FWF and cognitive impairment, revealed that FWF spatial variance was negatively related to SDMT score in the corpus callosum and the superior longitudinal fasciculus, WM structures known to be associated with cognitive impairment, in addition to the left corticospinal tract, the sagittal stratum, the right anterior limb of internal capsule. In conclusion, we found excess free water in brain parenchyma of MS patients, an alteration that involved not only MS lesions, but also the GM and NAWM, impinging on brain function and negatively associated with cognitive processing speed. We suggest that the FWF metric, derived from noninvasive, rapid MRI acquisitions and bearing good biological interpretability, may prove valuable as an MRI biomarker of tissue damage and associated cognitive impairment in MS.
Topics: Humans; Female; Male; Adult; Middle Aged; Brain; Multiple Sclerosis; Diffusion Magnetic Resonance Imaging; Water; Cognitive Dysfunction; Parenchymal Tissue; White Matter; Gray Matter; Processing Speed
PubMed: 38895882
DOI: 10.1002/hbm.26761 -
Sensors (Basel, Switzerland) May 2024Robotic devices are known to provide pivotal parameters to assess motor functions in Multiple Sclerosis (MS) as dynamic balance. However, there is still a lack of...
BACKGROUND
Robotic devices are known to provide pivotal parameters to assess motor functions in Multiple Sclerosis (MS) as dynamic balance. However, there is still a lack of validation studies comparing innovative technologies with standard solutions. Thus, this study's aim was to compare the postural assessment of fifty people with MS (PwMS) during dynamic tasks performed with the gold standard EquiTest and the robotic platform hunova, using Center of Pressure (COP)-related parameters and global balance indexes.
METHODS
Pearson's ρ correlations were run for each COP-related measure and the global balance index was computed from EquiTest and hunova in both open (EO) and closed-eyes (EC) conditions.
RESULTS
Considering COP-related parameters, all correlations were significant in both EO (0.337 ≤ ρ ≤ 0.653) and EC (0.344 ≤ ρ ≤ 0.668). Furthermore, Pearson's analysis of global balance indexes revealed relatively strong for visual and vestibular, and strong for somatosensory system associations (ρ = 0.573; ρ = 0.494; ρ = 0.710, respectively).
CONCLUSIONS
Findings confirm the use of hunova as a valid device for dynamic balance assessment in MS, suggesting that such a robotic platform could allow for a more sensitive assessment of balance over time, and thus a better evaluation of the effectiveness of personalized treatment, thereby improving evidence-based clinical practice.
Topics: Humans; Multiple Sclerosis; Postural Balance; Male; Robotics; Female; Adult; Middle Aged; Self-Help Devices
PubMed: 38894116
DOI: 10.3390/s24113325 -
Nutrients Jun 2024Multiple sclerosis (MS) is a debilitating autoimmune condition primarily affecting young adults, and its rise is evident globally. Despite this, its precise etiology...
Multiple sclerosis (MS) is a debilitating autoimmune condition primarily affecting young adults, and its rise is evident globally. Despite this, its precise etiology remains elusive. Both genetic and environmental factors contribute to MS susceptibility; however, the link between diet and MS lacks substantial evidence due to limited large-scale studies. We exploited the UK Biobank resources to explore the nexus between diet, lifestyle, and MS risk. The dietary and lifestyle habits of MS incident cases, derived from a general food frequency questionnaire (FFQ) completed by all participants at study enrollment, were compared to those of subjects who did not develop MS during the follow-up. Our findings suggest the protective role of moderate oily fish consumption and weekly alcohol intake. Furthermore, by analyzing food intake data obtained through 24 h recall, completed by a subset of participants, we found a protective, though non-significant, trend of an increased adherence to the Mediterranean diet (MD). These findings, derived from the analysis of the UK Biobank and representing an unprecedented approach for this inquiry, warrant further exploration and integration in future research.
Topics: Humans; Multiple Sclerosis; United Kingdom; Male; Female; Prospective Studies; Biological Specimen Banks; Diet, Mediterranean; Middle Aged; Diet; Adult; Life Style; Alcohol Drinking; Risk Factors; Feeding Behavior; Surveys and Questionnaires; UK Biobank
PubMed: 38892680
DOI: 10.3390/nu16111746 -
International Journal of Molecular... May 2024We have previously performed preclinical studies with the oxidized mannan-conjugated peptide MOG35-55 (OM-MOG35-55) in vivo (EAE mouse model) and in vitro (human...
We have previously performed preclinical studies with the oxidized mannan-conjugated peptide MOG35-55 (OM-MOG35-55) in vivo (EAE mouse model) and in vitro (human peripheral blood) and demonstrated that OM-MOG35-55 suppresses antigen-specific T cell responses associated with autoimmune demyelination. Based on these results, we developed different types of dendritic cells (DCs) from the peripheral blood monocytes of patients with multiple sclerosis (MS) or healthy controls presenting OM-MOG35-55 or MOG-35-55 to autologous T cells to investigate the tolerogenic potential of OM-MOG35-55 for its possible use in MS therapy. To this end, monocytes were differentiated into different DC types in the presence of IL-4+GM-CSF ± dexamethasone (DEXA) ± vitamin D3 (VITD3). At the end of their differentiation, the DCs were loaded with peptides and co-cultured with T cells +IL-2 for 4 antigen presentation cycles. The phenotypes of the DC and T cell populations were analyzed using flow cytometry and the secreted cytokines using flow cytometry or ELISA. On day 8, the monocytes had converted into DCs expressing the typical markers of mature or immature phenotypes. Co-culture of T cells with all DC types for 4 antigen presentation cycles resulted in an increase in memory CD4+ T cells compared to memory CD8+ T cells and a suppressive shift in secreted cytokines, mainly due to increased TGF-β1 levels. The best tolerogenic effect was obtained when patient CD4+ T cells were co-cultured with VITD3-DCs presenting OM-MOG35-55, resulting in the highest levels of CD4+PD-1+ T cells and CD4+CD25+Foxp3+ Τ cells. In conclusion, the tolerance induction protocols presented in this work demonstrate that OM-MOG35-55 could form the basis for the development of personalized therapeutic vaccines or immunomodulatory treatments for MS.
Topics: Humans; Myelin-Oligodendrocyte Glycoprotein; Dendritic Cells; Multiple Sclerosis; Immune Tolerance; Peptide Fragments; Adult; Female; Mannans; Male; Cell Differentiation; Monocytes; T-Lymphocytes; Cells, Cultured; Middle Aged; CD4-Positive T-Lymphocytes; Cytokines
PubMed: 38892275
DOI: 10.3390/ijms25116092