Multiple Sclerosis Phenotypes Research Articles

Structural and functional imaging features of cognitive phenotypes in pediatric multiple sclerosis.

The present study aimed to identify the clinical and MRI features of the distinct cognitive phenotypes in pediatric multiple sclerosis (pedMS). PedMS patients (n = 73) and healthy controls (n = 30) underwent clinical examination and 3.0T MRI. All patients completed neuropsychological testing, and cognitive phenotypes were identified by performing K-means clustering on cognitive scores. MRI metrics included brain T2-hyperintese lesion volume and normalized brain volumes. Within seven cognitively relevant cortical networks, structural disconnectivity (i.e., the mean percentage of streamlines connecting each pair of cortical regions passing through a lesion) and resting-state (RS) functional connectivity (FC) were estimated. Three cognitive phenotypes emerged: Preserved cognition (PC; n = 27, 37%), mild verbal learning and memory/semantic fluency involvement (MVS; n = 28, 38%), and multidomain involvement (MI; n = 18, 25%). Age, sex, and disease duration did not differ among groups. Compared with healthy subjects, PC patients had decreased RS FC within the default mode network (p = 0.045); MVS patients exhibited lower cortical volume and reduced RS FC within the frontoparietal network (all p = 0.045); and MI patients showed decreased volumes in all brain compartments except the hippocampus, and reduced RS FC within the frontoparietal network (all p ≤ 0.045). Compared to PC, MI patients had more severe disability and higher structural disconnectivity within four cortical networks (all p ≤ 0.045). Compared to PC and MVS, MI patients had lower intelligence quotient (all p ≤ 0.005). We identified three cognitive phenotypes in pedMS that demonstrate the existence of a spectrum of impairment. Such phenotypes showed distinct clinical and MRI characteristics that contributed to explain their cognitive profiles.

Cognitive impairment in multiple sclerosis: from phenomenology to neurobiological mechanisms.

Multiple sclerosis (MS) is an autoimmune-mediated disease of the central nervous system characterized by inflammation, demyelination and chronic progressive neurodegeneration. Among its broad and unpredictable range of clinical symptoms, cognitive impairment (CI) is a common and disabling feature greatly affecting the patients' quality of life. Its prevalence is 20% up to 88% with a wide variety depending on the phenotype of MS, with highest frequency and severity in primary progressive MS. Involving different cognitive domains, CI is often associated with depression and other neuropsychiatric symptoms, but usually not correlated with motor and other deficits, suggesting different pathophysiological mechanisms. While no specific neuropathological data for CI in MS are available, modern research has provided evidence that it arises from the disease-specific brain alterations. Multimodal neuroimaging, besides structural changes of cortical and deep subcortical gray and white matter, exhibited dysfunction of fronto-parietal, thalamo-hippocampal, default mode and cognition-related networks, disruption of inter-network connections and involvement of the γ-aminobutyric acid (GABA) system. This provided a conceptual framework to explain how aberrant pathophysiological processes, including oxidative stress, mitochondrial dysfunction, autoimmune reactions and disruption of essential signaling pathways predict/cause specific disorders of cognition. CI in MS is related to multi-regional patterns of cerebral disturbances, although its complex pathogenic mechanisms await further elucidation. This article, based on systematic analysis of PubMed, Google Scholar and Cochrane Library, reviews current epidemiological, clinical, neuroimaging and pathogenetic evidence that could aid early identification of CI in MS and inform about new therapeutic targets and strategies.

Glial cell injury and atrophied lesion volume as measures of chronic multiple sclerosis inflammation

BackgroundAtrophied lesion volume (aLV), a proposed biomarker of disability progression in multiple sclerosis (MS) and transition into progressive MS (PMS), depicts chronic periventricular white matter (WM) pathology. Meningeal infiltrates, imaged as leptomeningeal contrast enhancement (LMCE), are linked with greater cortical pathology. ObjectivesTo determine the relationship between serum-derived proteomic data with the development of aLV and LMCE in a heterogeneous group of people with MS (pwMS). MethodsProteomic and MRI data for 202 pwMS (148 clinically isolated syndrome /relapsing-remitting MS and 54 progressive MS (PMS)) were acquired at baseline and at 5.4-year follow-up. The concentrations of 21 proteins related to multiple MS pathophysiology pathways were derived using a custom-developed Proximity Extension Assay on the Olink™ platform. The accrual of aLV was determined as the volume of baseline T2-weighted lesions that were replaced by cerebrospinal fluid over the follow-up. Regression models and age-adjusted analysis of covariance (ANCOVA) were used. ResultsOlder age (standardized beta = 0.176, p = 0.022), higher glial fibrillary acidic protein (standardized beta = 0.312, p = 0.001), and lower myelin oligodendrocyte glycoprotein levels (standardized beta = −0.271, p = 0.002) were associated with accrual of aLV over follow-up. This relationship was driven by the pwPMS population. The presence of LMCE at the follow-up visit was not predicted by any baseline proteomic biomarker nor cross-sectionally associated with any protein concentration. ConclusionProteomic markers of glial activation are associated with chronic lesional WM pathology (measured as aLV) and may be specific to the progressive MS phenotype. LMCE presence in MS does not appear to relate to proteomic measures.

Evaluating the utility of serum NfL, GFAP, UCHL1 and tTAU as estimates of CSF levels and diagnostic instrument in neuroinflammation and multiple sclerosis

BackgroundThis study aimed to evaluate the utility of neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase L1 (UCHL1) and total tau (tTAU) serum concentrations as approximation for cerebrospinal fluid (CSF) concentrations of the respective biomarkers in the context of neuroinflammation and multiple sclerosis (MS). MethodsNfL, GFAP, UCHL1 and tTAU concentrations in serum and CSF were measured in 183 patients (122 with neuroinflammatory disease and 61 neurological or somatoform disease controls) using the single molecule array HD-1 analyzer (Quanterix, Boston, MA). Spearman's rank correlations were computed between serum and CSF concentrations. In a second step, the effects of age, BMI, gadolinium-enhancing lesions in MRI, integrity of the blood–brain barrier (BBB) and presence of acute relapse were accounted for by computing partial correlations. The analyses were repeated for a subsample consisting of MS phenotype patients only (n = 118). EDSS, MS disease activity and acute relapse were considered as additional covariates. Receiver operating characteristic (ROC) analysis was performed for each serum/CSF biomarker concentration to assess how well the particular biomarker concentration differentiates MS patients from somatoform disease controls. Correlations between serum and CSF levels as well as area under the curve (AUC) values were compared for the different biomarkers using z-test statistics. ResultsSerum concentrations correlated positively with CSF levels for NfL (r = 0.705, p < 0.01) as well as for GFAP (r = 0.259, p < 0.01). Correlation coefficients were significantly higher for NfL than for GFAP (z = 5.492, p < 0.01). We found no significant serum-CSF correlations for UCHL1 or tTAU. After adjusting for covariates, the results remained unchanged. In the analysis focusing only on MS patients, the results were replicated. ROC analysis demonstrated similarly acceptable performance of serum and CSF NfL values in differentiating MS phenotype patients from somatoform disease controls. AUC values were significantly higher for serum and CSF NfL compared to other biomarkers. ConclusionNfL and GFAP but not UCHL1 or tTAU serum concentrations are associated with CSF levels of the respective biomarker. NfL exhibits more robust correlations between its serum and CSF concentrations as compared to GFAP independently from BBB integrity, clinical and radiological covariates. Both serum and CSF NfL values differentiate between MS and controls.

Prevalence and Spectrum of Cognitive Phenotypes in Multiple Sclerosis and Related Risk Factors (P6-6.002)

Prevalence and Spectrum of Cognitive Phenotypes in Multiple Sclerosis and Related Risk Factors (P6-6.002)

Cognitive Phenotypes in Multiple Sclerosis: Mapping the Spectrum of Impairment (S28.010)

Cognitive Phenotypes in Multiple Sclerosis: Mapping the Spectrum of Impairment (S28.010)

A rapid review of differences in cerebrospinal neurofilament light levels in clinical subtypes of progressive multiple sclerosis.

Multiple sclerosis (MS) is divided into three clinical phenotypes: relapsing-remitting MS (RRMS), secondary progressive MS (SPMS), and primary progressive MS (PPMS). It is unknown to what extent SPMS and PPMS pathophysiology share inflammatory or neurodegenerative pathological processes. Cerebrospinal (CSF) neurofilament light (NfL) has been broadly studied in different MS phenotypes and is a candidate biomarker for comparing MS subtypes. Are CSF NfL levels different among clinical subtypes of progressive MS? A search strategy identifying original research investigating fluid neurodegenerative biomarkers in progressive forms of MS between 2010 and 2022 was applied to Medline. Identified articles underwent title and abstract screen and full text review against pre-specified criteria. Data abstraction was limited to studies that measured NfL levels in the CSF. Reported statistical comparisons of NfL levels between clinical phenotypes were abstracted qualitatively. 18 studies that focused on investigating direct comparisons of CSF NfL from people with MS were included in the final report. We found NfL levels were typically reported to be higher in relapsing and progressive MS compared to healthy controls. Notably, higher NfL levels were not clearly associated with progressive MS subtypes when compared to relapsing MS, and there was no observed difference in NfL levels between PPMS and SPMS in articles that separately assessed these phenotypes. CSF NfL levels distinguish individuals with MS from healthy controls but do not differentiate MS subtypes. Broad biological phenotyping is needed to overcome limitations of current clinical phenotyping and improve biomarker translatability to decision-making in the clinic.

Microstructure white matter changes and serum GFAP among different phenotypes of multiple sclerosis

Background. Multiple sclerosis (MS) is an autoimmune disease that targets the central nervous system (CNS). A patient’s degree of demyelination and axonal degeneration can only be roughly estimated based on clinical symptoms, neurochemical analysis or standard clinical MRI. Magnetic resonance diffusion tensor imaging (DTI) may provide more information on MS pathology than T1- and T2-weighted MRI alone. Glial fibrillary acidic protein (GFAP) uniquely found in astrocytes in the (CNS), non-myelinating Schwann cells in the peripheral nervous system (PNS), and enteric glial cells. GFAP is postulated to be a biomarker of astrocytic damage and reactive astrogliosis. Methods. A total of 60 patients with MS was categorized into three equal groups according to The Multiple Sclerosis Progression Discussion Tool (MSProDiscuss tool): RRMS, SPMS, RRMS with high risk to become SPMS and 20 healthy controls. Baseline clinical characteristics and detailed medical and neurological history were taken into consideration, as well as time of onset of MS, delay in diagnosis, initial symptoms, relapses features and behavior, EDSS and disease modifying therapy. They were subjected to DTI-MRI and blood sampling for GFAP. Results. DTI was able to differentiate between different MS phenotypes and was able to detect progression when we evaluated DTI changes in NAWM in different brain areas as low FA and high MD were associated with progression and increasing disability (p value =0.001). Serum GFAP differs significantly between patients with SPMS or patients in transition, also, it was higher in patients in transition than RRMS or control group (P value &lt;0.001). There was a significant correlation between serum GFAP and DTI changes in NAWM as higher titres of GFAP were associated with lower FA and higher MD values in NAWM of frontal, temporal lobes, and CC body. Conclusion. Serum GFAP in addition to DTI measurable microdamage in NAWM can give us a wide scope of view about potential progression in MS pathology and related astrocytopathy.

Targeted RNAseq Revealed the Gene Expression Signature of Ferroptosis-Related Processes Associated with Disease Severity in Patients with Multiple Sclerosis.

Detrimental molecular processes in multiple sclerosis (MS) lead to the cellular accumulation of lipid peroxidation products and iron in the CNS, which represents the main driving force for ferroptosis. Ferroptosis is an iron-dependent form of regulated cell death, with proposed roles in neurodegeneration, oligodendrocyte loss and neuroinflammation in the pathogenesis of MS. Ferroptosis-related gene expression signature and molecular markers, which could reflect MS severity and progression, are currently understudied in humans. To tackle these challenges, we have applied a curated approach to create and experimentally analyze a comprehensive panel of ferroptosis-related genes covering a wide range of biological processes associated with ferroptosis. We performed the first ferroptosis-related targeted RNAseq on PBMCs from highly distinctive MS phenotype groups: mild relapsing-remitting (RR) (n = 24) and severe secondary progressive (SP) (n = 24), along with protein detection of GPX4 and products of lipid peroxidation (MDA and 4-HNE). Out of 138 genes, 26 were differentially expressed genes (DEGs), indicating changes in both pro- and anti-ferroptotic genes, representing a molecular signature associated with MS severity. The top three DEGs, as non-core ferroptosis genes, CDKN1A, MAP1B and EGLN2, were replicated by qPCR to validate findings in independent patient groups (16 RR and 16 SP MS). Co-expression and interactions of DEGs were presented as additional valuable assets for deeper understanding of molecular mechanisms and key targets related to MS severity. Our study integrates a wide genetic signature and biochemical markers related to ferroptosis in easily obtainable PBMCs of MS patients with clinical data and disease severity, thus providing novel molecular markers which can complement disease-related changes in the brain and undergo further research as potential therapeutic targets.

The Impact of Cytomegalovirus Infection on Natural Killer and CD8+ T Cell Phenotype in Multiple Sclerosis.

Multiple sclerosis (MS) is a debilitating neurological disease that has been classified as an immune-mediated attack on myelin, the protective sheath of nerves. Some aspects of its pathogenesis are still unclear; nevertheless, it is generally established that viral infections influence the course of the disease. Cytomegalovirus (CMV) is a major pathogen involved in alterations of the immune system, including the expansion of highly differentiated cytotoxic CD8+ T cells and the accumulation of adaptive natural killer (NK) cells expressing high levels of the NKG2C receptor. In this study, we evaluated the impact of latent CMV infection on MS patients through the characterization of peripheral NK cells, CD8+ T cells, and NKT-like cells using flow cytometry. We evaluated the associations between immune cell profiles and clinical features such as MS duration and MS progression, evaluated using the Expanded Disability Status Scale (EDSS). We showed that NK cells, CD8+ T cells, and NKT-like cells had an altered phenotype in CMV-infected MS patients and displayed high levels of the NKG2C receptor. Moreover, in MS patients, increased NKG2C expression levels were found to be associated with higher EDSS scores. Overall, these results support the hypothesis that CMV infection imprints the immune system by modifying the phenotype and receptor repertoire of NK and CD8+ T cells, suggesting a detrimental role of CMV on MS progression.

The Impact of Aging on Multiple Sclerosis.

Multiple sclerosis (MS) is a chronic, immune-mediated demyelinating disorder of the central nervous system. Age is one of the most important factors in determining MS phenotype. This review provides an overview of how age influences MS clinical characteristics, pathology, and treatment. New methods for measuring aging have improved our understanding of the aging process in MS. New studies have characterized the molecular and cellular composition of chronic active or smoldering plaques in MS. These lesions are important contributors to disability progression in MS. These studies highlight the important role of immunosenescence and the innate immune system in sustaining chronic inflammation. Given these changes in immune function, several studies have assessed optimal treatment strategies in aging individuals with MS. MS phenotype is intimately linked with chronologic age and immunosenescence. While there are many unanswered questions, there has been much progress in understanding this relationship which may lead to more effective treatments for progressive disease.

Spasticity-Plus syndrome in multiple sclerosis patients in a tertiary hospital in Spain.

Spasticity is a common symptom in multiple sclerosis (MS) and it is often associated with other symptoms such as spasms/cramps and pain. The concept of Spasticity-Plus syndrome takes into account that spasticity is accompanied by one or more symptoms (spasms/cramps, pain, bladder dysfunction, sleep disorders, fatigue and/or tremor). As these symptoms share a common cannabinoid control, therapy acting on cannabinoid receptors may be useful. The main study objectives were to determine the number of MS patients who met Spasticity-Plus syndrome criteria and to identify the most common symptoms. Clinical records of MS patients treated with nabiximols in a tertiary hospital from 2002 to 2022 were reviewed retrospectively. Of the 73 patients included in the study, 53.4% were women, and most had secondary progressive MS (64.4%). All patients met the criteria for Spasticity-Plus syndrome: 100% had spasticity and at least another symptom. Pain was the second most common symptom (91.8%), followed by spasms/cramps (79.4%), and fatigue (76.7%). Sleep disturbances (p < 0.0001) and tremor (p < 0.027) were more frequent in patients with relapsing-remitting MS than in patients with progressive MS. No statistically significant differences were found for spasticity, pain, spasms/cramps, and fatigue between MS phenotypes. Regarding symptoms clusters, 94.4% of the patients had three or more symptoms. Spasticity was more frequently associated with pain (91.8%) and spasms/cramps (79.4%). Spasticity-Plus syndrome was present in all the study population of patients with different MS phenotypes, and treated with nabiximols.

Disentangling multiple sclerosis phenotypes through Mendelian disorders: A network approach

Background: The increasing knowledge about multiple sclerosis (MS) pathophysiology has reinforced the need for an improved description of disease phenotypes, connected to disease biology. Growing evidence indicates that complex diseases constitute phenotypical and genetic continuums with “simple,” monogenic disorders, suggesting shared pathomechanisms. Objectives: The objective of this study was to depict a novel MS phenotypical framework leveraging shared physiopathology with Mendelian diseases and to identify phenotype-specific candidate drugs. Methods: We performed an enrichment testing of MS-associated variants with Mendelian disorders genes. We defined a “MS-Mendelian network,” further analyzed to define enriched phenotypic subnetworks and biological processes. Finally, a network-based drug screening was implemented. Results: Starting from 617 MS-associated loci, we showed a significant enrichment of monogenic diseases (p < 0.001). We defined an MS-Mendelian molecular network based on 331 genes and 486 related disorders, enriched in four phenotypic classes: neurologic, immunologic, metabolic, and visual. We prioritized a total of 503 drugs, of which 27 molecules active in 3/4 phenotypical subnetworks and 140 in subnetwork pairs. Conclusion: The genetic architecture of MS contains the seeds of pathobiological multiplicities shared with immune, neurologic, metabolic and visual monogenic disorders. This result may inform future classifications of MS endophenotypes and support the development of new therapies in both MS and rare diseases.

Vitamin D Supplementation: Effect on Cytokine Profile in Multiple Sclerosis

Vitamin D is known for its role in modulating calcium and phosphate homeostasis and is implicated both in bone mineralization and immune system regulation. The immune-modulatory role of vitamin D and its impact on multiple sclerosis (MS) courses are still debated. The aim of this review was to check the effect of vitamin D supplementation on cytokine profile regulation in people with MS. A significant increase in serum concentrations of interleukin (IL)-10 and Transforming growth factor (TGF)-β1 after vitamin D supplementation was demonstrated in most studies, with some of them reporting a reduction in disability scores after vitamin D supplementation and an inverse correlation between IL-10 levels and disability. The effect of vitamin D on the serum levels of IL-17 and IL-6 was controversial; different results across studies could be explained by a variability in the treatment duration, route, and frequency of administration, as well as the dosage of vitamin D supplementation, responses to vitamin D treatment and the serum levels reached with supplementation, including the methods used for cytokine analysis and the different cell types investigated, the MS phenotype, the disease phase (active vs. non-active) and duration, and concomitant treatment with disease-modifying therapies. Nevertheless, the significant increase in the serum concentrations of IL-10 and TGF-β1, demonstrated in most studies, suggests an anti-inflammatory effect of vitamin D supplementation.

Time is myelin: early cortical myelin repair prevents atrophy and clinical progression in multiple sclerosis.

Cortical myelin loss and repair in multiple sclerosis (MS) have been explored in neuropathological studies, but the impact of these processes on neurodegeneration and the irreversible clinical progression of the disease remains unknown. Here, we evaluated in vivo cortical demyelination and remyelination in a large cohort of people with all clinical phenotypes of MS followed up for 5 years using magnetization transfer imaging (MTI), a technique that has been shown to be sensitive to myelin content changes in the cortex. We investigated 140 people with MS (37 clinically isolated syndrome, 71 relapsing-MS, 32 progressive-MS), who were clinically assessed at baseline and after 5 years and, along with 84 healthy controls, underwent a 3 T-MRI protocol including MTI at baseline and after 1 year. Changes in cortical volume over the radiological follow-up were computed with a Jacobian integration method. Magnetization transfer ratio was employed to calculate for each patient an index of cortical demyelination at baseline and of dynamic cortical demyelination and remyelination over the follow-up period. The three indices of cortical myelin content change were heterogeneous across patients but did not significantly differ across clinical phenotypes or treatment groups. Cortical remyelination, which tended to fail in the regions closer to CSF (-11%, P < 0.001), was extensive in half of the cohort and occurred independently of age, disease duration and clinical phenotype. Higher indices of cortical dynamic demyelination (β = 0.23, P = 0.024) and lower indices of cortical remyelination (β = -0.18, P = 0.03) were significantly associated with greater cortical atrophy after 1 year, independently of age and MS phenotype. While the extent of cortical demyelination predicted a higher probability of clinical progression after 5 years in the entire cohort [odds ratio (OR) = 1.2; P = 0.043], the impact of cortical remyelination in reducing the risk of accumulating clinical disability after 5 years was significant only in the subgroup of patients with shorter disease duration and limited extent of demyelination in cortical regions (OR = 0.86, P = 0.015, area under the curve = 0.93). In this subgroup, a 30% increase in cortical remyelination nearly halved the risk of clinical progression at 5 years, independently of clinical relapses. Overall, our results highlight the critical role of cortical myelin dynamics in the cascade of events leading to neurodegeneration and to the subsequent accumulation of irreversible disability in MS. Our findings suggest that early-stage myelin repair compensating for cortical myelin loss has the potential to prevent neuro-axonal loss and its long-term irreversible clinical consequences in people with MS.

Domain-specific cognitive impairment in multiple sclerosis: A systematic review and meta-analysis.

Methods of cognitive measurements in multiple sclerosis (MS) are not standardized. We aimed to identify the prevalence of cognitive domain-specific impairment (DSI) in MS by using subtests of the Brief Repeatable Battery of Neuropsychological Tests (BRB-N) with analyzing different cutoff values. The systematic review and meta-analysis were registered on PROSPERO (ID: CRD42021287004). The systematic literature search was performed via PubMed, Embase, and CENTRAL on 24 October 2021. Inclusion criteria were adults of different MS subtypes (CIS, RRMS, PPMS, and SPMS) with the condition of distinct DSI measured by BRB-N. Pediatric MS, computerized versions of BRB-N, and patients receiving steroids were excluded. Primary outcome was pooled prevalence rates of impaired patients within each cutoff and MS subtype, with 95% confidence interval, I-squared statistics for heterogeneity, and chi-squared test for subgroup differences. Risk of bias was assessed using the "JBI Quality Assessment Tool for Prevalence Studies." In 48 eligible observational studies (n = 3431 patients), the three most prevalent thresholds were the 2.0 SD and 1.5 SD below the mean of normative values, and the score below the fifth percentile of the normative values. A progressively increasing worsening of the overall DSI was observed from CIS, moving toward RRMS, PPMS, and SPMS. Cognitive impairment is observed in all MS phenotypes, with varying degrees. Due to several potential influencing factors, our comprehensive literature review has not revealed consistent findings, and we, therefore, recommend considering a more sophisticated, "individual referencing" approach, acknowledging the diverse clinical and sociodemographic characteristics among populations and disparities in cognitive testing.

Autoimmune demyelination alters hypothalamic transcriptome and endocrine function

The hypothalamus is a brain structure that is deputed to maintain organism homeostasis by regulating autonomic function and hormonal production as part of the neuroendocrine system. Dysfunction in hypothalamic activity results in behavioral alterations, depression, metabolic syndromes, fatigue, and infertility. Remarkably, many of these symptoms are associated with multiple sclerosis (MS), a chronic autoimmune disorder of the central nervous system (CNS) characterized by focal demyelination, immune cell infiltration into the brain parenchyma, and neurodegeneration. Furthermore, altered hormonal levels have been documented in MS patients, suggesting the putative involvement of hypothalamic deficits in MS clinical manifestations. Yet, a systematic analysis of hypothalamic function in response to neuroinflammatory stress is still lacking. To fill this gap, here we performed a longitudinal profiling of the hypothalamic transcriptome upon experimental autoimmune encephalomyelitis (EAE)—a murine disease model recapitulating key MS phenotypes at both histopathological and molecular levels. We show that changes in gene expression connected with an anti-inflammatory response start already at pre-onset and persist along EAE progression. Altered levels of hypothalamic neuropeptides were also detected, which possibly underlie homeostatic responses to stress and aberrant feeding behaviors. Last, a thorough investigation of the principal endocrine glands highlighted defects in the main steroidogenic pathways upon disease. Collectively, our findings corroborate the central role of hypothalamic dysfunction in CNS autoimmunity.

Seasonality and clinical characteristics of MS in an equatorial country

BackgroundMonth and season of birth have been associated with risk of multiple sclerosis (MS), but there is relatively little evidence regarding their influence on the timing and severity of disease at onset. ObjectiveTo assess whether month and season of birth influence the age and phenotype at onset of MS as well as its severity in a cohort of Colombian patients. MethodsThis study is an analysis on MS cases only, drawn from a previously published case-control study. MS cases confirmed with current diagnostic criteria cared for at least once in our center were included. We assessed the influence of the month and season of birth in the age at MS onset, MS severity score, and age-related MS severity score using multiple and pairwise comparisons. Age at onset was also studied using Kaplan–Meier survival estimates compared with the log-rank test. The likelihood of progressive MS onset was evaluated with OR estimated from logistic regression models adjusted for age at onset and sex. Results668 MS cases were included. No significant differences were found in the age at MS onset according to month of birth or season of birth. Neither month of birth nor season of birth conferred significant differences in MS severity score or age-related MS severity score. No significant association was found between month (ORs ranging from 0.62 to 3.11, none significant) or season of birth (OR 0.91; 95 %CI: 0.46–1.84) with primary progressive MS. ConclusionThe month or season of birth do not appear to influence the age onset and phenotype of MS in our country.

Autologous HSCT for Multiple Sclerosis Should be Done Early in the Course of the Disease

Introduction: Multiple sclerosis (MS) is a disabling disease that affects young adults. Treatments for MS have increased exponentially in number, efficacy and risk. Autologous hematopoietic stem cell transplantation (aHSCT) can change the natural history of the disease. To analyze if aHSCT should be done early in the course of the disease or after failing of other therapies, we have studied the long-term results of aHSCT in a cohort of persons with MS Materials and methods: Patients with MS referred to our center for aHSCT between June 2015 and July 2023 were prospectively entered in the study. All phenotypes of MS were included (relapsing remitting, primary progressive and secondary progressive). The follow up was assessed with the patient reported EDSS score in an online form; only patients followed by three or more years were included in the analysis. ). The progression of MS was assessed by changes in the expanded disability status scale (EDSS).The response rate was analyzed for four variables: Disease-modyfing treatment (DMT) given or not before the HSCT and delay in the diagnosis and treatment: More (delayed diagnosis DD), or less (non-delayed diagnosis NDD) than 8 months after the onset of symptoms. Results: 1518 subjects were prospectively enrolled. In a subset of 103 patients, detailed pre- and post-transplant evolution could be recorded. Two groups of patients were analyzed according to the time of evolution between the onset of symptoms and the definite diagnosis of MS: More than 8 months, (delayed diagnosis, DD) or less than 8 months (non-delayed diagnosis, NDD). The time elapsed between the onset of symptoms and the correct diagnosis was lower for the NDD group (1.55 vs 35.87 months, p&amp;lt;0.05). Both groups of patients showed a similar EDSS score at diagnosis (1.5 vs 1.5); however, the EDSS at the time of the transplant was higher in the DD group (4.5 vs 3.0, p= 0.3) and the response of the EDSS score to the transplant was significantly better for the NDD group, the last censored values for the EDSS being 2.5 vs 4.25 (p= 0.03). The two groups of patients responded to aHSCT by diminishing the EDSS, but the response was significantly better in the NDD group. On the other hand, 74 patients were followed for more than 36 months, and the subsequent analysis was done in this cohort. The response rate (RR = improvement + stabilization) at 12, 24 and 36 mo was 84%, 84% and 58% respectively for patients not receiving prior disease modifying treatments (DMT) and 72%, 90% and 67% for patients receiving DMT. In the whole group, the EDSS score dropped from a mean of 5.5 to 4.5 at 12 mo, to 5.0 at 24 mo and to 5.5 at 36 mo, after the aHSCT. The EDSS score was on average worsening in patients before the aHSCT, but the transplant stabilized the EDSS score at 3 years in patients with prior exposure to DMT, whereas in persons not given DMT, the transplant resulted in a significant decrease (p = .01) of the EDSS score. This indicates a positive response in all patients given aHSCT, but significantly better in those not exposed to DMT before the graft. Conclusion: These data indicate that both the pre-transplant progression of the disease and the response to aHSCT were significantly worse in persons with a delayed diagnosis. An early diagnosis and an early aHSCT intervention are critical for a good prognosis, in terms of lowering and stabilizing the motor disability in MS patients given autografts. Moreover, the response to aHSCT was better for persons not exposed to immunosuppressive DMT before the transplant, thus suggesting that aHSCT should be done early in the course of the disease and probably before the treatment with DMT. Additional studies are needed to further analyze the impact of the use of DMT therapies before the aHSCT in MS, as well as the timing of the procedure.

Cognitive phenotypes in multiple sclerosis: mapping the spectrum of impairment.

Available criteria for cognitive phenotypes in multiple sclerosis (MS) do not consider the severity of impairment. To identify cognitive phenotypes with varying degrees of impairment in MS patients and describe their demographic, clinical and MRI characteristics. Two hundred and forty-three MS patients and 158 healthy controls underwent neuropsychological tests to assess memory, attention, and executive function. For each domain, mild impairment was defined as performing 1.5 standard deviations below the normative mean on two tests, while the threshold for significant impairment was 2 standard deviations. Patients were classified into cognitive phenotypes based on severity of the impairment (mild/significant) and number of domains affected (one/more). Five cognitive phenotypes emerged: Preserved cognition (PC; 56%), Mild Single-Domain Impairment (MSD; 15%), Mild Multi-Domain Impairment (MMD; 9%), Significant Single-Domain Impairment (SSD; 12%), Significant Multi-Domain Impairment (SMD; 8%). Compared with PC, MSD patients were older, had longer disease duration (DD) and higher T2-hyperintense lesion volume (LV; all p ≤ 0.02); MMD patients were older, had longer DD, higher disability, higher T2 LV and lower thalamic volume (all p ≤ 0.01); SSD patients had longer DD and lower gray matter cortical volume, thalamic, caudate, putamen and accumbens volumes (all p ≤ 0.04); and SMD patients were older, had longer DD, higher disability and more extensive structural damage in all brain regions explored (all p ≤ 0.03), except white matter and amygdala volumes. We identified five cognitive phenotypes with graded levels of impairment. These phenotypes were characterized by distinct demographic, clinical and MRI features, indicating potential variations in the neural substrates of dysfunction throughout disease stages.