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Multiple sclerosis (MS) is a neurological disorder characterized by immune dysregulation. It begins with a first clinical manifestation, a clinically isolated syndrome (CIS), which evolves to definite MS in case of further clinical and/or neuroradiological episodes. Here we evaluated the diagnostic value of transcriptional alterations in MS and CIS blood by machine learning (ML). Deep sequencing of more than 200 blood RNA samples comprising CIS, MS and healthy subjects, generated transcriptomes that were analyzed by the binary classification workflow to distinguish MS from healthy subjects and the Time-To-Event pipeline to predict CIS conversion to MS along time. To identify optimal classifiers, we performed algorithm benchmarking by nested cross-validation with the train set in both pipelines and then tested models generated with the train set on an independent dataset for final validation. The binary classification model identified a blood transcriptional signature classifying definite MS from healthy subjects with 97% accuracy, indicating that MS is associated with a clear predictive transcriptional signature in blood cells. When analyzing CIS data with ML survival models, prediction power of CIS conversion to MS was about 72% when using paraclinical data and 74.3% when using blood transcriptomes, indicating that blood-based classifiers obtained at the first clinical event can efficiently predict risk of developing MS. Coupling blood transcriptomics with ML approaches enables retrieval of predictive signatures of CIS conversion and MS state, thus introducing early non-invasive approaches to MS diagnosis.
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Neurological disorders, including multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS), may be associated with alterations in blood cell composition and phenotype. Here, we focused our attention on circulating mucosal-associated invariant T (MAIT) cells, a CD8+ T cell memory population expressing the invariant Vα7.2 region in the T cell receptor and high surface levels of the CD161 marker. Transcriptomics data relative to peripheral blood mononuclear cells (PBMC) highlighted downregulation of CD161 and other MAIT-associated markers in progressive MS and not relapsing remitting (RR)-MS when gene expressions relative to each disease course were compared to those from healthy controls. Multiparametric flow cytometry of freshly isolated PBMC samples from untreated RR-MS, primary or secondary progressive MS (PP- or SP-MS), ALS and age- and sex-matched healthy controls revealed specific loss of circulating CD8+ MAIT cells in PP-MS and no other MS courses or another neurological disorder such as ALS. Overall, these observations point to the existence of immunological changes in blood specific for the primary progressive course of MS that may support clinical definition of disease.
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Esclerose Lateral Amiotrófica , Células T Invariantes Associadas à Mucosa , Humanos , Esclerose Lateral Amiotrófica/imunologia , Esclerose Lateral Amiotrófica/sangue , Células T Invariantes Associadas à Mucosa/imunologia , Células T Invariantes Associadas à Mucosa/metabolismo , Masculino , Pessoa de Meia-Idade , Feminino , Adulto , Idoso , Esclerose Múltipla/imunologia , Esclerose Múltipla/sangue , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Biomarcadores , Citometria de FluxoRESUMO
BACKGROUND: Vitamin D (VitD) affects the risk of multiple sclerosis (MS), but the impact on disease activity is controversial. We assessed whether VitD is associated with the No-Evidence of Disease Activity-3 (NEDA-3) status at 2 years from disease-modifying treatment (DMT) start, and whether this association is causal or the result of confounding factors. Furthermore, we explored if a genetic predisposition to higher VitD levels affects the risk of disease activity. METHODS: 230 untreated relapsing-remitting MS patients underwent serum 25-OH-vitamin-D measurement, and the association between seasonally adjusted VitD and disease activity was tested. Modelling a Polygenic Risk Score from a Genome-Wide Association Study on ~400 000 individuals, we studied the impact of genetic predisposition to higher VitD on the NEDA-3 status in 1408 independent MS patients. Two-sample Mendelian randomisation (MR) was used to assess causality. RESULTS: Lower baseline VitD was associated with decreased probability of NEDA-3 at 2 years (p=0.019). Particularly, VitD levels <20 ng/mL conferred an over twofold risk of disease activity (OR 2.36, 95% CI 1.30 to 3.88, p=0.0037). Genetic predisposition to higher VitD levels was associated with delayed age at MS onset (p=0.018) and with a higher probability of NEDA-3 status (p=0.034). MR confirmed causality between VitD and the risk of disease activity (p=0.041). CONCLUSIONS: VitD levels before DMT start affect the risk of disease activity in MS. Genetic predisposition to higher VitD levels confers a lower risk of disease activity and is associated with delayed MS onset. Our work prompts future prospective studies regarding VitD supplementation and lifestyle interventions to hamper disease activity in MS.
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Multiple sclerosis (MS) is a complex disorder characterized by high heterogeneity in terms of phenotypic expression, prognosis and treatment response. In the present study, we aimed to explore the genetic contribution to MS disease activity at different levels: genes, pathways and tissue-specific networks. Two cohorts of relapsing-remitting MS patients who started a first-line treatment (n = 1294) were enrolled to evaluate the genetic association with disease activity after 4 years of follow-up. The analyses were performed at whole-genome SNP and gene level, followed by the construction of gene-gene interaction networks specific for brain and lymphocytes. The resulting gene modules were evaluated to highlight key players from a topological and functional perspective. We identified 23 variants and 223 genes with suggestive association to 4-years disease activity, highlighting genes like PON2 involved in oxidative stress and in mitochondria functions and other genes, like ILRUN, involved in the modulation of the immune system. Network analyses led to the identification of a brain module composed of 228 genes and a lymphocytes module composed of 287 genes. The network analysis allowed us to prioritize genes relevant for their topological properties; among them, there are MPHOSPH9 (connector hub in both brain and lymphocyte module) and OPA1 (in brain module), two genes already implicated in MS. Modules showed the enrichment of both shared and tissue-specific pathways, mainly implicated in inflammation. In conclusion, our results suggest that the processes underlying disease activity act on shared mechanisms across brain and lymphocyte tissues.
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BACKGROUND: While John Cunningham virus (JCV) is known to cause neuronal damage in progressive multifocal leukoencephalopathy (PML) among natalizumab-treated MS patients, its association with axonal loss in non-PML conditions remains unclear. METHODS: In a cohort of 128 natalizumab-treated MS patients, serum neurofilament (sNfL) levels and JCV antibody titres were measured. RESULTS: Among 128 patients (mean age = 38.4 years, 71.9% female), 51 (40%) were JCV positive. NfL levels increased by 15.3% for JCV index <0.7 (95% confidence interval [CI] = 0.963-1.381), by 18.6% for index 0.7-1.5 (95% CI = 1.009-1.394) and by 21.1% for index >1.5 (95% CI = 1.040-1.409) compared to JCV negative patients. CONCLUSION: These findings indicate a potential link between JCV burden and neuroaxonal degeneration in natalizumab-treated MS patients.
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BACKGROUND AND OBJECTIVES: The diagnosis of multiple sclerosis (MS) can be challenging in clinical practice because MS presentation can be atypical and mimicked by other diseases. We evaluated the diagnostic performance, alone or in combination, of the central vein sign (CVS), paramagnetic rim lesion (PRL), and cortical lesion (CL), as well as their association with clinical outcomes. METHODS: In this multicenter observational study, we first conducted a cross-sectional analysis of the CVS (proportion of CVS-positive lesions or simplified determination of CVS in 3/6 lesions-Select3*/Select6*), PRL, and CL in MS and non-MS cases on 3T-MRI brain images, including 3D T2-FLAIR, T2*-echo-planar imaging magnitude and phase, double inversion recovery, and magnetization prepared rapid gradient echo image sequences. Then, we longitudinally analyzed the progression independent of relapse and MRI activity (PIRA) in MS cases over the 2 years after study entry. Receiver operating characteristic curves were used to test diagnostic performance and regression models to predict diagnosis and clinical outcomes. RESULTS: The presence of ≥41% CVS-positive lesions/≥1 CL/≥1 PRL (optimal cutoffs) had 96%/90%/93% specificity, 97%/84%/60% sensitivity, and 0.99/0.90/0.77 area under the curve (AUC), respectively, to distinguish MS (n = 185) from non-MS (n = 100) cases. The Select3*/Select6* algorithms showed 93%/95% specificity, 97%/89% sensitivity, and 0.95/0.92 AUC. The combination of CVS, CL, and PRL improved the diagnostic performance, especially when Select3*/Select6* were used (93%/94% specificity, 98%/96% sensitivity, 0.99/0.98 AUC; p = 0.002/p < 0.001). In MS cases (n = 185), both CL and PRL were associated with higher MS disability and severity. Longitudinal analysis (n = 61) showed that MS cases with >4 PRL at baseline were more likely to experience PIRA at 2-year follow-up (odds ratio 17.0, 95% confidence interval: 2.1-138.5; p = 0.008), whereas no association was observed between other baseline MRI measures and PIRA, including the number of CL. DISCUSSION: The combination of CVS, CL, and PRL can improve MS differential diagnosis. CL and PRL also correlated with clinical measures of poor prognosis, with PRL being a predictor of disability accrual independent of clinical/MRI activity.
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Imageamento por Ressonância Magnética , Esclerose Múltipla , Humanos , Feminino , Masculino , Adulto , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/diagnóstico , Pessoa de Meia-Idade , Estudos Transversais , Prognóstico , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/patologia , Veias Cerebrais/diagnóstico por imagem , Veias Cerebrais/patologia , Progressão da Doença , Estudos LongitudinaisAssuntos
Síndrome da Leucoencefalopatia Posterior , Humanos , Síndrome da Leucoencefalopatia Posterior/induzido quimicamente , Síndrome da Leucoencefalopatia Posterior/diagnóstico por imagem , Feminino , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/complicações , Esclerose Múltipla/diagnóstico por imagem , Interferon beta-1a/efeitos adversos , Adulto , Imageamento por Ressonância Magnética , Fatores Imunológicos/efeitos adversosRESUMO
BACKGROUND: Sequelae of COVID-19 in people with multiple sclerosis (PwMS) have not been characterised. We explored whether COVID-19 is associated with an increased risk of disease activity, disability worsening, neuropsychological distress and cognitive dysfunction during the 18-24 months following SARS-COV-2 infection. METHODS: We enrolled 174 PwMS with history of COVID-19 (MS-COVID) between March 2020 and March 2021 and compared them to an age, sex, disease duration, Expanded Disability Status Scale (EDSS), and a line of treatment-matched group of 348 PwMS with no history of COVID-19 in the same period (MS-NCOVID). We collected clinical, MRI data and SARS-CoV2 immune response in the 18-24 months following COVID-19 or baseline evaluation. At follow-up, PwMS also underwent a complete neuropsychological assessment with brief repeatable battery of neuropsychological tests and optimised scales for fatigue, anxiety, depression and post-traumatic stress symptoms. RESULTS: 136 MS-COVID and 186 MS-NCOVID accepted the complete longitudinal evaluation. The two groups had similar rate of EDSS worsening (15% vs 11%, p=1.00), number of relapses (6% vs 5%, p=1.00), disease-modifying therapy change (7% vs 4%, p=0.81), patients with new T2-lesions (9% vs 11%, p=1.00) and gadolinium-enhancing lesions (7% vs 4%, p=1.00) on brain MRI. 22% of MS-COVID and 23% MS-NCOVID were cognitively impaired at 18-24 months evaluation, with similar prevalence of cognitive impairment (p=1.00). The z-scores of global and domain-specific cognitive functions and the prevalence of neuropsychiatric manifestations were also similar. No difference was detected in terms of SARS-CoV2 cellular immune response. CONCLUSIONS: In PwMS, COVID-19 has no impact on disease activity, course and cognitive performance 18-24 months after infection.
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COVID-19 , Esclerose Múltipla , Humanos , Esclerose Múltipla/complicações , Esclerose Múltipla/tratamento farmacológico , RNA Viral/uso terapêutico , COVID-19/complicações , SARS-CoV-2 , CogniçãoRESUMO
BACKGROUND: Monoaminergic network dysfunction may have a role in multiple sclerosis (MS) fatigue pathogenesis. OBJECTIVE: To investigate modifications of fatigue severity and resting state (RS) functional connectivity (FC) in monoaminergic networks of 45 fatigued MS patients after different symptomatic treatments. METHODS: Patients were randomly, blindly assigned to fampridine (n = 15), amantadine (n = 15) or placebo (n = 15) treatment and underwent clinical and 3T-MRI evaluations at baseline (t0) and week 4 (w4), i.e. after four weeks of treatment. Fifteen healthy controls (HC) were enrolled. Dopamine-, noradrenaline- and serotonin-related RS FC was assessed by PET-guided constrained independent component analysis. RESULTS: At t0, MS patients showed widespread monoamine-related RS FC abnormalities. At w4, fatigue scores decreased in all groups (p = range < 0.001-0.002). Concomitantly, fampridine and amantadine patients showed increased insular RS FC in dopamine-related and noradrenaline-related networks (p < 0.001, uncorrected). Amantadine patients also showed increased RS FC of anterior cingulate cortex in dopamine-related and noradrenaline-related networks (p < 0.001, uncorrected). Placebo patients showed increased precuneus/middle cingulate RS FC in the noradrenaline-related network (p < 0.001, uncorrected). In fampridine and placebo patients, just tendencies towards correlations between RS FC and fatigue modifications were found. CONCLUSIONS: In MS patients, specific RS FC modifications in PET-guided monoaminergic networks were observed, concomitantly with fatigue improvements following treatment. TRIAL REGISTRATION NUMBER: EudraCT 2010-023678-38.
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Dopamina , Esclerose Múltipla , Humanos , Esclerose Múltipla/complicações , Fadiga/diagnóstico por imagem , Fadiga/tratamento farmacológico , Fadiga/etiologia , Imageamento por Ressonância Magnética , Amantadina/uso terapêutico , Encéfalo/patologia , Mapeamento EncefálicoRESUMO
Hepatocyte nuclear factor 4 α (HNF4α), a transcription factor (TF) essential for embryonic development, has been recently shown to regulate the expression of inflammatory genes. To characterize HNF4a function in immunity, we measured the effect of HNF4α antagonists on immune cell responses in vitro and in vivo. HNF4α blockade reduced immune activation in vitro and disease severity in the experimental model of multiple sclerosis (MS). Network biology studies of human immune transcriptomes unraveled HNF4α together with SP1 and c-myc as master TF regulating differential expression at all MS stages. TF expression was boosted by immune cell activation, regulated by environmental MS risk factors and higher in MS immune cells compared to controls. Administration of compounds targeting TF expression or function demonstrated non-synergic, interdependent transcriptional control of CNS autoimmunity in vitro and in vivo. Collectively, we identified a coregulatory transcriptional network sustaining neuroinflammation and representing an attractive therapeutic target for MS and other inflammatory disorders.
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Autoimunidade , Fator 4 Nuclear de Hepatócito , Esclerose Múltipla , Humanos , Autoimunidade/genética , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Fator 4 Nuclear de Hepatócito/genética , Fator 4 Nuclear de Hepatócito/metabolismo , Esclerose Múltipla/genética , Esclerose Múltipla/imunologia , Transcriptoma , Genes mycRESUMO
INTRODUCTION: Cladribine is approved for the treatment of active relapsing MS (RRMS), but its positioning in MS therapeutic scenario still needs to be fully elucidated. METHODS: This is a monocentric, observational, real-world study on RRMS patients treated with cladribine. Relapses, magnetic resonance imaging (MRI) activity, disability worsening, and loss of no-evidence-of-disease-activity-3 (NEDA-3) status were assessed as outcomes. White blood cell, lymphocyte counts and side effects were also evaluated. Patients were analyzed overall and in subgroups according to the last treatment before cladribine. The relationship between baseline characteristics and outcomes was tested to identify predictors of response. RESULTS: Among the 114 patients included, 74.9% were NEDA-3 at 24 months. We observed a reduction of relapses and MRI activity, along with a stabilization of disability. A higher number of gadolinium-enhancing lesions at baseline was the only risk factor for loss of NEDA-3 during follow-up. Cladribine was more efficacious in switchers from first-line therapies or naïves. Grade I lymphopenia was more frequent at month 3 and 15. No grade IV lymphopenia cases were observed. Independent predictors of grade III lymphopenia were a lower baseline lymphocyte count and a higher number of previous treatments. Sixty-two patients presented at least one side effect and globally 111 adverse events were recorded, none of them was serious. CONCLUSIONS: Our study confirms previous data on cladribine effectiveness and safety. Cladribine is more effective when placed early in the treatment algorithm. Real-world data on larger populations with longer follow-up are needed to confirm our findings.
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Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Linfopenia , Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Humanos , Cladribina/efeitos adversos , Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagem , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/induzido quimicamente , Imunossupressores/efeitos adversos , Esclerose Múltipla/tratamento farmacológico , Linfopenia/induzido quimicamente , RecidivaRESUMO
Interleukin (IL)-10 is a main player in peripheral immune tolerance, the physiological mechanism preventing immune reactions to self/harmless antigens. Here, we investigate IL-10-induced molecular mechanisms generating tolerogenic dendritic cells (tolDC) from monocytes. Using genomic studies, we show that IL-10 induces a pattern of accessible enhancers exploited by aryl hydrocarbon receptor (AHR) to promote expression of a set of core genes. We demonstrate that AHR activity occurs downstream of IL-10 signaling in myeloid cells and is required for the induction of tolerogenic activities in DC. Analyses of circulating DCs show that IL-10/AHR genomic signature is active in vivo in health. In multiple sclerosis patients, we instead observe significantly altered signature correlating with functional defects and reduced frequencies of IL-10-induced-tolDC in vitro and in vivo. Our studies identify molecular mechanisms controlling tolerogenic activities in human myeloid cells and may help in designing therapies to re-establish immune tolerance.
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Interleucina-10 , Receptores de Hidrocarboneto Arílico , Humanos , Células Dendríticas/metabolismo , Tolerância Imunológica , Interleucina-10/metabolismo , Monócitos/metabolismo , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismoRESUMO
BACKGROUND: Disease and treatment-associated immune system abnormalities may confer higher risk of Coronavirus disease 2019 (COVID-19) to people with multiple sclerosis (PwMS). We assessed modifiable risk factors associated with COVID-19 in PwMS. METHODS: Among patients referring to our MS Center, we retrospectively collected epidemiological, clinical and laboratory data of PwMS with confirmed COVID-19 between March 2020 and March 2021 (MS-COVID, n = 149). We pursued a 1:2 matching of a control group by collecting data of PwMS without history of previous COVID-19 (MS-NCOVID, n = 292). MS-COVID and MS-NCOVID were matched for age, expanded disability status scale (EDSS) and line of treatment. We compared neurological examination, premorbid vitamin D levels, anthropometric variables, life-style habits, working activity, and living environment between the two groups. Logistic regression and Bayesian network analyses were used to evaluate the association with COVID-19. RESULTS: MS-COVID and MS-NCOVID were similar in terms of age, sex, disease duration, EDSS, clinical phenotype and treatment. At multiple logistic regression, higher levels of vitamin D (OR 0.93, p < 0.0001) and active smoking status (OR 0.27, p < 0.0001) emerged as protective factors against COVID-19. In contrast, higher number of cohabitants (OR 1.26, p = 0.02) and works requiring direct external contact (OR 2.61, p = 0.0002) or in the healthcare sector (OR 3.73, p = 0.0019) resulted risk factors for COVID-19. Bayesian network analysis showed that patients working in the healthcare sector, and therefore exposed to increased risk of COVID-19, were usually non-smokers, possibly explaining the protective association between active smoking and COVID-19. CONCLUSIONS: Higher Vitamin D levels and teleworking may prevent unnecessary risk of infection in PwMS.
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COVID-19 , Esclerose Múltipla , Humanos , Esclerose Múltipla/complicações , Esclerose Múltipla/epidemiologia , Esclerose Múltipla/tratamento farmacológico , Estudos de Casos e Controles , Estudos Retrospectivos , Teorema de Bayes , Vitamina D/uso terapêutico , Fatores de RiscoRESUMO
BACKGROUND AND OBJECTIVES: The major histocompatibility complex (MHC) locus has a predominant role in the genetic predisposition to multiple sclerosis (MS), with 32 associations found to be involved. We aimed to investigate the impact of MHC MS-risk alleles on T-cell repertoire in patients with MS. METHODS: We studied 161 untreated patients with relapsing-remitting MS for whom Class I and II human leukocyte antigen (HLA) alleles were inferred from whole-genome genotyping data, and T-cell receptor (TCR) CDR3 sequences were obtained through next-generation sequencing. T-cell repertoire features including diversity, public clones, and architecture were evaluated. RESULTS: We identified 5 MS-risk loci associated with TCR diversity: HLA-DRB1*15:01 (7.65 × 10-3), rs9271366 (1.96 × 10-3), rs766848979 A (1.89 × 10-2), rs9277626 (2.95 × 10-2), and rs11751659 (1.92 × 10-2), with evidence of expanded clonotypes in carriers of risk alleles. Moreover, HLA-DRB1*15:01 (4.99 × 10-3), rs9271366 (6.54 × 10-3), rs1049079 C (4.37 × 10-2), AA DQΒ1 position -5 L (1.05 × 10-3), and AA DQΒ1 position 221 Q (9.39 × 10-4) showed an association with the CDR3 aminoacidic sequence architecture, suggesting an impact on the antigen recognition breadth as well. Evaluating the sharing of clones across MS-risk allele carrier individuals revealed the presence of highly shared clonotypes predicted to target viral antigens, including Epstein-Barr virus. DISCUSSION: Our study supports the association between MHC-risk alleles and macrofeatures of the T-cell repertoire in the context of MS. Further studies are needed to understand the underlying molecular mechanisms.
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Infecções por Vírus Epstein-Barr , Esclerose Múltipla , Humanos , Herpesvirus Humano 4 , Cadeias HLA-DRB1/genética , Esclerose Múltipla/genética , Receptores de Antígenos de Linfócitos T/genética , Linfócitos T , Antígenos HLA/genéticaRESUMO
Innovative pro-regenerative treatment strategies for progressive multiple sclerosis (PMS), combining neuroprotection and immunomodulation, represent an unmet need. Neural precursor cells (NPCs) transplanted in animal models of multiple sclerosis have shown preclinical efficacy by promoting neuroprotection and remyelination by releasing molecules sustaining trophic support and neural plasticity. Here we present the results of STEMS, a prospective, therapeutic exploratory, non-randomized, open-label, single-dose-finding phase 1 clinical trial ( NCT03269071 , EudraCT 2016-002020-86), performed at San Raffaele Hospital in Milan, Italy, evaluating the feasibility, safety and tolerability of intrathecally transplanted human fetal NPCs (hfNPCs) in 12 patients with PMS (with evidence of disease progression, Expanded Disability Status Scale ≥6.5, age 18-55 years, disease duration 2-20 years, without any alternative approved therapy). The safety primary outcome was reached, with no severe adverse reactions related to hfNPCs at 2-year follow-up, clearly demonstrating that hfNPC therapy in PMS is feasible, safe and tolerable. Exploratory secondary analyses showed a lower rate of brain atrophy in patients receiving the highest dosage of hfNPCs and increased cerebrospinal fluid levels of anti-inflammatory and neuroprotective molecules. Although preliminary, these results support the rationale and value of future clinical studies with the highest dose of hfNPCs in a larger cohort of patients.
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Transplante de Células-Tronco Hematopoéticas , Esclerose Múltipla , Células-Tronco Neurais , Adolescente , Adulto , Humanos , Pessoa de Meia-Idade , Adulto Jovem , Esclerose Múltipla/terapia , Estudos Prospectivos , Transplante de Células-Tronco/métodosRESUMO
A personalized approach is strongly advocated for treatment selection in Multiple Sclerosis patients due to the high number of available drugs. Machine learning methods proved to be valuable tools in the context of precision medicine. In the present work, we applied machine learning methods to identify a combined clinical and genetic signature of response to fingolimod that could support the prediction of drug response. Two cohorts of fingolimod-treated patients from Italy and France were enrolled and divided into training, validation, and test set. Random forest training and robust feature selection were performed in the first two sets respectively, and the independent test set was used to evaluate model performance. A genetic-only model and a combined clinical-genetic model were obtained. Overall, 381 patients were classified according to the NEDA-3 criterion at 2 years; we identified a genetic model, including 123 SNPs, that was able to predict fingolimod response with an AUROC= 0.65 in the independent test set. When combining clinical data, the model accuracy increased to an AUROC= 0.71. Integrating clinical and genetic data by means of machine learning methods can help in the prediction of response to fingolimod, even though further studies are required to definitely extend this approach to clinical applications.
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BACKGROUND: The precuneus is involved in cognition and depression; static functional connectivity (SFC) abnormalities of this region have been observed in neuromyelitis optica spectrum disorders (NMOSD). Time-varying functional connectivity (TVC) underpins dynamic variations of brain connectivity. OBJECTIVE: The aim of this study was to explore precuneus SFC and TVC in NMOSD patients and their associations with neuropsychological features. METHODS: This retrospective study includes 27 NMOSD patients and 30 matched healthy controls undergoing resting state functional magnetic resonance imaging (MRI) and a neuropsychological evaluation of cognitive performance and depressive symptoms. A sliding-window correlation analysis using bilateral precuneus as seed region assessed TVC, which was quantified by the standard deviation of connectivity across windows. Mean connectivity indicated SFC. RESULTS: Compared to controls, patients had reduced SFC between precuneus, temporal lobe, putamen and cerebellum, and reduced TVC between precuneus and prefronto-parietal-temporo-occipital cortices and caudate. Patients also had increased intra-precuneal TVC and increased TVC between the precuneus and the temporal cortex. More severe depressive symptoms correlated with increased TVC between the precuneus and the temporal lobe; worse cognitive performance mainly correlated with higher TVC between the precuneus and the parietal lobe. CONCLUSION: TVC rather than SFC of the precuneus correlates with NMOSD neuropsychological features; different TVC abnormalities underlie depressive symptoms and cognitive impairment.