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Background/Objectives: Axonal Charcot–Marie–Tooth disease type 2 (CMT2) accounts for 24% of Hereditary Motor/Sensory Peripheral Neuropathies. CMT2 type GG, due to four distinct heterozygous mutations in the Golgi brefeldin A resistant guanine nucleotide exchange factor 1 (GBF1) gene (OMIM 606483), was described in seven cases from four unrelated families with autosomal dominant inheritance. It is characterized by slowly progressive distal muscle weakness and atrophy, primarily affecting the lower limbs. Here, we present two siblings sharing a novel GBF1 variant. Methods: Patient II.1 (male, 61 years at onset) presented lower limb hypoesthesia and walking difficulty; the examination revealed a postural tremor, a positive Romberg test, and muscle atrophy in the lower limbs and hands. Patient II.2 (his sister, 59 years at onset) had lower limb dysesthesias, hand paresthesia, and lower-limb stiffness. They underwent clinical evaluations, blood tests, and electroneurography. Their father represents a potentially affected individual, although a genetic analysis was not conducted. Results: All tests for peripheral neuropathies were unremarkable, including metabolic and autoimmune screening. Both showed a mixed demyelinating–axonal sensory–motor neuropathy. Genetic analysis revealed a new heterozygous GBF1 variant of uncertain significance. Conclusions: Based on autosomal dominant inheritance, as well as clinical and physiological features, a possible novel CMT2GG was diagnosed. Further research, including functional assays and in vitro studies, is necessary to confirm this variant's causal link. [ABSTRACT FROM AUTHOR]

Background: Multiple sclerosis (MS) is a common chronic autoimmune disease of the central nervous system. In MS, disability progresses unpredictably. Dopamine (DA) is a modulator of immune functions, and compelling evidence supports its involvement in both pathogenesis and treatment of MS. Although single nucleotide polymorphisms (SNPs) in dopaminergic receptor (DR) genes have been extensively studied, their role in MS progression remains unexplored. Therefore, the aim of this explorative study is to investigate the potential association between functional SNPs in DR genes and MS progression. Methods: Caucasian patients with relapsing–remitting (RR) MS were enrolled, and disease progression assessed by the Multiple Sclerosis Severity Score (MSSS). Results: Out of the 59 RRMS patients enrolled, those with the G/G genotype for rs6280 and rs1800828 SNPs in DRD3 showed significantly higher MSSSs compared to those with ancestral and heterozygous genotypes. Conclusions: If confirmed in a larger prospective study, the reported findings could contribute to a better understanding of MS pathophysiological mechanisms, opening the way for the identification of marker(s) for assessing MS progression as well as novel therapeutic strategies. A personalized approach to MS management has the potential to improve the overall well-being of MS patients and alleviate the burden on their caregivers. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Introduction: The protein growth arrest-specific 6 (Gas6) and its tyrosine kinase receptors Tyro-3, Axl, and Mer (TAM) are ubiquitous proteins involved in regulating inflammation and apoptotic body clearance. Multiple sclerosis (MS) is the most common inflammatory demyelinating disease of the central nervous system leading to progressive and irreversible disability if not diagnosed and treated promptly. Gas6 and TAM receptors have been associated with neuronal remyelination and stimulation of oligodendrocyte survival. However, few data are available regarding clinical correlation in MS patients. We aimed to evaluate soluble levels of these molecules in the cerebrospinal fluid (CSF) and serum at MS diagnosis and correlate them with short-term disease severity. Methods: In a prospective cohort study, we enrolled 64 patients with a diagnosis of clinical isolated syndrome (CIS), radiological isolated syndrome (RIS) and relapsing-remitting (RR) MS according to the McDonald 2017 Criteria. Before any treatment initiation, we sampled the serum and CSF, and collected clinical data: disease course, presence of gadolinium-enhancing lesions, and expanded disability status score (EDSS). At the last clinical follow-up, we assessed EDSS and calculated MS severity score (MSSS) and age-related MS severity (ARMSS). Gas6 and TAM receptors were determined using an ELISA kit (R&D Systems) and compared to neurofilament (NFLs) levels evaluated with SimplePlex™ fluorescence-based immunoassay. Results: At diagnosis, serum sAxl was higher in patients receiving none or lowefficacy disease-modifying treatments (DMTs) versus patients with high-efficacy DMTs (p = 0.04). Higher CSF Gas6 and serum sAXL were associated with an EDSS <3 at diagnosis (p = 0.04; p = 0.037). Serum Gas6 correlates to a lower MSSS (r² = -0.32,p = 0.01). Serumand CSF NFLs were confirmed as disability biomarkers in our cohort according to EDSS (p = 0.005; p = 0.002) and MSSS (r² = 0.27, p = 0.03; r² = 0.39, p = 0.001). Results were corroborated using multivariate analysis. Conclusions: Our data suggest a protective role of Gas6 and its receptors in patients with MS and suitable severity disease biomarkers. [ABSTRACT FROM AUTHOR]

Introduction: This study aimed to assess the prognostic role of visual evoked potentials (VEPs) of the non-neuritic eye at the diagnosis of multiple sclerosis (MS). Patients and methods: We enrolled 181 MS patients (62% females, mean age at diagnosis: 38 years, standard deviation: 12) at the time of the first diagnostic work-up, including VEPs. We collected P100 latency and N75-P100 amplitude of non-neuritic eyes at diagnosis, and then we calculated the mean values in 127 patients with no history of optic neuritis (ON) or considered the unaffected eye in the remaining. At last follow-up (minimum: one year), disability was evaluated according to MS Severity Score or MSSS (median: 2.44, range: 0.18–9.63). Statistical analysis included Mann–Whitney descriptive analysis, Spearman correlation for independent samples, and linear regression for significant predictors of MSSS. Results: 38/181 patients had P100 latency >115 ms, and 63/181 showed N75-P100 amplitude < 5 microV in the unaffected eyes at MS diagnosis. At last follow-up, MSSS correlated with P100 latency (rho = 0.21, p = 0.004) and N75-P100 amplitude (rho = 0.19, p = 0.009) collected at diagnosis. P100 latency (not N75-P100 amplitude) resulted in a predictor for disability over time (MSSS) in the regression model (along with age at onset, MS course, and disease-modifying treatments). Conclusions: Our study showed a prognostic value of VEPs in clinically unaffected eyes at MS diagnosis to predict future disability, independently from a history of ON. [ABSTRACT FROM AUTHOR]

We conducted a retrospective analysis on multiple sclerosis (MS) patients with perceived cognitive decline and long disease duration to investigate early predictors of future cognitive impairment (CI) and motor disability. Sixty-five patients complaining of cognitive decline were assessed with an extensive neuropsychological battery at the last clinical follow-up and classified as mildly impaired, severely impaired, and cognitively spared based on the results. Motor disability was assessed with EDSS, MSSS, and ARMSS. Baseline demographic, clinical, and imaging parameters were retrospectively collected and inserted in separate multivariate regression models to investigate the predictive power of future impairment. Twenty-one patients (32.3%) showed no CI, seventeen (26.2%) showed mild CI, and twenty-seven (41.5%) showed severe CI. Older and less educated patients with higher EDSS, longer disease duration, and higher white matter lesion load (WMLL) at diagnosis (particularly with cerebellar involvement) were more likely to develop CI after a mean follow-up from diagnosis of 16.5 ± 6.9 years. DMT exposure was protective. The multivariate regression analyses confirmed WMLL, disease duration, and educational levels as the parameters with significant predictive value for future CI (R2 adjusted: 0.338 p: 0.001). Older patients with progressive phenotype both at diagnosis and T1 were more likely to be not fully ambulatory at T1 (R2 adjusted: 0.796 p: 0.0001). Our results further expand knowledge on early predictors of cognitive decline and evolution over time. [ABSTRACT FROM AUTHOR]

Cerebral vasculitides, both isolated or in systemic disorders, could be triggered by infections, and few cases have been associated to coronavirus disease 2019 (COVID-19). This study searched for publications in Pubmed, EMBASE, and Cochrane library databases for case reports and series of isolated central nervous system (CNS) vasculitides triggered by severe acute respiratory syndrome coronavirus-2. We included 12 studies (published from June 2020 to July 2022) and collected 39 adult patients (5/39 pathologically or radiologically proven, 34/39 suggestive for primary CNS vasculitis or PCNSV). All cases had a positive real-time polymerase chain reaction on a nasopharyngeal swab or a respiratory tract specimen. About the 85% of the included cases were males, and disease onset occurred later than 50 years old in all but three subjects. In total, 33/39 patients presented severe COVID-19 pneumonia, frequently requiring intensive care unit care. The most common neurological features were headache, obnubilation, and coma. PCNSV was suspected mainly on radiological findings, whereas the cerebrospinal fluid analysis was minimally altered. Magnetic resonance imaging showed vessel wall enhancement in 32/39 cases, generally with the concomitant presence of microbleeds, subarachnoid haemorrhages, and/or multiple ischemic lesions. Despite the severe respiratory and neurological disease course, most cases (93%) improved spontaneously or after a course of high-dose intravenous steroids with no need for immunosuppression. In conclusion, PCNSV could rarely relate to COVID-19 and independently from pulmonary disease severity. Adults with COVID-19-related PCNSV could have a favourable prognosis. [ABSTRACT FROM AUTHOR]

Background: Cerebrospinal fluid (CSF) free light chains (FLCs) can be an alternative assay to oligoclonal bands (OCBs) in inflammatory neurological disorders, but threshold has no consensus. Objective: To assess the diagnostic accuracy of CSF FLCs in multiple sclerosis (MS) and other neurological diseases. Methods: A total of 406 patients from five Italian centers. FLCs were measured in CSF and serum using Freelite MX assays on Optilite. Results: A total of 171 patients were diagnosed as MS, 154 non-inflammatory neurological diseases, 48 inflammatory central nervous system (CNS) diseases, and 33 peripheral neurological diseases. Both kFLC and λFLC indices were significantly higher in patients with MS compared to other groups (p < 0.0001). The kFLC index ⩾ 6.4 is comparable to OCB for MS diagnosis (area under the receiver operating characteristic curve (AUC) = 0.876; sensitivity 83.6% vs 84.2%; specificity 88.5% vs 90.6%). λFLC index ⩾ 5 showed an AUC of 0.616, sensitivity of 33.3% and specificity of 90.6%. In all, 12/27 (44.4%) MS patients with negative OCB had kFLC index ⩾ 6.4. Interestingly, 37.5% of 24 patients with a single CSF IgG band showed high kFLC index and 12.5% positive λFLC index. Conclusion: Our findings support the diagnostic utility of FLC indices in MS and other CNS inflammatory disorders, suggesting a combined use of FLC and OCB to help clinicians with complementary information. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a chronic inflammatory disease of the immune system affecting the central nervous system. Several phenotypes are possible, and cases usually present with a relapsing-remitting (RR) course with disease onset at a young age. MS diagnosis can represent a traumatic event for the patient, possibly evolving into adjustment disorder (AD). AD is defined by the presence of emotional or behavioral symptoms in response to identifiable stress occurring within the prior three months and similarly to post-traumatic stress disorder (PTSD) can significantly affect quality of life. Usually, neuropsychological disorders are not associated with AD. Several treatments are available for AD, and among them, eye movement desensitization and reprocessing (EMDR) is one of the most effective in relieving depression and anxiety. However, little is known about AD and PTSD in the MS population and no data are available on the effectiveness of EMDR for cognitive impairment associated with AD. We describe a 25-year-old patient with RR MS developing an AD with a verbal memory deficit after being diagnosed. Both the psychological and cognitive deficits were diagnosed using an extensive neuropsychological battery. Considering the high impact of the verbal memory deficit, on the patient's quality of life, an EMDR intervention was planned. After a six-month EMDR intervention performed by two trained neuropsychologists, the patient was retested. There was an improvement in verbal memory tests and depression anxiety scales and the Dissociative Experiences Scale. It is recognized that emotional changes and psychiatric disorders, frequently affect MS patients at diagnosis. It is imperative to recognize this and promptly set a neuropsychological treatment. Moreover, we suggest checking cognition along with depression and anxiety. Finally, to our knowledge, this is the first report of AD with an isolated neuropsychological deficit (verbal memory) developed after the MS diagnosis and treated beneficially with e EMDR. More studies are needed to confirm the efficacy of EMDR in treating cognitive impairment associated with AD in MS patients. [ABSTRACT FROM AUTHOR]

Aquaporin-4 antibody (AQP4-IgG) neuromyelitis optica spectrum disorders (NMOSD) are rare idiopathic autoimmune diseases, presenting with optic neuritis (ON), longitudinally extensive transverse myelitis (LETM), and brainstem syndromes and a prevalence range between 0.5 and 4/100,000. Only 3% to 25% of NMOSD have been described as a paraneoplastic (PN) syndrome (PNNMOSD). Both idiopathic NMOSD (INMOSD) and PNNMOSD cases mostly affect females, but PNNMOSD usually presents with a spinal cord or brainstem involvement in elderly patients. Few cases of both malignancies (for the majority breast or lung cancer) and benign tumors (monoclonal gammopathy) were previously reported. Currently, there is no consensus on treatment approach for PNNMOSD (only surgical removal or surgery combined with chronic immunosuppression). Here, we present a series of three newly diagnosed PNNMOSD cases, who differ from each other for demographic and clinical features, tumor association, long-term treatment, and outcome. We propose that a PN etiology should be considered always whenever a new diagnosis of NMOSD is made, not only in patients over 50 years old or in spinal cord/brainstem lesions presentations. Our findings add to existing evidence and raise awareness on PNNMOSD. We enhance the importance for the clinicians of recognizing tumor symptoms and signs whenever a NMOSD is newly diagnosed. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the action of cannabinoids on spasticity and pain in secondary progressive multiple sclerosis, by means of neurophysiological indexes. Material and Methods: We assessed 15 patients with progressive MS (11 females) using clinical scales for spasticity and pain, as well as neurophysiological variables (H/M ratio, cutaneous silent period or CSP). Testing occurred before (T0) and during (T1) a standard treatment with an oral spray containing delta‐9‐tetrahydrocannabinol (THC) and cannabidiol (CBD). Neurophysiological measures at T0 were compared with those of 14 healthy controls of similar age and sex (HC). We then compared the patient results at the two time points (T1 vs T0). Results: At T0, neurophysiological variables did not differ significantly between patients and controls. At T1, spasticity and pain scores improved, as detected by the Modified Ashworth Scale or MAS (P =.001), 9‐Hole Peg Test or 9HPT (P =.018), numeric rating scale for spasticity or NRS (P =.001), and visual analogue scale for pain or VAS (P =.005). At the same time, the CSP was significantly prolonged (P =.001). Conclusions: The THC‐CBD spray improved spasticity and pain in secondary progressive MS patients. The spray prolonged CSP duration, which appears a promising tool for assessing and monitoring the analgesic effects of THC‐CBD in MS. [ABSTRACT FROM AUTHOR]

Background: Lumbar puncture (LP) is a safe procedure commonly performed in the diagnostic work-up of multiple sclerosis (MS), and its main adverse event is post-LP headache (PLPH). Predictors for PLPH in MS are not established.Aims: To describe the occurrence of, and, factors related to PLPH in patients with suspected MS, studied on a daily-basis admission.Patients and Methods: One hundred patients (70 females) were admitted for a diagnostic LP (standardized with a traumatic 19-G needle), observed for 6 h, and evaluated for adverse events 2 and 7 days later. Descriptive statistics and a multivariate analysis (for PLPH) were performed.Results: Fifty-seven (57%) patients had PLPH at 48 h, which persisted 1 week in 31, and only two presented beyond the first 2 days. Other adverse events were tinnitus and neck stiffness. None required investigations or was hospitalized. Age was the only predictor for PLPH at day 2, whereas the onset of headache within 48 h and female gender were predictors for PLPH at day 7.Conclusion: PLPH is a frequent complication of LP performed on daily-basis admission in MS work-up. The maximum onset is within the first 48 h. Age and gender seem the only predictors for the appearance and persistence of PLPH. [ABSTRACT FROM AUTHOR]

• Novel coronavirus (COVID-19) directly or indirectly may affect cerebral nervous system. • We described the first case of cerebral nervous system vasculitis triggered by COVID-19. • Medical treatment with both immunoglobulins and steroids ameliorated both MRI and clinical symptoms. We describe a patient affected by Covid-19 acute respiratory distress syndrome with a cerebral nervous system vasculitis triggered by SARS-Cov-2, managed at the University hospital, in Novara, Italy in the area most impacted by the pandemic and where 749 Covid-19 positive patients were admitted from March 1st until April 25th, 2020. [ABSTRACT FROM AUTHOR]

Osteopontin (OPN) is highly expressed in demyelinating lesions in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). OPN is cleaved by thrombin into N- (OPN-N) and C-terminal (OPN-C) fragments with different ligands and functions. In EAE, administering recombinant OPN induces relapses, whereas treatment with anti-OPN antibodies ameliorates the disease. Anti-OPN autoantibodies (autoAbs) are spontaneously produced during EAE but have never been detected in MS. The aim of the study was to evaluate anti-OPN autoAbs in the serum of MS patients, correlate them with disease course, and recapitulate the human findings in EAE. We performed ELISA in the serum of 122 patients collected cross-sectionally, and 50 patients with relapsing-remitting (RR) disease collected at diagnosis and followed longitudinally for 10 years. In the cross-sectional patients, the autoAb levels were higher in the RR patients than in the primary- and secondary-progressive MS and healthy control groups, and they were highest in the initial stages of the disease. In the longitudinal group, the levels at diagnosis directly correlated with the number of relapses during the following 10 years. Moreover, in patients with active disease, who underwent disease-modifying treatments, autoAbs were higher than in untreated patients and were associated with low MS severity score. The autoAb displayed neutralizing activity and mainly recognized OPN-C rather than OPN-N. To confirm the clinical effect of these autoAbs in vivo, EAE was induced using myelin oligodendrocyte glycoprotein MOG35-55 in C57BL/6 mice pre-vaccinated with ovalbumin (OVA)-linked OPN or OVA alone. We then evaluated the titer of antibodies to OPN, the clinical scores and in vitro cytokine secretion by spleen lymphocytes. Vaccination significantly induced antibodies against OPN during EAE, decreased disease severity, and the protective effect was correlated with decreased T cell secretion of interleukin 17 and interferon-γ ex vivo. The best effect was obtained with OPN-C, which induced significantly faster and more complete remission than other OPN vaccines. In conclusion, these data suggest that production of anti-OPN autoAbs may favor remission in both MS and EAE. Novel strategies boosting their levels, such as vaccination or passive immunization, may be proposed as a future strategy in personalized MS therapy. [ABSTRACT FROM AUTHOR]

Importance: Chronic, intractable neuropathic pain is a common and debilitating consequence of neuromyelitis optica spectrum disorder (NMOSD) myelitis, with no satisfactory treatment; few studies have yet to explore its aetiology.Objective: To establish if myelitis-associated chronic pain in NMOSD is related to the craniocaudal location of spinal cord lesions.Method: (1) Retrospective cohort of 76 aquaporin 4-antibody (AQP4-Ab)-positive patients from Oxford and Liverpool's national NMOSD clinics, assessing current pain and craniocaudal location of cord lesion contemporary to pain onset. (2) Focused prospective study of 26 AQP4-Ab-positive Oxford patients, a subset of the retrospective cohort, assessing current craniocaudal lesion location and current pain.Results: Patients with isolated thoracic cord myelitis at the time of pain onset were significantly more disabled and suffered more pain. Cervical and thoracic lesions that persisted from pain onset to 'out of relapse' follow-up (current MRI) had highly significant (p<0.01) opposing effects on pain scores (std. β=-0.46 and 0.48, respectively). Lesion length, total lesion burden and number of transverse myelitis relapses did not correlate with pain.Conclusions: Persistent, caudally located (ie, thoracic) cord lesions in AQP4-Ab-positive patients associate with high postmyelitis chronic pain scores, irrespective of number of myelitis relapses, lesion length and lesion burden. Although disability correlated with pain in isolation, it became an insignificant predictor of pain when analysed alongside craniocaudal location of lesions. [ABSTRACT FROM AUTHOR]

Slowed information processing speed (IPS) is the hallmark and first cognitive domain to be altered in multiple sclerosis (MS) patients. Insufficient serum vitamin D was previously associated with disease development, relapses, and progression, but little is reported on cognition. However, vitamin D and cognitive impairment (CI) in other neurodegenerative diseases have already been linked. We explored the possible correlation between vitamin D and IPS at diagnosis and early disability at last follow-up in 81 MS patients. At diagnosis, we collected vitamin D levels and performed a Symbol Digit Modalities Test (SDMT). Raw scores were adjusted for age, gender, and educational level. Early disability was evaluated with MS severity score (MSSS) and age-related MSSS (ARMSS). A total of 71 patients (86.58%) showed hypovitaminosis D (19.71 ± 8.76 ng/mL) and 18 patients (21.95%) had CI. Patients with CI showed severe hypovitaminosis D (p = 0.004). No patients with sufficient vitamin D levels had CI. We found a positive correlation between vitamin D levels at diagnosis and (1) SDMT raw and z-score that persisted after correction for sunlight exposure and MRI baseline characteristics, and (2) EDSS, MSSS, and ARMSS after a mean 2 year follow-up. Low vitamin D levels may affect both cognition and early disability in newly diagnosed MS patients. [ABSTRACT FROM AUTHOR]

Known multiple sclerosis (MS) susceptibility variants can only explain half of the disease's estimated heritability, whereas low-frequency and rare variants may partly account for the missing heritability. Thus, here we sought to determine the occurrence of rare functional variants in a large Italian MS multiplex family with five affected members. For this purpose, we combined linkage analysis and next-generation sequencing (NGS)-based whole exome and whole genome sequencing (WES and WGS, respectively). The genetic burden attributable to known common MS variants was also assessed by weighted genetic risk score (wGRS). We found a significantly higher burden of common variants in the affected family members compared to that observed among sporadic MS patients and healthy controls (HCs). We also identified 34 genes containing at least one low-frequency functional variant shared among all affected family members, showing a significant enrichment in genes involved in specific biological processes—particularly mRNA transport—or neurodegenerative diseases. Altogether, our findings point to a possible pathogenic role of different low-frequency functional MS variants belonging to shared pathways. We propose that these rare variants, together with other known common MS variants, may account for the high number of affected family members within this MS multiplex family. [ABSTRACT FROM AUTHOR]

Neurolymphomatosis (NL) is a rare peripheral or cranial neuropathy caused by non-Hodgkin's lymphoma (NHL). Diagnosis is often delayed and prognosis is poor. The authors described a woman in her 70s with a facial left peripheral palsy, complete right abducent palsy, left hypoacusia and balance deficit. Then she presented with low progressive hyposthenia at four limbs and cognitive impairment, sudden facial right peripheral palsy and complete left abducent palsy. The authors performed brain and spinal MRI, cerebrospinal fluid (CSF) analysis and extensive haematological examinations for infections, autoimmune and neoplastic diseases. All the results were not diagnostic. Only repeating for the third time a spinal tap, CSF presented neoplastic B cells suggestive for large B-NHL. The authors diagnosed primary NL. The patient was treated with R-CHOP but she died 2 months later. In front of rapidly progressive neuropathy, a NL has to be considered performing different examinations, especially and repeating them after a short period. [ABSTRACT FROM AUTHOR]

The K free light chain (K) index has been suggested as a reliable marker of intrathecal synthesis, despite the 2017 McDonald criteria for multiple sclerosis (MS) suggesting to "interpret with caution positive immunoglobulin G (IgG) index when testing for oligoclonal bands (OB) is negative or not performed". The aim of this study was to compare the performance of K and IgG indexes for MS diagnosis and OB detection in a cohort of Italian patients. We enrolled 385 patients (127 MS, 258 non-MS) who had cerebrospinal fluid (CSF) analysis, including isoelectric focusing (IEF), to detect OB in the diagnostic work-up. Albumin, IgG and free light chains were measured by nephelometry and used to calculate IgG and K indexes. Although the two markers were highly related (r = 0.75, r2 = 0.55, p < 0.0001), the K index showed greater sensitivity and negative predictive value (versus the IgG index) for OB detection (97% versus 48% and 97% versus 71%) and MS diagnosis (96% versus 50% and 98% versus 78%). These results support K index (and not IgG index) as a first-line marker for MS, followed by IEF, according to a sequential testing approach in CSF analysis. [ABSTRACT FROM AUTHOR]

The function of proteasomes in extracellular space is still largely unknown. The extracellular proteasome-osteopontin circuit has recently been hypothesized to be part of the inflammatory machinery regulating relapse/remission phase alternation in multiple sclerosis. However, it is still unclear what dynamics there are between the different elements of the circuit, what the role of proteasome isoforms is, and whether these inflammatory circuit dynamics are associated with the clinical severity of multiple sclerosis. To shed light on these aspects of this novel inflammatory circuit, we integrated in vitro proteasome isoform data, cell chemotaxis cell culture data, and clinical data of multiple sclerosis cohorts in a coherent computational inference framework. Thereby, we modeled extracellular osteopontin-proteasome circuit dynamics during relapse/remission alternation in multiple sclerosis. Applying this computational framework to a longitudinal study on single multiple sclerosis patients suggests a complex interaction between extracellular proteasome isoforms and osteopontin with potential clinical implications. [ABSTRACT FROM AUTHOR]