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New clinical activity in multiple sclerosis (MS) is often accompanied by acute inflammation which subsides. However, there is growing evidence that a substantial proportion of lesions remain active well beyond the acute phase. Chronic active lesions are most frequently found in progressive MS and are characterised by a border of inflammation associated with iron-enriched cells, leading to ongoing tissue injury. Identifying imaging markers for chronic active lesions in vivo are thus a major research goal. We reviewed the literature on imaging of chronic active lesion in MS, focussing on ‘slowly expanding lesions’ (SELs), detected by volumetric longitudinal magnetic resonance imaging (MRI) and ‘rim-positive’ lesions, identified by susceptibility iron-sensitive MRI. Both SELs and rim-positive lesions have been found to be prognostically relevant to future disability. Little is known about the co-occurrence of rims around SELs and their inter-relationship with other emerging techniques such as dynamic contrast enhancement (DCE) and positron emission tomography (PET).

LncRNA PCR arrays containing 90 common LncRNAs were used to screen lncRNA expression levels in PBMC from a discovery population of patients with MS. Data from discovery and replications cohorts showed a generalized dysregulation of lncRNA levels in MS patients compared with controls. MALAT1, MEG9, NRON, ANRIL, TUG1, XIST, SOX2OT, GOMAFU, HULC, BACE-1AS were significantly downregulated in MS patients in comparison with controls. Therefore, we performed a validation analysis in an independent cohort of Belgian origin. In this study, NRON and TUG1 downregulations in MS patients compared with controls were confirmed (p ≤ .05 and p ≤ .0001 respectively), whereas considering the other lncRNAs, the statistical threshold was not reached. LncRNAs profiling could thus represent a new challenge in the research of easy detectable biomarkers of disease susceptibility and progression. ispartof: Journal Of Neuroimmunology vol:324 pages:129-135 ispartof: location:Netherlands status: Published online

Graphical abstract, Highlights • We present SPACE-MS, a tool to assess the spatial distribution of brain lesions. • SPACE-MS metrics mainly reflect caudality and spatial spreading of brain lesions. • More caudal and more widespread brain lesions correlate with worse disability. • SPACE-MS metrics can be automatically obtained using routine anatomical scans. • The usefulness of the SPACE-MS approach should be explored in other conditions., Predicting disability in progressive multiple sclerosis (MS) is extremely challenging. Although there is some evidence that the spatial distribution of white matter (WM) lesions may play a role in disability accumulation, the lack of well-established quantitative metrics that characterise these aspects of MS pathology makes it difficult to assess their relevance for clinical progression. This study introduces a novel approach, called SPACE-MS, to quantitatively characterise spatial distributional features of brain MS lesions, so that these can be assessed as predictors of disability accumulation. In SPACE-MS, the covariance matrix of the spatial positions of each patient’s lesional voxels is computed and its eigenvalues extracted. These are combined to derive rotationally-invariant metrics known to be common and robust descriptors of ellipsoid shape such as anisotropy, planarity and sphericity. Additionally, SPACE-MS metrics include a neuraxis caudality index, which we defined for the whole-brain lesion mask as well as for the most caudal brain lesion. These indicate how distant from the supplementary motor cortex (along the neuraxis) the whole-brain mask or the most caudal brain lesions are. We applied SPACE-MS to data from 515 patients involved in three studies: the MS-SMART (NCT01910259) and MS-STAT1 (NCT00647348) secondary progressive MS trials, and an observational study of primary and secondary progressive MS. Patients were assessed on motor and cognitive disability scales and underwent structural brain MRI (1.5/3.0 T), at baseline and after 2 years. The MRI protocol included 3DT1-weighted (1x1x1mm3) and 2DT2-weighted (1x1x3mm3) anatomical imaging. WM lesions were semiautomatically segmented on the T2-weighted scans, deriving whole-brain lesion masks. After co-registering the masks to the T1 images, SPACE-MS metrics were calculated and analysed through a series of multiple linear regression models, which were built to assess the ability of spatial distributional metrics to explain concurrent and future disability after adjusting for confounders. Patients whose WM lesions laid more caudally along the neuraxis or were more isotropically distributed in the brain (i.e. with whole-brain lesion masks displaying a high sphericity index) at baseline had greater motor and/or cognitive disability at baseline and over time, independently of brain lesion load and atrophy measures. In conclusion, here we introduced the SPACE-MS approach, which we showed is able to capture clinically relevant spatial distributional features of MS lesions independently of the sheer amount of lesions and brain tissue loss. Location of lesions in lower parts of the brain, where neurite density is particularly high, such as in the cerebellum and brainstem, and greater spatial spreading of lesions (i.e. more isotropic whole-brain lesion masks), possibly reflecting a higher number of WM tracts involved, are associated with clinical deterioration in progressive MS. The usefulness of the SPACE-MS approach, here demonstrated in MS, may be explored in other conditions also characterised by the presence of brain WM lesions.

Background: Neurodegeneration plays a major role in determining disability in multiple sclerosis (MS) patients. Hence, there is increasing need to identify reliable biomarkers, which could serve as prognostic measure of disease progression. Objectives: To assess whether cerebrospinal fluid (CSF) tau and β-amyloid (Aβ) levels were altered in newly diagnosed MS patients and correlated with disability. Moreover, we investigated whether these CSF biomarkers associate with macroscopic brain tissue damage measures. Methods: CSF Aβ and tau levels were determined by enzyme-linked immunosorbent assay in CSF samples from 48 newly diagnosed MS patients, followed-up clinically for 3 years by recording their Expanded Disability Status Scale score at 6-month intervals, and 45 controls. All patients underwent magnetic resonance imaging at baseline and at the end of follow-up to quantify their lesion load (LL). Results: CSF Aβ levels were significantly reduced in patients compared to controls ( p Conclusion: CSF Aβ reduction is a promising biomarker of neurodegeneration and may predict patients’ clinical outcome. Therefore, CSF Aβ should be considered as a potential biomarker of prognostic value.

Nasu-Hakola disease (NHD), also known as polycystic lipomembranous osteodysplasia and sclerosing leukoencephalopathy, is an autosomal recessive disorder characterized by dementia and multifocal bone cysts. NHD is associated with the loss-of-function mutation of triggering receptor expressed on myeloid cells-2 gene ( TREM2 ), leading to an aberrant form of TREM2.1

Balò's concentric sclerosis (BCS) is considered a rare demyelinating disease and regarded as an aggressive variant of multiple sclerosis (MS). We describe three cases (one male and two females) with neuroimaging features suggestive of BCS and heterogeneous symptoms, with benign long-term clinical course upon treatment with natalizumab and fingolimod. Neurological examination, blood and cerebrospinal fluid analyses, brain and spinal cord magnetic resonance imaging (MRI) and brain proton magnetic resonance spectroscopy were performed. At onset, patient #1 showed predominant cognitive impairment with consciousness disturbances; patient #2 presented with left hemiparesis; patient #3 demonstrated hesitance in speech and in written word production, along with right central facial palsy. All patients showed the typical MRI changes associated with BCS, such as concentric rings or a whorled appearance on T2-weighted and contrast-enhanced T1-weighted images. They were treated with high dosage i.v. steroid with clinical improvement and followed-up for 3 years with different clinical course. Two patients fulfilled the revised McDonald criteria for MS and received preventive therapy, natalizumab and fingolimod, respectively, whereas the third patient is still stable without clinical and radiological evolution. All of them did not have new exacerbations or MRI lesions over 2-4 year follow-up. Our descriptions demonstrate the heterogeneity of clinical presentation of BCS. Moreover, these case reports suggest that BCS may neither be rapidly progressive nor fatal and may be considered part of the MS spectrum. In line with this hypothesis, current treatments for MS were effective in our patients.

MicroRNAs (miRNAs) have recently found to be dysregulated in serum from multiple sclerosis (MS) patients. Cell free circulating miR-15b, -23a and 223 levels were analyzed by Real Time PCR in a cohort consisting of 30 serum samples from Relapsing Remitting MS patients at baseline (T0) and after three, six, nine and twelve months (T1, T2, T3, T4) after starting the treatment. A down-regulation of miRNA levels in patients at T0 compared with controls was present (p0.001). MiRNA levels slightly increased at T1 and this trend reached the statistical significance at T2 vs T0 and remains stable at T3 and T4. Our preliminary results suggest that aberrant levels of circulating miRNAs are recovered in fingolimod treated MS patients. Circulating miRNAs profiling could thus represent an easy detectable biomarker of disease and response to treatment.

Background First recognized at the beginning of twentieth century and named after three authors who independently described some affected patients, Vogt-Koyanagi-Harada syndrome is a rare multisystemic autoimmune disease targeting melanin-containing tissues of the eye, meninges, inner ear and skin. It predominantly affects Asian people, but also people with darker skin pigmentation such as Native Americans and Hispanics (Mestizos), whose ancestors moved from Asia across the Bering strait to North America and further down to Central and South America. Heterogenous presentation is observed, especially among different ethnic groups. Here we describe the case of an Hispanic South American patient presenting with multiple visual relapses and thus mimicking recurrent optic neuritis; we provide insights into the differential diagnosis and a brief review of the literature concerning the epidemiology of Vogt-Koyanagi-Harada syndrome in Hispanic patients compared with other ethnic groups. Case presentation A 34-year-old Ecuadorian woman presented over years with multiple relapses involving the visual system. She was investigated in both neurologic and ophthalmic clinical settings. Brain Magnetic Resonance Imaging, cerebrospinal fluid examination, Spectral Domain Optical Coherence Tomography and Fluorescein Angiography were performed. She was misdiagnosed first as an optic neuritis pointing to a demyelinating disorder, then as a posterior scleritis. Due to the protean manifestations of Vogt-Koyanagi-Harada syndrome and the incomplete clinical presentation at the beginning, the right diagnosis was made only at a later disease stage using retrospective criteria. Conclusions Hispanic patients often present without extraocular symptoms in early phases of the disease and they have globally lower rates of intertegumentary signs compared to Asian patients. The diagnosis of a multisystemic disease such as Vogt-Koyanagi-Harada syndrome is a challenge involving specialists operating in different medical fields; especially in urban multiethnic populations, rare etiologies of common symptoms have to be taken into account when performing a differential diagnosis.

The Free and Cued Selective Reminding Test (FCSRT) is the most commonly used neuropsychological test to evaluate episodic memory. Two variants of FCSRT exist, using the recall of words (FCSRT-w) or pictures (FCSRT-p). Fourteen patients with mild cognitive impairment underwent neuropsychological evaluation and brain magnetic resonance. We found differences in FCSRT-w and FCSRT-p variants scores. FCSRT-p was correlated with atrophy in areas involved in visual stimuli processing while FCSRT-w was correlated to hippocampal atrophy. Our study suggests that FCSRT-w and FCSRT-p scores are not equivalent, but a larger cohort of patients is needed to validate these results.

ObjectiveTo assess the connection between amyloid pathology and white matter (WM) macrostructural and microstructural damage in demented patients compared with controls.MethodsEighty-five participants were recruited: 65 with newly diagnosed Alzheimer’s disease (AD), non-AD dementia or mild cognitive impairment and 20 age-matched and sex-matched healthy controls. β-amyloid1-42 (Aβ) levels were determined in cerebrospinal fluid (CSF) samples from all patients and five controls. Among patients, 42 had pathological CSF Aβ levels (Aβ(+)), while 23 had normal CSF Aβ levels (Aβ(−)). All participants underwent neurological examination, neuropsychological testing and brain MRI. We used T2-weighted scans to quantify WM lesion loads (LLs) and diffusion-weighted images to assess their microstructural substrate. Non-parametric statistical tests were used for between-group comparisons and multiple regression analyses.ResultsWe found an increased WM-LL in Aβ(+) compared with both, healthy controls (p=0.003) and Aβ(−) patients (p=0.02). Interestingly, CSF Aβ concentration was the best predictor of patients’ WM-LL (r=−0.30, pConclusionsWM damage is crucial in AD pathogenesis. The correlation between CSF Aβ levels and WM-LL suggests a direct link between amyloid pathology and WM macrostructural and microstructural damage.

Mutations in progranulin gene (GRN) are a common cause of autosomal dominant frontotemporal lobar degeneration and are associated with a wide phenotypic heterogeneity. Here, we describe two probands with behavioral variant frontotemporal dementia with a novel mutation in this gene (1159_1160delTG). Both had a positive family history for dementia and showed atypical features at imaging. Their progranulin plasma levels were undetectable, and the mutation was not present in cDNA, suggesting haploinsufficiency. Progranulin levels were low even in asymptomatic carriers of the variant. Results described enlarge current knowledge on genetic causes of the disease and clinical characteristics of carriers.

Progressive multifocal leukoencephalopathy (PML) is a rare and severe complication of natalizumab therapy in patients with multiple sclerosis and it may be accompanied by immune reconstitution inflammatory syndrome (IRIS). Here, we describe a case of abnormally severe IRIS, which occurred 2 months after natalizumab-associated PML in a 38-year-old woman affected by multiple sclerosis. The patient was John Cunningham virus-positive and was treated for 21 months when she developed PML. The subsequent IRIS diffusely afflicted the brain, producing edema and signs of intracranial hypertension, with a clinically severe form compromising the state of consciousness, requiring intensive care and high-dosage steroid treatment. Nevertheless, she survived and partially recovered. There is still difficulty in differentiating PML progression from IRIS onset and there is not a clear description in the literature about different clinical forms of IRIS, prognostic factors and guidelines to properly treat this complication in order to reduce the residual disability of the patient surviving this treatment complication.

A hexanucleotide repeat expansion in the chromosome 9 Open Reading Frame 72 gene (C9ORF72) has recently been reported to be cause of familial amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Nevertheless, in the last few years this mutation has been found to be associated with heterogeneous phenotypes, including multiple sclerosis (MS) in concurrence with amyotrophic lateral sclerosis. In this study, we sought to evaluate the presence of the C9ORF72 repeat expansion in a cohort consisting of 314 patients with MS and 222 control subjects. No pathogenic expansion was found in MS and control populations, suggesting that C9ORF72 does not play a major role in MS pathogenesis. © 2014 Elsevier Inc.

Evidence underlines the importance of microRNAs (miRNAs) in the pathogenesis of multiple sclerosis (MS). Based on the fact that miRNAs are present in human biological fluids, we previously showed that miR-223, miR-23a and miR-15b levels were downregulated in the sera of MS patients versus controls. Here, the expression levels of these candidate miRNAs were determined in peripheral blood mononuclear cells (PBMCs) and the serum of MS patients, in addition to three genotyped single nucleotide polymorphisms (SNPs). Mapping in the genomic regions of miR-223, miR-23a and miR-15b genes, 399 cases and 420 controls were tested. Expression levels of miR-223 and miR-23a were altered in PBMCs from MS patients versus controls. Conversely, there were no differences in the expression levels of miR-15b. A significantly decreased genotypic frequency of miR-223 rs1044165 T/T genotype was observed in MS patients. Moreover, the allelic frequency of miR-23a rs3745453 C allele was significantly increased in patients versus controls. In contrast, there were no differences in the distribution of miR-15b SNP. In conclusion, our results suggest that miR-223 and miR-23a could play a role in the pathogenesis of MS. Moreover, miR-223 rs1044165 polymorphism likely acts as a protective factor, while miR-23a rs3745453 variant seems to act as a risk factor for MS. © 2013 by the authors; licensee MDPI, Basel, Switzerland.

Background: Multiple sclerosis (MS) affects both brain and spinal cord. However, studies of the neuraxis with advanced magnetic resonance imaging (MRI) are rare because of long acquisition times. We investigated neurodegeneration in MS brain and cervical spinal cord using neurite orientation dispersion and density imaging (NODDI). Objective: The aim of this study was to investigate possible alterations, and their clinical relevance, in neurite morphology along the brain and cervical spinal cord of relapsing–remitting MS (RRMS) patients. Methods: In total, 28 RRMS patients and 20 healthy controls (HCs) underwent brain and spinal cord NODDI at 3T. Physical and cognitive disability was assessed. Individual maps of orientation dispersion index (ODI) and neurite density index (NDI) in brain and spinal cord were obtained. We examined differences in NODDI measures between groups and the relationships between NODDI metrics and clinical scores using linear regression models adjusted for age, sex and brain tissue volumes or cord cross-sectional area (CSA). Results: Patients showed lower NDI in the brain normal-appearing white matter (WM) and spinal cord WM than HCs. In patients, a lower NDI in the spinal cord WM was associated with higher disability. Conclusion: Reduced neurite density occurs in the neuraxis but, especially when affecting the spinal cord, it may represent a mechanism of disability in MS.