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Background and ObjectivesInflammation of the choroid plexus (CP) has been reported in multiple sclerosis (MS). The AU1 association between CP inflammation and clinical disability progression is still under debate. The objective of the current study was to assess the relationship between measures of CP inflammation and investigate their associations with clinical disability progression in MS.MethodsIn this retrospective analysis of a longitudinal study, 174 patients with MS (118 with relapsing-remitting MS and 56 with progressive MS [PMS]) and 56 healthy controls (HCs), group matched for age and sex, were imaged on a 3T MRI scanner at baseline and after an average of 5.5 years of follow-up. T2 lesion volume (T2-LV) was assessed. Regional tissue volumes were calculated. CP volume was measured, and pseudo-T2 (pT2) mapping was performed to asses CP inflammation. Group comparisons and correlations were adjusted for age and sex.ResultsPatients with MS presented with significantly larger CP volume (p= 0.01) and increased CP pT2 (p= 0.001), even after controlling for all other factors significantly associated with disability progression (p= 0.030), including T2-LV, normalized brain volume, normalized gray matter volume, and normalized thalamic volumes. Changes in CP volume and CP pT2 were not related to changes in clinical parameters such as relapse rate over the course of the follow-up.DiscussionCP inflammation, as evidenced by MRI, is clinically relevant in MS. CP inflammation may have a relevant role in driving disease progression.

Parkinson’s disease (PD) is the second most common neurological disease affecting the elderly population. Pharmacological and surgical interventions usually employed for PD treatment show transient effectiveness and are associated with the insurgence of side effects. Therefore, motor rehabilitation has been proposed as a promising supplement in the treatment of PD, reducing the global burden of the disease and improving patients quality of life. The present systematic review aimed to critically analyse the literature concerning MRI markers of brain functional and structural response to motor rehabilitation in PD. Fourteen out of 1313 studies were selected according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria. Despite the limited number of retrieved studies coupled with their heterogeneity prevent ultimate conclusions from being drawn, motor rehabilitation seems to have beneficial effects on PD as measured both with clinical outcomes and MRI derived indices. Interestingly, consistent results seem to indicate that motor rehabilitation acts via a dual mechanism of strengthening cortico-subcortical pathways, restoring movements automaticity, or activating compensatory networks such as the fronto-parietal one. The employment of more advanced and quantitative MRI methods is warranted to establish and validate standardized metrics capable of reliably determining the changes induced by rehabilitative intervention.

Dimethyl fumarate (DMF) is an effective treatment for relapsing remitting Multiple Sclerosis (MS) and its mechanisms of action encompass immunomodulatory and cytoprotective effects. Despite DMF is known to activate the Nrf2 pathway, Nrf2-independent mechanisms have been also reported and new insights on the underlying molecular mechanisms are still emerging including transcriptional and post-transcriptional events. At this regard, we focused on a small family of RNA-binding proteins, the ELAV-like proteins, that play a pivotal role in post-transcriptional mechanisms and are involved in the pathogenesis of several psychiatric and neurologic disorders. HuR, the ubiquitously expressed member of the family, is implicated in many cellular functions, including survival, inflammation and proper functioning of the immune system. We previously documented the potential entanglement of HuR in MS pathogenesis. In the present work, we explored HuR protein levels in peripheral blood mononuclear cells (PBMCs) from MS patients before and after DMF treatment compared to healthy controls (HC). Considering that HuR may act on various targets, playing a protective role against oxidative stress, our main goals were to evaluate whether manganese-dependent superoxide dismutase transcript (SOD2) could represent a new molecular target of HuR and to study the potential influence of DMF treatment on this interaction.PBMCs from 20 patients with MS and 20 frequency-matched HC by sex and age were used to evaluate HuR, MnSOD (the protein coded by SOD2) and Nrf2 protein content by Western blot, before and after 12 months of DMF treatment. Immunoprecipitation experiments coupled with RNA extraction in PBMCs were performed to explore whether SOD2 mRNA could be physically bound by HuR and whether the expression of MnSOD protein could be affected by 12 months of DMF treatment.In PBMCs, HuR protein binds SOD2 transcript in HC and in MS patients naïve to disease modifying treatment. The expression of MnSOD protein is positively affected by 12 months of DMF treatment. PBMCs from MS patients have a lower HuR and MnSOD protein content compared to matched HC (HuR: p0.01, MnSOD: p0.01). Of interest, 12 months of DMF treatment in MS patients restores the amount of both HuR protein and MnSOD enzyme to the levels observed in HC. We also confirmed that Nrf2 is an HuR target, and we report that its levels are significantly increased in MS patients naïve to disease modifying treatment and remain elevated following DMF administration.SOD2 transcript is a new target of HuR protein. DMF induces an increased expression of HuR protein, which ultimately interacts more strongly with SOD2 transcript promoting the expression of this antioxidant protein. The activation of this molecular cascade can constitute an additional tool that the cells can exploit to counteract the oxidative stress associated with MS development, and can account for the multifaceted molecular mechanisms underlying DMF efficacy in MS.

Introduction Conventional imaging measures remain a key clinical tool for the diagnosis multiple sclerosis (MS) and monitoring of patients. However, most measures used in the clinic show unsatisfactory performance in predicting disease progression and conversion to secondary progressive MS. Areas covered Sophisticated imaging techniques have facilitated the identification of imaging biomarkers associated with disease progression, such as global and regional brain volume measures, and with conversion to secondary progressive MS, such as leptomeningeal contrast enhancement and chronic inflammation. The relevance of emerging imaging approaches partially overcoming intrinsic limitations of traditional techniques is also discussed. Expert opinion Imaging biomarkers capable of detecting tissue damage early on in the disease, with the potential to be applied in multicenter trials and at an individual level in clinical settings, are strongly needed. Several measures have been proposed, which exploit advanced imaging acquisitions and/or incorporate sophisticated post-processing, can quantify irreversible tissue damage. The progressively wider use of high-strength field MRI and the development of more advanced imaging techniques will help capture the missing pieces of the MS puzzle. The ability to more reliably identify those at risk for disability progression will allow for earlier intervention with the aim to favorably alter the disease course.

Introduction: The approval of 9-δ-tetrahydocannabinol (THC)+cannabidiol (CBD) oromucosal spray (Sativex®) in Italy as an add-on medication for the management of moderate to severe spasticity in multiple sclerosis (MS) has provided a new opportunity for MS patients with drug-resistant spasticity. We aimed to investigate the improvement of MS spasticity-related symptoms in a large cohort of patients with moderate to severe spasticity in daily clinical practice. Materials and methods: MS patients with drug-resistant spasticity were recruited from 30 Italian MS centers. All patients were eligible for THC:CBD treatment according to the approved label: ≥ 18 years of age, at least moderate spasticity (MS spasticity numerical rating scale [NRS] score ≥ 4) and not responding to the common antispastic drugs. Patients were evaluated at baseline (T0) and after 4 weeks of treatment (T1) with the spasticity NRS scale and were also asked about meaningful improvements in 6 key spasticity-related symptoms. Results: Out of 1615 enrolled patients, 1432 reached the end of the first month trial period (T1). Of these, 1010 patients (70.5%) reached a ≥ 20% NRS score reduction compared with baseline (initial responders; IR). We found that 627 (43.8% of 1432) patients showed an improvement in at least one spasticity-related symptom (SRSr group), 543 (86.6%) of them belonging to the IR group and 84 (13.4%) to the spasticity NRS non-responders group. Conclusion: Our study confirmed that the therapeutic benefit of cannabinoids may extend beyond spasticity, improving spasticity-related symptoms even in non-NRS responder patients. © 2020, Fondazione Società Italiana di Neurologia.

Atrophied T2-lesion volume (LV) is a novel MRI marker representing brain-lesion loss due to atrophy, able to predict long-term disability progression and conversion to secondary-progressive multiple sclerosis (MS). To better characterize atrophied T2-LV via comparison with other multidisciplinary markers of MS progression. We studied 127 MS patients (85 relapsing–remitting, RRMS and 42 progressive, PMS) and 20 clinically isolated syndrome (CIS) utilizing MRI, optical coherence tomography, and serum neurofilament light chain (sNfL) at baseline and at 5-year follow-up. Symbol Digit Modalities Test (SDMT) was obtained at follow-up. Atrophied T2-LV was calculated by combining baseline lesion masks with follow-up CSF partial-volume maps. Measures were compared between MS patients who developed or not disease progression (DP). Partial correlations between atrophied T2-LV and other biomarkers were performed, and corrected for multiple comparisons. Atrophied T2-LV was the only biomarker that significantly differentiated DP from non-DP patients over the follow-up (p = 0.007). In both DP and non-DP groups, atrophied T2-LV was associated with baseline T2-LV and T1-LV (both p = 0.003), absolute change of T1-LV (DP p = 0.038; non-DP p = 0.003) and percentage of brain volume change (both p = 0.003). Furthermore, in the DP group, atrophied T2-LV was related to baseline brain parenchymal (p = 0.017) and thalamic (p = 0.003) volumes, thalamic volume change and follow-up SDMT (both p = 0.003). In non-DP patients, atrophied T2-LV was significantly related to baseline sNfL (p = 0.008), contrast-enhancing LV (p = 0.02) and percentage ventricular volume change (p = 0.003). Atrophied T2-LV is associated with disability accrual in MS, and to several multimodal markers of disease evolution.

BACKGROUND Although reduced thalamic volume is associated with multiple sclerosis (MS)-related clinical impairment, the role of individual thalamic nuclei remains poorly understood. PURPOSE/HYPOTHESIS To test whether individual thalamic nuclei volumes are more strongly associated with clinical disability than the whole thalamic volume. STUDY TYPE Retrospective analysis of a prospective dataset. SUBJECTS A total of 108 MS patients and 48 age- and sex-matched healthy controls (HCs) FIELD STRENGTH: 3T. SEQUENCES 3D T1 -weighted inversion recovery spoiled gradient echo; 2D T2 -weighted fluid-attenuated inversion recovery spin echo; 2D dual-echo proton density-weighted/T2 -weighted spin echo. ASSESSMENTS Clinical assessments included the Expanded Disability Status Scale (EDSS), Nine-Hole Peg Test (9HPT), Timed 25-Foot Walk (T25FW), Symbol Digit Modalities Test (SDMT), Brief Visuospatial Memory Test-Revised (BVMTR), and the California Verbal Learning Test (CVLT2). FreeSurfer provided anterior, intralaminar, lateral, medial, ventral, posterior, and total volumes. STATISTICAL TESTS False discovery rate-corrected partial correlations (controlling for age, sex, and education) to assess the relationships between volumes and neuroperformance. RESULTS Compared to HCs, MS patients presented with lower thalamic nuclei volumes (P

Optical coherence tomography (OCT) is a technique that allows for the assessment of retinal nerve fiber layer thickness (RNFLT) and total macular volume (TMV), which reflect neuroaxonal integrity within the retina. As such it has been used in multiple sclerosis (MS) to study neurodegeneration. Glatiramer acetate (GA) is a widely used treatment for MS, which is suggested to have a possible neuroprotective role. The aim of this study was to assess RFNLT and TMV changes in relapsing–remitting MS (RRMS) patients who started treatment with GA and were followed for a 24-month period. A cohort of 60 RRMS patients and 40 healthy controls (HCs) were imaged with OCT at baseline and follow-up. All subjects also underwent clinical and neurological examination. Measurements were compared between the RRMS patients and HCs as well as between optic neuritis (ON)-affected and ON-unaffected eyes. At baseline, MS patients showed lower average RNFLT (p = 0.046) and TMV (p = 0.013) when compared with HCs. No significant differences in the evolution of OCT measures were detected over the follow-up between MS patients and HCs. MS patients with both affected and unaffected eyes showed significantly lower average RNFLT, temporal inferior RNFLT, and TMV at baseline, compared with HCs. No significant differences between ON-affected and ON-unaffected eyes in MS patients were detected over the follow-up, except for the nasal superior RNFLT (p = 0.019). This study suggests a beneficial role of GA on retinal axonal degeneration in MS, and further confirms the utility of OCT to monitor the neuroprotective effect of disease-modifying treatment.

Glatiramer acetate (GA) 40 mg × 3/weekly was approved for the treatment of relapsing-remitting multiple sclerosis (RRMS). While the beneficial effect of GA 20 mg/daily in MS patients on non-conventional MRI measures has been demonstrated, the effect of GA 40 mg × 3/weekly at the microstructural tissue level has yet to be explored.To investigate the effect of switching from GA 20 mg/daily to GA 40 mg × 3/weekly on the evolution of microstructural changes in the thalamus and normal appearing white matter (NAWM), using diffusion tensor imaging (DTI).In this observational, longitudinal, cross-over, 34-month MRI study, we recruited 150 RRMS patients that underwent MRI 12-18 months before switching (pre-index), during the switch (index) and 12-18 months after switching (post-index) from GA 20 mg/daily to GA 40 mg × 3/weekly. Regional DTI metrics and tract-based spatial statistics (TBSS) analyses were performed. Mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD) and fractional anisotropy (FA) were measured in thalamus and NAWM.Regional DTI measures, measures of whole brain, white and gray matter, and thalamus volumes, as well as lesion volume, showed no significant changes. However, the voxel-wise TBSS analysis showed increased FA both in the NAWM and thalamus, as well as increased MD and AD in NAWM, and decreased RD in NAWM (p .05). Areas of increased FA and MD as well as decreased RD in the NAWM, and increased AD both in the NAWM and thalamus were detected between index to post-index (p .05).This study confirms a comparable effect of GA 40 mg × 3/weekly to GA 20 mg/daily on DTI measures over 34 months.

While iron has an important role in the normal functioning of the brain due to its involvement in several physiological processes, dyshomeostasis has been found in many neurodegenerative disorders, as evidenced by both histopathological and imaging studies. Although the exact causes have remained elusive, the fact that altered iron levels have been found in disparate diseases suggests that iron may contribute to their development and/or progression. As such, the processes involved in iron dyshomeostasis may represent novel therapeutic targets. There are, however, many questions about the exact interplay between neurodegeneration and altered iron homeostasis. Some insight can be gained by considering the parallels with respect to what occurs in healthy aging, which is also characterized by increased iron throughout many regions in the brain along with progressive neurodegeneration. Nevertheless, the exact mechanisms of iron-mediated damage are likely disease-specific to a certain degree, given that iron plays a crucial role in many disparate biological processes, which are not always affected in the same way across different neurodegenerative disorders. Moreover, it is not even entirely clear yet whether iron actually has a causative role in all of the diseases where altered iron levels have been noted. For example, there is strong evidence of iron dyshomeostasis leading to neurodegeneration in Parkinson’s disease, but there is still some question as to whether or not changes in iron concentrations are merely an epiphenomenon in multiple sclerosis. Recent advances in neuroimaging now offer the possibility to detect and monitor iron levels in vivo, which allows for an improved understanding of both the temporal and spatial dynamics of iron changes and associated neurodegeneration compared to post-mortem studies. In this regard, iron-based imaging will likely play an important role in the development of therapeutic approaches aimed at addressing altered iron dynamics in neurodegenerative diseases. As of now, the bulk of such therapies have focused on chelating excess iron. Although there is some evidence that these treatment options may yield some benefit, they are not without their own limitations. They are generally effective at reducing brain iron levels, as assessed by imaging, but clinical benefits are more modest. New drugs that specifically target iron-related pathological processes may offer the possibility to prevent, or at the least slow down, irreversible neurodegeneration, which represents an as of yet unmet therapeutic target.

BACKGROUND AND PURPOSE With respect to healthy controls (HCs), increased iron concentrations in the deep gray matter (GM) and decreased white matter (WM) integrity are common findings in multiple sclerosis (MS) patients. The association between these features of the disease remains poorly understood. We investigated the relationship between deep iron deposition in the deep GM and WM injury in associated fiber tracts in MS patients. METHODS Sixty-six MS patients (mean age 50.0 years, median Expanded Disability Status Scale 5.25, mean disease duration 19.1 years) and 29 HCs, group matched for age and sex were imaged on a 1.5T scanner. Susceptibility-weighted imaging and diffusion tensor imaging (DTI) were used for assessing high-pass filtered phase values in the deep GM and normal appearing WM (NAWM) integrity in associated fiber tracts, respectively. Correlation analyses investigated the associations between filtered phase values (suggestive of iron content) and WM damage. RESULTS Areas indicative of increased iron levels were found in the left and right caudates as well as in the left thalamus. MS patients presented with decreased DTI-derived measures of tissue integrity in the associated WM tracts. Greater mean, axial and radial diffusivities were associated with increased iron levels in all three GM areas (r values .393 to .514 with corresponding P values .003 to

ObjectiveTo study the association between serum neurofilament light chain (sNfL) and multiple optical coherence tomography (OCT) measures in patients with MS and healthy controls (HCs).MethodsIn this prospective study, 110 patients with MS were recruited, together with 52 age- and sex-matched HCs. Clinical evaluation and spectral domain OCT and sNfL were obtained at baseline and after 5.5 years of follow-up. Nested linear mixed models were used to assess differences between MS vs HC and associations between sNfL and OCT measures. Partial correlation coefficients are reported, and p values were adjusted for the false discovery rate.ResultsAt baseline, peripapillary retinal nerve fiber layer thickness (pRNFLT) and macular ganglion cell and inner plexiform layer thickness (mGCIP) were significantly lower in MS than HC both in MS-associated optic neuritis (MSON) (p = 0.007, p = 0.001) and nonaffected MSON (n-MSON) eyes (p = 0.003, p = 0.018), along with total macular volume (TMV) in n-MSON eyes (p = 0.011). At follow-up, MS showed significantly lower pRNFLT, mGCIP, and TMV both in MSON and n-MSON eyes (p < 0.001) compared with HC. In MS n-MSON eyes, sNfL was significantly associated with baseline pRNFLT and mGCIP (q = 0.019). No significant associations were found in MSON eyes.ConclusionsThis study confirms the ability of sNfL to detect neurodegeneration in MS and advocates for the inclusion of sNfL and OCT measures in clinical trials.Classification of evidenceThis study provides Class III evidence that sNfL levels were associated with MS neurodegeneration measured by OCT.

BACKGROUND AND PURPOSE: Leptomeningeal inflammation is associated with the development of global cortical gray matter atrophy in multiple sclerosis. However, its association with localized loss of tissue remains unclear. The purpose of this study was to evaluate the relationship between leptomeningeal contrast enhancement, a putative marker of leptomeningeal inflammation, and focal cortical thinning in MS. MATERIALS AND METHODS: Forty-three patients with relapsing-remitting MS and 15 with secondary-progressive MS were imaged on a 3T scanner. Cortical reconstruction was performed with FreeSurfer. Leptomeningeal contrast-enhancement foci were visually identified on 3D-FLAIR postcontrast images and confirmed using subtraction imaging. Leptomeningeal contrast-enhancement foci were mapped onto the cortex, and ROIs were obtained by dilating along the surface multiple times (n = 5, 10, 15, 20, 25, 30, 35, 40). Resulting ROIs were then mapped onto the homologous region of the contralateral hemisphere. Paired t tests compared the thickness of the cortex surrounding individual leptomeningeal contrast-enhancement foci and the corresponding contralateral region. Results were corrected for the false discovery rate. RESULTS: Differences between ipsilateral and contralateral ROIs progressively decreased with larger ROIs, but no significant effects were detected when considering the entire MS sample. In patients with relapsing-remitting MS only, significantly reduced cortical thickness was found for 5 dilations (−8.53%, corrected P = .04) and 10 dilations (−5.20%, corrected P = .044). CONCLUSIONS: Focal leptomeningeal contrast enhancement is associated with reduced thickness of the surrounding cortex in patients with relapsing-remitting MS, but not in those with secondary-progressive MS. Our results suggest that pathology associated with the presence of leptomeningeal contrast-enhancement foci has a stronger, localized effect on cortical tissue loss earlier in the disease.

Introduction: Persons with multiple sclerosis (MS) have deficits in many aspects of physical and cognitive functioning that can impact on mobility and participation in daily life. The effect of a 4 week intensive multimodal treadmill training on functional mobility, balance, executive functions and participation in persons with MS with moderate to severe disability was investigated. Methods: Thirty eight persons with MS admitted to a rehabilitation center participated in a two arm randomized 2:1 controlled trial. Participants in the experimental group received supervised intensive treadmill training including cognitive and motor dual tasks (DT-group, N = 26), 5 sessions per week and a control group received the same amount of supervised strength training (S-group, N = 12). The participants were assessed before and after the rehabilitation period with the 2 Minutes Walking Test (2MWT), speed and, static and dynamic balance measures, the Frontal Assessment Battery and the Short Form-12 questionnaire. The main hypothesis was related to the superiority of the treadmill intervention based on a greater proportion of people making a clinically relevant gain (15% increase on 2MWT) in gait resistance following treatment. ANCOVA (Analysis of covariance) models adjusting for baseline measurement of the respective outcome variable, as well as sex and age, were used to evaluate differences in efficacy for all variables. P was set at 0.05. Results: Nineteen out of 26 persons in the DT-group made a clinically relevant gain and two out of 12 in the S-Group (P = 0.001). The DT-group improved more in gait resistance, speed and mobility (P < 0.01). Balance and executive functions instead improved moderately in both groups following training while perception of health remained similar in both groups. Conclusion: A four week multimodal training on treadmill was highly effective in augmenting gait resistance and mobility in moderately to severely affected persons with MS.

Purpose To study deep gray matter susceptibility in multiple sclerosis (MS) by using quantitative susceptibility mapping (QSM) and to assess the relationship between susceptibility and clinical disability. Materials and Methods For this prospective study between March 2009 and November 2013, 600 participants with MS (452 with relapsing-remitting MS and 148 with secondary progressive MS) and 250 age- and sex-matched healthy control participants were imaged with 3.0-T MRI to measure magnetic susceptibility. Deep gray matter susceptibility (in parts per billion) was analyzed by using region of interest and voxelwise methods. QSM and MRI volumetric differences between study groups and associations with clinical outcomes were assessed. Analysis of covariance, multivariable linear regression, and voxelwise analyses, controlling for age and sex, were used to compare study groups and to explore associations between MRI and clinical outcomes. Results Compared with control participants, participants with MS presented with lower thalamic susceptibility (-7.5 ppb vs -1.1 ppb; P < .001) and higher susceptibility of basal ganglia (62 ppb vs 54.8 ppb; P < .001). Lower thalamic susceptibility was associated with longer disease duration (β = -0.42; P = .002), higher degree of disability (β = -0.64; P = .03), and secondary-progressive course (β = -4.3; P = .009). Higher susceptibility of the globus pallidus was associated with higher disability (β = 2; P = .03). After correcting for each individual structural volume in voxelwise analysis, lower thalamic susceptibility and higher susceptibility of the globus pallidus remained associated with clinical disability (P < .05). Conclusion Quantitative susceptibility mapping (QSM) suggests that altered deep gray matter iron is associated with the evolution of multiple sclerosis (MS) and on disability accrual, independent of tissue atrophy. © RSNA, 2018 Online supplemental material is available for this article.

Rehabilitation seems to promote brain plasticity, but objective measures of efficacy are lacking and there is a limited understanding of the mechanisms underlying functional recovery. To study functional and structural brain changes induced by gait rehabilitation. We enrolled MS inpatients (EDSS 4.5–6.5) undergoing a 4-week neurorehabilitation. Several clinical measures were obtained, including: 2-min walk test (2MWT), dynamic gait index (DGI), Berg balance scale (BBS). Furthermore, motor-task functional MRI (fMRI) of plantar dorsiflexion, resting state fMRI, and regional diffusion tensor imaging (DTI) metrics were obtained. All the assessments were performed at baseline (T0), after the end of the rehabilitation period (T1) and 3 months later (T2). Twenty-nine patients were enrolled at T0, 26 at T1, and 16 completed all timepoints. At T1, there was a significant improvement of 2MWT, DGI, and BBS scores, along with a reduced extent of the widespread activation related to the motor task at the fMRI and an increased functional connectivity in the precentral and post-central gyrus, bilaterally. None of these changes were maintained at T2. Our findings show a short-term beneficial effect of motor rehabilitation on gait performances in MS, accompanied by brain functional reorganization in the sensory-motor network.

BACKGROUND AND PURPOSE Dimethyl fumarate (DMF) is an oral treatment for relapsing-remitting multiple sclerosis (MS) with anti-inflammatory and possible neuroprotective properties. Its effect on white matter and gray matter pathology is still not fully understood. The aim of the study was to characterize the effect of DMF on normal-appearing white matter (NAWM) and thalamic pathology longitudinally. METHODS In this observational, longitudinal, 24-month magnetic resonance imaging study, 75 patients with relapsing-remitting MS treated with DMF and 40 age- and sex-matched healthy individuals were enrolled. Regional diffusion tensor imaging metrics and tract-based spatial statistics analyses were used to assess differences between groups. Mean diffusivity, axial diffusivity, radial diffusivity and fractional anisotropy were measured in the thalamus and NAWM. Baseline differences and changes over time were evaluated within and between study groups. RESULTS At baseline, patients with MS showed significantly increased diffusivity and decreased fractional anisotropy in the thalamus (P

Iron deposition has been noted widely in the subcortical deep gray matter (SDGM) of multiple sclerosis (MS) patients. Recent evidence suggests that serum iron may cross the blood-brain barrier and might be associated with SDGM iron deposition. The aim of the current study was to assess whether an iron-sensitive MRI measure is related to serum iron concentrations. This was a retrospective, cross-sectional study of 22 MS patients and 24 healthy controls (HCs), group matched for age and sex. Participants were imaged on a 1.5-T MRI scanner. High-resolution T1-weighted images and susceptibility-weighted images were acquired for assessing SDGM volumes and iron deposition within the SDGM, respectively. All participants also had blood drawn for the measurement of serum iron concentrations. MS and HC groups were compared with respect to SDGM tissue volumes and iron content. Partial correlations, controlling for age, sex, and structural volume, were used to assess the relationship between serum iron and SDGM iron content. MS patients presented with significantly smaller SDGM tissue volumes of the caudate, globus pallidus, putamen, and thalamus (all P≤0.0001). With respect to HCs, increased iron content was observed for MS patients in the globus pallidus (P=0.009) only. In MS patients only, there was a significant relationship between serum iron and putaminal iron volume (partial r=0.449, P=0.041), whereas trends were evidenced for the caudate (partial r=0.396, P=0.078) and the globus pallidus (partial r=0.410, P=0.065). Serum iron content in MS patients may be related to SDGM iron content. These results warrant confirmation in a larger study of MS patients.

With respect to healthy controls (HCs), increased iron concentrations in the deep gray matter (GM) and decreased white matter (WM) integrity are common findings in multiple sclerosis (MS) patients. The association between these features of the disease remains poorly understood. We investigated the relationship between deep iron deposition in the deep GM and WM injury in associated fiber tracts in MS patients.Sixty-six MS patients (mean age 50.0 years, median Expanded Disability Status Scale 5.25, mean disease duration 19.1 years) and 29 HCs, group matched for age and sex were imaged on a 1.5T scanner. Susceptibility-weighted imaging and diffusion tensor imaging (DTI) were used for assessing high-pass filtered phase values in the deep GM and normal appearing WM (NAWM) integrity in associated fiber tracts, respectively. Correlation analyses investigated the associations between filtered phase values (suggestive of iron content) and WM damage.Areas indicative of increased iron levels were found in the left and right caudates as well as in the left thalamus. MS patients presented with decreased DTI-derived measures of tissue integrity in the associated WM tracts. Greater mean, axial and radial diffusivities were associated with increased iron levels in all three GM areas (r values .393 to .514 with corresponding P values .003 to.0001). Global NAWM diffusivity measures were not related to mean filtered phase values within the deep GM.Increased iron concentration in the deep GM is associated with decreased tissue integrity of the connected WM in MS patients.

HIV-associated neurocognitive disorders (HAND) describes different levels of neurocognitive impairment, which are a common complication of HIV infection. The most severe of these, HIV-associated dementia (HIV D), has decreased in incidence since the introduction of combination antiretroviral therapy (cART), while an increase in the less severe, minor neurocognitive disorder (MND), is now seen. The neuropathogenesis of HAND is not completely understood, however macrophages (MΦ)s/microglia are believed to play a prominent role in the development of the more severe HIV-D. Here, we report evidence of neuroinflammation in autopsy tissues from patients with HIV infection and varying degrees of neurocognitive impairment but without HIV encephalitis (HIVE). MΦ/microglial and astrocyte activation is less intense but similar to that seen in HIVE, one of the neuropathologies underlying HIV-D. MΦs and microglia appear to be activated, as determined by CD163, CD16 and HLA-DR expression, many having a rounded or ramified morphology with thickened processes, classically associated with activation. Astrocytes also show considerable morphological alterations consistent with an activated state and have increased expression of GFAP and vimentin, as compared to seronegative controls. Interestingly, in some areas, astrocyte activation appears to be limited to perivascular locations, suggesting events at the blood-brain barrier may influence astrocyte activity. In contrast to HIVE, productive HIV infection was not detectable by tyramide signal-amplified immunohistochemistry or in situ hybridization in the CNS of HIV infected persons without encephalitis. These findings suggest significant CNS inflammation, even in the absence of detectable virus production, is a common mechanism between the lesser and more severe HIV-associated neurodegenerative disease processes and supports the notion that MND and HIV-D are a continuum of the same disease process.

Until two decades ago, steroids were the only available treatment for multiple sclerosis (MS). Recently, several new compounds have been developed and approved with the aim of favourably changing the disease course, but with varied success. The evaluation of the effectiveness of treatments for MS is

Progressive multifocal leukoencephalopathy (PML) is a severe disease of the central nervous system (CNS), caused by infection with the Polyomavirus JC virus (JCV). Because there are no known treatments or prognostic factors, we performed a long-term study focusing mainly on cerebrospinal fluid (CSF) samples from PML patients to describe the virological features akin to the different forms of the disease. Twenty-eight PML patients were enrolled: 10 HIV-1+ patients with classical PML (CPML), 9 HIV-1+ patients with slowly progressing or stable neurological symptoms (benign PML), 3 HIV-1+ asymptomatic patients and 6 HIV-1-negative patients. CSF, urine and blood samples were collected at the enrollment (baseline) and every six months afterwards when possible. The JCV DNA and HIV-1 RNA loads were determined, and the JCV strains were characterized. At baseline , the mean CSF JCV load was log 6.0 ± 1.2 copies/ml for CPML patients, log 4.0 ± 1.0 copies/ml for benign PML patients, log 4.2 ± 0.5 copies/ml for asymptomatic PML patients and log 5.8 ± 1.3 copies/ml for HIV-1-negative PML patients (CPML versus benign: p

Viral infections of the central nervous system (CNS) are associated with an increased risk for seizures during the acute infection period and the subsequent development of chronic epilepsy that is often difficult to treat. In previous work, we have shown that mice of the C57BL/6 strain infected with Theiler's murine encephalomyelitis virus (TMEV) exhibit a similar sequence, thereby providing a potential useful model of virus-induced epilepsy. The present study examines spontaneous and miniature excitatory postsynaptic currents in CA3 pyramidal cells recorded from brain slices prepared during both the acute phase during encephalitis and 2 months following TMEV infection. Animals that develop chronic epilepsy following TMEV infection exhibit considerable hippocampal sclerosis, directly implicating this brain region in the process of epileptogenesis. There are significant increases in amplitude and frequency of spontaneous and miniature excitatory currents in CA3 cells recorded in brain slices prepared during the acute infection period and 2 months after infection. However, the patterns of changes observed are markedly different during these two periods, suggesting that there are underlying changes in the network over time. These differences have implications for the treatment used during the acute infection and after chronic seizures develop.

Guillain-Barré syndrome (GBS) is an acute immune-mediated disorder of the peripheral nervous system and a triggering infectious event is often reported in the weeks before the disease onset. Influenza viruses have been associated with Guillain-Barré syndrome (GBS), both after infection and, in rare cases, after vaccination. However, GBS has rarely reported to be a neurological complication of the recent pandemic influenza A(H1N1) 2009 virus infections. Here we describe the case of a young man, who developed acute severe motor inflammatory demyelinating polyradiculoneuropathy during influenza A(H1N1)2009 infection. Peculiar features are the findings of a mutated haemagglutinin gene (D222E variant), which has never previously been associated with neurological involvement, and the almost simultaneous appearance of respiratory infectious and immune-mediated neurological symptoms. Moreover we review the clinical presentation, laboratory findings and outcome of influenza-related GBS.

Background: Several authors have used advanced magnetic resonance imaging (MRI) techniques to investigate whether patients with neuromyelitis optica (NMO) have occult damage in normal-appearing brain tissue, similarly to multiple sclerosis (MS). To date, the literature contains no data derived from the combined use of several advanced MRI techniques in the same NMO subjects. Objective: We set out to determine whether occult damage could be detected in the normal-appearing brain tissue of a small group of patients with NMO using a multiparametric MRI approach. Methods: Eight female patients affected by NMO (age range 44–58 years) and seven sex- and age-matched healthy controls were included. The techniques used on a 1.5 T MRI imaging scanner were magnetization transfer imaging, diffusion tensor imaging, tract-based spatial statistics, spectroscopy and voxel-based morphometry in order to analyse normal-appearing white matter and normal-appearing grey matter. Results: Structural and metabolic parameters showed no abnormalities in normal-appearing white matter of patients with NMO. Conversely, tract-based spatial statistics demonstrated a selective alteration of the optic pathways and the lateral geniculate nuclei. Diffusion tensor imaging values in the normal-appearing grey matter were found to be significantly different in the patients with NMO versus the healthy controls. Moreover, voxel-based morphometry analysis demonstrated a significant density and volume reduction of the sensorimotor cortex and the visual cortex. Conclusions: Our data disclosed occult structural damage in the brain of patients with NMO, predominantly involving regions connected with motor and visual systems. This damage seems to be the direct consequence of transsynaptic degeneration triggered by lesions of the optic nerve and spine.

The fatal CNS demyelinating disease, progressive multifocal leukoencephalopathy (PML), is rare and appears to occur almost always as a consequence of immune dysfunction. Thus, it is associated with HIV/AIDS and also as a side effect of certain immunomodulatory monoclonal antibody therapies. In contrast to the rarity of PML, the etiological agent of the disease, the polyomavirus JC (JCV), is widespread in populations worldwide. In the 40 years since JCV was first isolated, much has been learned about the virus and the disease from laboratory and clinical observations. However, there are many aspects of the viral life cycle and of the pathogenesis of the disease that remain unclear, and our understanding is constantly evolving. In this review, we will discuss our current understanding of the clinical features of PML and molecular characteristics of JCV and of how they relate to each other. Clinical observations can inform molecular studies of the virus, and likewise, molecular findings concerning the life cycle of the virus can guide the development of novel therapeutic strategies.

The introduction of highly active antiretroviral therapy does not seem to have altered the incidence of progressive multifocal leukoencephalopathy (PML) in HIV infection. Moreover, the occurrence of a HIV-related leukoencephalopathy, called not determined leukoencephalopaties (NDLE), has been reported. As neuropsychological impairment remains highly prevalent in HIV infection, the aim of this study is to describe the neuropsychological profile of PML and NDLE patients, analyzing the time-related changes. Clinical and neuropsychological data from 32 patients (17 PML, 15 NDLE) were compared with two control groups: (1) asymptomatic HIV+ patients without magnetic resonance imaging evidence of leukoencephalopathy; (2) age-/gender-/education-matched healthy subjects. Patients with rapidly worsening PML were significantly impaired on all neuropsychological tests, while PML with more benign course and NDLE groups showed a dysexecutive pattern of impairment. Asymptomatic HIV+ subjects showed mild and isolated cognitive deficits, without functional impact. Cognitive impairment should therefore be considered a key feature from HIV infection diagnosis.