Longitudinal study of the substantia nigra in Parkinson disease: A high-field (1) H-MR spectroscopy imaging study.

INTRODUCTION: The value of biomarkers in early diagnosis and development of therapeutics in Parkinson's disease (PD) is well established. METHODS: We used proton magnetic resonance spectroscopy in a prospective, longitudinal study of 23 patients with early PD, naïve to dopaminergic therapy, and six age-matched healthy controls to examine the temporal changes in metabolic profile of substantia nigra over a period of 3 months. RESULTS: N-acetyl aspartate to creatine ratio at month 3 was compared with baseline values in the PD and control groups, as well as the side-to-side difference of the ratio at baseline. By month 3, n-acetyl aspartate to creatine ratio had decreased by 4.4% in patients with PD (P = 0.024), without a concomitant change in healthy controls. The side-to-side asymmetry was significantly higher in the PD group (16.7%) vs. healthy controls (1.6%, P = 0.0024). CONCLUSION: Estimation of change in the n-acetyl aspartate to creatine ratio appears to be a fast, quantifiable, and reliable marker of dopaminergic neuronal viability in PD.

Choroid plexus volume as a marker of retinal atrophy in relapsing remitting multiple sclerosis.

OBJECTIVE: To evaluate choroid plexus (CP) volume as a biomarker for predicting clinical disability and retinal layer atrophy in relapsing remitting multiple sclerosis (RRMS). METHODS: Ninety-five RRMS patients and 26 healthy controls (HCs) underwent 3 T whole brain MRI, expanded disability status scale (EDSS) and optical coherence tomography (OCT). Fully automated intra-retinal segmentation was performed to obtain the volumes of the retinal nerve fiber layer (RNFL), combined ganglion cell layer -inner plexiform layer (GCIPL), inner nuclear layer (INL), outer plexiform layer (OPL), outer nuclear layer (ONL), retinal pigment epithelium (RPE), total macular volume (TMV) and papillomacular bundle (PMB). Automated segmentation of the CP within the lateral ventricles was performed and the choroid plexus volume (CPV) was normalized by total intracranial volume (TIV). Linear regression analysis and generalized estimating equation (GEE) models were applied to evaluate relationships between nCPV and EDSS, T2 lesion volume, disease duration, and retinal layer volumes, followed by Bonferroni correction analysis for multiple comparisons. RESULTS: RRMS patients had larger tChPV compared to HCs (p < 0.001). After Bonferroni correction, there was a significant positive correlation between tChPV and EDSS (r2 = 0.25, p = 0.0002), disease duration (r2 = 0.30, p = 0.01), and T2 lesion volume (r2 = 0.39, p = 0.0000). A robust negative correlation was found between tChPV and RNFL (p < 0.001), GCIPL (p = 0.003), TMV (p = 0.0185), PMB (p < 0.0001), G (p = 0.04), T(p = 0.0001). CONCLUSIONS: Our findings support the association of tChPV with disability and altered retinal integrity in RRMS.

The effect of ocrelizumab on Balo's tumefactive lesion: A case report.

Balo's concentric sclerosis (BCS) is a rare subtype of multiple sclerosis. Advanced MRI metrics, such as magnetization transfer ratio (MTR), fractional anisotropy (FA), mean diffusivity (MD), and the ratio of total N-acetylaspartate concentration/total creatine concentration (tNAA/tCr) using proton magnetic resonance spectroscopy (1H-MRS), are commonly used in research studies to investigate the effect of a disease modifying therapy (DMT). We report a patient diagnosed with BCS, receiving ocrelizumab, and provide a comparison of the lesion volume, T1-gadolinium lesion volume, MTR, FA, MD, and MRS metrics at baseline, 6- and 12-month follow-up. There was a reduction in Balo's lesion volume on fluid-attenuated inversion recovery (FLAIR) imaging observed in our patient from baseline (23.925 mL) to 12-month follow-up (2.391 mL), with the largest decrease from baseline to 6-month follow-up (3.650 mL). There was no T1-gadolinium enhancement seen at month 6 and 12. The MTR of the lesion did not change significantly (baseline = 50.9%, 6-month = 49.9%, 12-month =50.1%) but the FA increased from 0.188 (at baseline) to 0.304 (at 6 months), while the 12-month follow-up FA was 0.297. We also noted a reduction in MD from baseline (1.333 × 10-3 mm2/s) to 6-month follow-up (1.037 × 10-3 mm2/s), while the 12-month follow-up MD was 1.086 × 10-3 mm2/s. There was a 10.3% increase in tNAA/tCr from 1.583 (at month 0) to 1.747 (at month 12). Our results demonstrate for the first time a direct effect of ocrelizumab on BCS lesions. To validate our findings, more observations are needed in a larger group of BCS patients.

Impact of Disease Modifying Therapy on MS-Related Fatigue: A Narrative Review.

Multiple sclerosis (MS) is a chronic autoimmune disease that affects the central nervous system by causing inflammation, demyelination and neurodegeneration. Fatigue is the most prevalent and one of the most disabling symptoms among people with MS (pwMS). Due to its complexity and subjective character, fatigue is still little understood despite its frequent occurrence and severe impact. The potential causes, effects, and treatments of fatigue associated with MS have been extensively studied in recent years. Though the benefits of such a variety of contributions are obvious, there have not been many attempts to evaluate the effect of disease modifying therapies (DMTs) on MS-related fatigue. In this review, we summarize clinical trials and research studies, and we discuss the effect of different DMTs on MS-related fatigue.

Role of white matter in cognitive impairment among relapsing remitting multiple sclerosis patients.

BACKGROUND: Multiple Sclerosis (MS) associated cognitive impairment is believed to be mostly connected with damage to gray matter. The contribution of white matter is still poorly understood. We aim to examine the relationship between cognition and white matter tracts among relapsing remitting MS (RRMS) patients. METHODS: Thirty RRMS patients were selected undergo the (3-seconds-interstimulus-interval paced auditory serial addition test) PASAT-3, the (symbol digit modalities test (SDMT) and full-brain MRI scans on a SIEMENS 3 Tesla Verio scanner. Diffusion Tensor Imaging (DTI) parameters, such as fractional anisotropy (FA) and mean diffusivity (MD) were examined in 37 white matter (WM) tracts. WM tracts were selected from the association pathways, projection pathways, commissural pathways by applying Human Connectome project (HCP)842 tractography atlas after DTI data reconstruction and registration to HCP1065 diffusion template in DSI Studio (version March 2021) In SPSS v26, Spearman's rank correlation analysis was used to examine the connection between DTI WM tracts and cognitive scores. The power of the study was increased by using false discovery rate (FDR) software. RESULTS: The mean scores on the PASAT-3 and SDMT were 31.5 ± 12.8 and 46.9 ± 16.7 respectively. Better cognitive performance was correlated to higher FA values, while lower cognitive function was correlated to higher MD values. There was a positive correlation between FA values in the right medial lemniscus and superior cerebellar peduncle and SDMT scores (p 0.05). Additionally, there was a trend for significance between the FA values in the left corticothalamic tract and SDMT scores. MD values in the superior cerebellar peduncle, left arcuate Fasciculus and left extreme capsule were negatively correlated with SDMT scores (p<0.05). PASAT-3 scores were negatively correlated with MD values in the right cerebellum, however, there was no significant correlation between PASAT-3 and FA values. CONCLUSIONS: White matter tracts, particularly the superior cerebellar peduncle, contribute to the cognitive impairment in RRMS. Larger sample sizes for longitudinal research are necessary.

4,6-Dibromo-isophthalic acid monohydrate.

In the crystal structure of the title hydrate, C(8)H(4)Br(2)O(4)·H(2)O, O-H⋯O hydrogen bonds link the mol-ecules into a two-dimensional network parallel to (10-2). The acid groups of the main mol-ecule and the water mol-ecule are all involved in the supra-molecular structure. The dihedral angles between the benzene ring and the acid groups are 37.8 (4) and 36.4 (5)°, while the dihedral angle between the acid groups is 10.9 (4)°.

[Interaction of protein kinase C-extracellular signal-regulated kinase 1/2 signal pathway in the process of plasminogen activator inhibitor-1 expression induced by nicotine in human umbilical vein endothelial cells].

OBJECTIVE: To explore the role of protein kinase C (PKC)- extracellular signal-regulated kinase (ERK)1/2 signal pathway in the process of plasminogen activator inhibitor-1 (PAI-1) protein and mRNA expression in cultured human umbilical vein endothelial cells (HUVECs) induced by nicotine. METHODS: HUVECs were cultured to examine the effect of nicotine on the expression of secreting PAI-1 in HUVECs on different experimental conditions. The expression of PAI-1 protein was measured by ELISA. PKC inhibitor staurosporine (STS) and ERK1/2 inhibitor PD98059 were used to detect PKC or ERK1/2 function on the expression of PAI-1 in HUVECs induced by nicotine. The PAI-1 mRNA expression was determined by RT-PCR. RESULTS: The expression level of PAI-1 protein in 100 µmol/L nicotine treated group [(22.6 ± 1.1) µg/L] increased significantly compared to the control group [(14.2 ± 2.8) µg/L; q = 5.64, P < 0.05]. After stimulation with 100 µmol/L nicotine for 0, 4, 6, 8, 12 and 24 h, the levels of PAI-1 protein increased over time and reached the peak at 12 h (F = 32.063, P < 0.05). The PAI-1 mRNA and protein expression in nicotine treated group [(1.32 ± 0.20), (21.08 ± 0.83) µg/L] increased significantly compared to the control group [(0.73 ± 0.10), (13.39 ± 0.93) µg/L; q = 8.43, 11.97, all P < 0.05].Compared with nicotine treated group, the PAI-1 mRNA and protein expression in nicotine and STS treated group [(1.07 ± 0.10), (16.19 ± 2.15) µg/L] decreased significantly(q = 5.61, 7.61, all P < 0.05), but still higher than the control group (q = 7.84, 4.36, all P < 0.05). In nicotine and PD98059 treated group, the PAI-1 mRNA and protein expression [(1.12 ± 0.11), (17.52 ± 1.72) µg/L] decreased significantly compared to the nicotine treated group(q = 4.68, 5.54, all P < 0.05), still higher than the control group (q = 8.77, 6.43, all P < 0.05). CONCLUSION: PKC-ERK1/2 signal pathway may play a partial role in the up-regulation of PAI-1 induced by nicotine in HUVECs.

[Effect of isopsoralen on the proliferation and differentiate of osteoblasts in vitro].

OBJECTIVE: To investigate the effect of isopsoralen on proliferation, osteogenic differentiation and calcification capacity of rat calvarial osteoblasts (ROB). METHODS: Segregated neonatal SD rat skull,and digestion with enzyme to obtain bone cells and cultured in MEM containing 10% FBS. Exchange the medium after three days, proceeded serial subcultivation when cells covered with 90% culture dish. Proliferation analysis was performed in 96-well plates use MTT method, isopsoralen's final concentration were 1 x 10(-4), 1 x10(-5), 1 x 10(-6), 1 x 10(-7) mmol/L. Differentiation analysis was performed in 24-well plates, the Alkaline phosphatase activity and calcium salt sediment yield and osteocalcin measured at the 4th, 8th, 12th, 16th day. At 12th day, proceeded ALP stain, and at 14th day for alizarin red staining and calcified nodule count. RESULTS: When the Isopsoralen's final concentration was 1 x 10(-5) mmol/L, there was no significant effect on the ROB's proliferation, but it could promote osteogenesis. It also could raise the ALP activity and calcium salt sediment yield and osteocalcin, increase calcified tubercle amount. CONCLUSION: When the isopsoralen final concentration is 1 x 10(-5) mmol/L, it promoted ROB differentiation and maturation. Isopsoralen may be the active ingredients of preventing anti-osteoporosis in Psoralea corylifolia.

Cortical surface thickness, subcortical volumes and disability between races in relapsing-remitting multiple sclerosis.

BACKGROUND: The interplay between cortical surface thickness (CTh), subcortical volumes (SCV) and disability in patients with relapsing remitting multiple sclerosis (RRMS) is still not clear. OBJECTIVE: To examine the relationship between CTh, SCV, and disability and investigate differences in CTh, SCV and disability between African Americans (AA) and Caucasian Americans (CA). METHODS: Sixty-five RRMS (33AA, 32 CA) participants underwent Expanded Disability Status Scale and Multiple Sclerosis Functional Composite (MSFC) assessments, including timed 25-foot walk (T25FW), nine-hole peg test (9HPT) on dominant (D) and non-dominant hand (ND) and paced auditory serial addition test (PASAT-3). Symbol digit modalities test (SDMT) was also administered. All participants underwent 3T brain MRI. CTh was measured in the Frontal (FA), Parietal (PA), Temporal (TA), Occipital (OA), Cingulate (CA), and Global (GA) cortical surface areas (CSA). SCV measurements included Thalamus (TV), Caudate (CV), Putamen (PV), Pallidum (PaV), Hippocampus (HV), Amygdala (AV), Accumbens (AcV), Brain Stem (BSV), and Deep Gray Matter Total Volume (DGMTV). A general linear model with multivariate analysis (MANOVA) was used to determine the differences between the two cohorts (SPSS vs 25). Spearman rank correlation analysis was performed to investigate the relationship between CTh and MSFC. RESULTS: AA have significantly decreased FA, PA, TA, GA CTh compared to CA (p = 0.004, p = 0.018, p = 0.013, p = 0.015, respectively). SCV measurements were not significantly different. Only in CA, the MSFC measures correlate significantly with regional CSA CTh. In both races and in the entire group, T25FW correlates with TV, PV, AV, AcV and DGMTV (p < 0.05). Only in AA and the entire cohort, PASAT-3 correlates with TV and AcV(p = 0.041, p = 0.006, p = 0.006, p = 0.000 respectively). CONCLUSIONS: Differences in CSA CTh reinforce the different disease pathobiology between AA and CA. Regional CTh may represent a useful biomarker related to multi-domain disability only in CA, while in AA DGM injury might be a more important contributor to disability. Longitudinal, large-scale studies are warranted to confirm our findings.

Effect of Obesity on Retinal Integrity in African Americans and Caucasian Americans With Relapsing Multiple Sclerosis.

Objective: To study the effect of obesity on retinal structures in African Americans (AAs) and Caucasian Americans (CAs) with relapsing-remitting multiple sclerosis (RRMS). Methodology: About 136 patients with RRMS without history of optic neuritis were divided into two groups, based on body mass index (BMI): 67 obese (40 AA, 27 CA, mean BMI ± SD: 36.7 ± 5.8), and 69 non-obese (23 AA, 46 CA, mean BMI ± SD: 24.0 ± 3.1). The peripapillary retinal nerve fiber layer (pRNFL) thickness was quantified by optical coherence tomography (OCT) and was segmented into quadrant thickness: superior (S), inferior (I), temporal (T), and nasal (N). Papillomacular bundle (PMB) thickness, retinal nerve fiber layer (RNFL), ganglion cell + inner plexiform layer (GCIPL), inner nuclear (INL), outer plexiform (OPL), outer nuclear (ONL), and total macular (TMV) volumes were obtained. Results: Obesity was associated with lower T thickness (58.54 ± 15.2 vs. 61.9 12.4, p = 0.044), higher INL (0.98 ± 0.07 vs. 0.96 ± 0.06, p = 0.034), and lower RNFL (0.77 ± 0.14 vs. 0.82 ± 0.12, p = 0.009) volumes. Obese AA had significantly thinner T (58.54 ± 15.19 vs. 61.91 ± 12.39, p = 0.033), N (68.94 ± 2.7 vs. 77.94 ± 3.3, p = 0.044), and TMV (8.15 ± 0.07 vs. 8.52 ± 0.09, p = 0.003), RNFL (0.74 ± 0.02 vs. 0.82 ± 0.02, p = 0.013), OPL (0.76 ± 0.01 vs. 0.79 ± 0.1, p = 0.050), ONL (1.68 ± 0.031 vs. 1.79 ± 0.038, p = 0.026), and GCIPL (1.78 ± 0.04 vs. 1.9 ± 0.05, p = 0.038) compared to obese CA. Among patients with non-obesity, the ONL was significantly lower in AA (1.78 ± 0.04 vs. 1.9 ± 0.05, p < 0.001). Conclusions: Obesity is associated with retinal structure abnormalities in patients with RRMS. Its impact might be more prominent in AA than CA. Large longitudinal studies are needed to validate our findings.

Multimodal MRI Response to Fingolimod in Multiple Sclerosis: A Nonrandomized, Single Arm, Observational Study.

BACKGROUND AND PURPOSE: Fingolimod has a favorable effect on conventional MRI measures; however, its neuroprotective effect is not clear. We aim to investigate changes of conventional and advanced MRI measures in lesions and normal-appearing white matter (NAWM) over 2 years in fingolimod-treated patients. METHODS: Fifty relapsing-remitting multiple sclerosis patients and 27 healthy controls were enrolled in the study and underwent baseline, 1-year, and 2-year 3T MRI scans. T2 lesion volume, whole brain volume, cortical gray matter volume, white matter volume, corpus callosum area, percentage brain volume change (PBVC), Expanded Disability Status Scale, gadolinium-enhancing lesions, PBVC, magnetization transfer ratio (MTR), and diffusion tensor imaging metrics (fractional anisotropy [FA] and median diffusivity [MD]) in lesions and NAWM were calculated. Longitudinal changes were examined using one-way repeated measures ANOVA. Bonferroni correction for multiple testing was used when appropriate. RESULTS: Conventional MRI measures were unchanged in both groups. Lesion MTR increased significantly (P < .001), but NAWM-MTR remained unchanged. Lesion FA improved significantly in year 1 (P = .003) and over the study duration (P = .05). Lesion MD changed significantly from baseline to year 1 (P < .001) and remained stable over 2 years. NAWM-FA was significant from baseline to year 1 (P = .002) and from baseline to year 2 (P < .001). NAWM-MD was significant only from baseline to year 1 (P = .001). CONCLUSIONS: These findings suggest a possible neuroreparative effect of fingolimod on the MS lesions and NAWM. Larger and longer randomized studies are required to confirm these results.

White and Gray Matter Abnormalities in Manifest Huntington's Disease: Cross-Sectional and Longitudinal Analysis.

BACKGROUND AND PURPOSE: Early white matter (WM) changes and cortical atrophy in Huntington's disease (HD) are often evident before disease onset and extend through the brain during manifest stages. The trajectory of these brain abnormalities in symptomatic stages remains relatively unexplored. The aim of this study is to investigate how the pattern of WM and gray matter (GM) alterations progress over time. METHODS: We investigated alterations in brain WM, cortical thickness, and subcortical structures using diffusion and structural magnetic resonance imaging, in manifest HD patients (n = 13) compared to age-matched healthy controls (n = 11). Imaging and clinical data for the HD group were collected at follow-up (7 months) to explore possible longitudinal changes. RESULTS: Cross-sectional analyses identified significant posterior cortical thinning (P < .05) and symmetric fractional anisotropy (FA) reduction (P < .01) in brain WM of HD group compared to HC. These changes were strongly correlated with impairment in motor symptoms and processing speed. Subcortical atrophy was significant in caudate, putamen, globus pallidus, and thalamus (P < .001). Regions of interest analysis revealed a significant reduction in FA of the corpus callosum (CC) (-2.19%, P < .05) upon follow-up, whereas no significant cortical thinning and subcortical atrophy was found. CONCLUSIONS: This study showed broad GM and WM abnormalities in manifest HD patients. Reductions in FA and cortical thinning correlated significantly with the disturbances of motor and cognitive processing that describe HD. Follow-up assessment showed that the CC is compromised in the absence of detectable GM changes or motor decline, suggesting it plays an important role in disease progression.

Racial differences in retinal neurodegeneration as a surrogate marker for cortical atrophy in multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) has both an inflammatory and a neurodegenerative component, with gray matter (GM) atrophy being an important contributor to disability. Optical coherence tomography (OCT) may serve as a prognostic tool for neuroaxonal health by measuring ganglion cell inner plexiform layer (GCIPL) thickness. There is a paucity of literature regarding the effects of race on pathobiology of MS, as racial minorities are underrepresented in research studies. OBJECTIVE: The aim of this paper is to compare the correlation between GM fraction (GMF) and GCIPL thickness in Caucasian Americans with MS (CAMS) and African Americans with MS (AAMS). METHODS: Fifty-nine patients with relapsing-remitting multiple sclerosis (RRMS) were included. Using a cross-sectional design, we compared the OCT (GCIPL thickness) and MRI (GMF) data of 32 CAMS and 27 AAMS patients. RESULTS: No significant correlation was observed between GMF and GCIPL in our study group (p = 0.127, r = 0.148). CAMS exhibited a significant correlation between these measures (p = 0.0004, r = 0.434), while in AAMS these measures did not correlate significantly (p = 0.187, r = -0.201). CONCLUSION: GCIPL might be a sensitive biomarker predicting GM atrophy and disability in CAMS, but not in AAMS. Larger studies are needed to investigate reliable biomarkers across races. Inclusion of AAMS in research studies is necessary to shed more light on the pathobiology of MS.

Characterizing Fatigue-Related White Matter Changes in MS: A Proton Magnetic Resonance Spectroscopy Study.

Few cross-sectional studies have investigated the correlation between neurochemical changes and multiple sclerosis (MS) fatigue, but little is known on the fatigue-related white matter differences between time points. We aim to investigate the longitudinal neurometabolite profile of white matter in MS fatigue. Forty-eight relapsing remitting multiple sclerosis (RRMS) patients with an expanded disability status scale (EDSS) ≤ 4 underwent high field 1H-multivoxel magnetic resonance spectroscopy (MRS) at baseline and year 1. Fatigue severity was evaluated by the fatigue severity scale (FSS). Patients were divided into low (LF, FSS ≤ 3), moderate (MF, FSS = 3.1-5), and high fatigue (HF, FSS ≥ 5.1) groups. In a two-way analysis of variance (ANOVA), we observed a decline in the ratio of the sum of N-acetylaspartate (NAA) and N-acetylaspartylglutamate (NAAG) to the sum of creatine (Cr) and phosphocreatine (PCr) in the right anterior quadrant (RAQ) and left anterior quadrant (LAQ) of the MRS grid in the HF group at baseline and year 1. This decline was significant when compared with the LF group (p = 0.018 and 0.020). In a one-way ANOVA, the fatigue group effect was significant and the ratio difference in the right posterior quadrant (RPQ) and left posterior quadrant (LPQ) of the HF group was also significant (p = 0.012 and 0.04). Neurochemical changes in the bilateral frontal white matter and possibly parietooccipital areas were noted in the HF group at two different time points. Our findings may shed some light on the pathology of MS fatigue.

Acute transverse myelitis with normal brain MRI : long-term risk of MS.

OBJECTIVE: To investigate the long-term risk of developing MS in patients presenting with acute transverse myelitis (ATM) and normal brain MRI scans at onset. METHODS: We studied 58 ATM patients with normal brain MRI at presentation for up to 5 years with serial neurologic and imaging studies. All patients underwent CSF analysis at onset which was defined positive if two or more IgG oligoclonal bands and/or elevated IgG index were present. Brain and spinal cord MRI scans were obtained every 6 months for the first 2 years, and annually thereafter unless the patient experienced a second neurologic attack different from the initial episode to confirm CDMS or there was demonstration of MRI lesions confirming dissemination in time and space to fulfill McDonald imaging criteria to diagnose MS. RESULTS: Seventeen of 58 (29%) patients developed MS of which 7 (41%) patients developed CDMS and 10 (59%) developed MS using McDonald Imaging Criteria. Mean time to CDMS by a second clinical attack was 11. 1 months compared to 19. 2 months by MRI lesions (P = 0. 03). None of the patients developed MS after 24 months of onset. All 17 patients who developed MS had positive CSF although 15 patients who had positive CSF did not develop MS during the 5 years of follow-up. CONCLUSIONS: The majority of patients with ATM and normal brain MRI do not develop MS after 5 years of follow-up confirming the relatively low risk compared to patients with abnormal brain MRI scans. CSF is helpful in distinguishing patients more likely to develop MS. Compared to clinical attacks, serial imaging may not lead to an earlier diagnosis in ATM patients with normal brain MRI.

Long-term safety of rituximab induced peripheral B-cell depletion in autoimmune neurological diseases.

BACKGROUND: B-cells play a pivotal role in several autoimmune diseases, including patients with immune-mediated neurological disorders (PIMND), such as neuromyelitis optica (NMO), multiple sclerosis (MS), and myasthenia gravis (MG). Targeting B-cells has been an effective approach in ameliorating both central and peripheral autoimmune diseases. However, there is a paucity of literature on the safety of continuous B-cell depletion over a long period of time. OBJECTIVE: The aim of this study was to examine the long-term safety, incidence of infections, and malignancies in subjects receiving continuous therapy with a B-cell depleting agent rituximab over at least 3 years or longer. METHODS: This was a retrospective study involving PIMND who received continuous cycles of rituximab infusions every 6 to 9 months for up to 7 years. The incidence of infection related adverse events (AE), serious adverse events (SAE), and malignancies were observed. RESULTS: There were a total of 32 AE and 4 SAE with rituximab treatment. The 3 SAE were noted after 9 cycles (48 months) and 1 SAE was observed after 11 cycles (60 months) of rituximab. There were no cases of Progressive multifocal leukoencephalopathy (PML) and malignancies observed throughout the treatment period. Rituximab was well tolerated without any serious infusion reactions. Also, rituximab was found to be beneficial in treating PIMND over a 7-year period. CONCLUSIONS: This study demonstrates that long-term depletion of peripheral B-cells appears safe and efficacious in treating PIMND. Longer and larger prospective studies with rituximab are needed to carefully ascertain risks associated with chronic B-cell depletion, including malignancies. Recognizing that this is a small, retrospective study, such data nonetheless complement the growing literature documenting the safety and tolerability of B-cell depleting agents in neurological diseases.

Cerebrospinal fluid humoral immunity in the differential diagnosis of multiple sclerosis.

BACKGROUND: The diagnostic accuracy of cerebrospinal fluid oligoclonal bands (CSF-OCB) detected by isoelectric focusing (IEF) in patients with multiple sclerosis (MS) was evaluated in our study. METHODS: Three hundred and twenty-one patients with MS and other central nervous system (CNS) immune mediated disorders were assessed (CIMD). Cerebrospinal fluid and matched serum samples were examined for the presence of OCB by IEF-IB (isoelectric focusing with immunoblotting). RESULTS: Isolated oligoclonal bands (ISO-OCB) were the only predictor of MS diagnosis independent of age, gender and CSF-OCB. ISO-OCB ≥ 3.5 detected by IEF yielded a sensitivity of 98% and specificity of 87% in distinguishing MS from MS mimickers. CONCLUSIONS: For the neurologist, a score of ≥ 4 ISO-OCB supports the diagnosis of MS. On the other hand, ISO-OCB ≤3 favors CIMD. Further studies with larger population samples are warranted to confirm these findings.

Structural and Neuronal Integrity Measures of Fatigue Severity in Multiple Sclerosis.

Fatigue is a common and disabling symptom in Multiple Sclerosis (MS). However, consistent neuroimaging correlates of its severity are not fully elucidated. In this article, we study the neuronal correlates of fatigue severity in MS. Forty-three Relapsing Remitting MS (RRMS) patients with MS-related fatigue (Fatigue Severity Scale (FSS) range: 1-7) and Expanded Disability Status Scale (EDSS) ≤ 4, were divided into high fatigue (HF, FSS ≥ 5.1) and low fatigue groups (LF, FSS ≤ 3). We measured T2 lesion load using a semi-automated technique. Cortical thickness, volume of sub-cortical nuclei, and brainstem structures were measured using Freesurfer. Cortical Diffusion Tensor Imaging (DTI) parameters were extracted using a cross modality technique. A correlation analysis was performed between FSS, volumetric, and DTI indices across all patients. HF patients showed significantly lower volume of thalamus, (p = 0.02), pallidum (p = 0.01), and superior cerebellar peduncle ((SCP), p = 0.002). The inverse correlation between the FSS score and the above volumes was significant in the total study population. In the right temporal cortex (RTC), the Radial Diffusivity ((RD), p = 0.01) and Fractional Anisotropy ((FA), p = 0.01) was significantly higher and lower, respectively, in the HF group. After Bonferroni correction, thalamic volume, FA-RTC, and RD-RTC remained statistically significant. Multivariate regression analysis identified FA-RTC as the best predictor of fatigue severity. Our data suggest an association between fatigue severity and volumetric changes of thalamus, pallidum, and SCP. Early neuronal injury in the RTC is implicated in the pathogenesis of MS-related fatigue.

The Relationship Between Brain MR Spectroscopy and Disability in Multiple Sclerosis: 20-Year Data from the U.S. Glatiramer Acetate Extension Study.

BACKGROUND AND PURPOSE: Conventional MRI techniques do not necessarily provide information about multiple sclerosis (MS) disease pathology or progression. Nonconventional MRI techniques, including proton magnetic resonance spectroscopy (1 H-MRS), are increasingly used to improve the qualitative and quantitative specificity of MR images. This study explores potential correlations between MRI measures of disease and disability progression as measured by the Expanded Disability Status Scale (EDSS), Functional Systems (FS), and ambulation index scores in a unique cohort of MS patients treated with glatiramer acetate that has been closely monitored for over 20 years. METHODS: This was a multicenter, open-label, cross-sectional MRI substudy among participants in the GA-9004 open-label extension of the 36-month, double-blind GA-9001 study, timed to coincide with the prospectively planned 20-year clinical exam. RESULTS: Of 64 patients who participated in the MRI substudy, results are presented for the 39 patients (61%) who had a 1 H-MRS assessment at 20 years of treatment. Both total N-acetylaspartate relative to total creatinine (tNAA/tCr) concentration ratio and T1 lesion volume were found to be robustly associated with disability levels with different statistical approaches. Gray matter (GM) volume was found to be a more consistent parameter than white matter (WM) volume for disability allocation. The elastic net algorithm showed a trade-off between WM and GM volumes for disability estimation when different disability definitions were used. CONCLUSIONS: Among patients with MS receiving long-term glatiramer acetate therapy, consistent effects on disability levels indicated by EDSS and pyramidal FS score thresholds were found for tNAA/tCr concentration ratio and T1 lesion volume.

Cerebral Gray Matter Atrophy Is Associated with the CSF IgG index in African American with Multiple Sclerosis.

BACKGROUND AND PURPOSE: African American (AA) patients with multiple sclerosis (MS) have been reported to have a more aggressive disease course compared to their white counterparts. We explored the relation of gray matter (GM) volume, a marker of tissue injury, and cerebrospinal fluid (CSF) IgG index in both AA and white MS patients. METHODS: This was a cross-sectional study of 150 self-identified AA and 150 white patients with MS who underwent magnetic resonance imaging scan of brain and CSF sampling. Intrathecal IgG synthesis was quantified as IgG index. The Spearman test was used for univariate correlation analysis, followed by generalized linear model (GLM) to assess the effect of race on the correlation between IgG index and GM volume. RESULTS: The GM volume was inversely related to the IgG index for the entire group (rho = -.57, P < .0004). The AA group showed a stronger correlation (rho = -.893, P < .00004), as compared to whites (rho = -.019, P = .85), between GM and IgG index. Furthermore, GLM analysis showed a significant effect of race on the relation between IgG index and GM volume (P < .0005). CONCLUSIONS: AA patients with MS have lower GM volume and a stronger inverse correlation between GM volume and CSF IgG index, compared to the whites. These findings suggest a potentially prominent role of humoral immunity in mediating tissue injury in AA patients with MS.