Utility of an untargeted metabolomics approach using a 2D GC-GC-MS platform to distinguish relapsing and progressive multiple sclerosis.

Introduction: Multiple sclerosis (MS) is the most common inflammatory neurodegenerative disease of the central nervous system (CNS) in young adults and results in progressive neurological defects. The relapsing-remitting phenotype (RRMS) is the most common disease course in MS and may progress to the progressive form (PPMS). Objectives: There is a gap in knowledge regarding whether the relapsing form can be distinguished from the progressive course or healthy subjects (HS) based on an altered serum metabolite profile. In this study, we performed global untargeted metabolomics with the 2D GCxGC-MS platform to identify altered metabolites between RRMS, PPMS, and HS. Methods: We profiled 235 metabolites in the serum of patients with RRMS (n=41), PPMS (n=31), and HS (n=91). A comparison of RRMS and HS patients revealed 22 significantly altered metabolites at p<0.05 (false discovery rate [FDR]=0.3). The PPMS and HS comparisons revealed 28 altered metabolites at p<0.05 (FDR=0.2). Results: Pathway analysis using MetaboAnalyst revealed enrichment of four metabolic pathways in both RRMS and PPMS (hypergeometric test p<0.05): 1) galactose metabolism; 2) amino sugar and nucleotide sugar metabolism; 3) phenylalanine, tyrosine, and tryptophan biosynthesis; and 4) aminoacyl-tRNA biosynthesis. The Qiagen IPA enrichment test identified the sulfatase 2 (SULF2) (p=0.0033) and integrin subunit beta 1 binding protein 1 (ITGB1BP1) (p=0.0067) genes as upstream regulators of altered metabolites in the RRMS vs. HS groups. However, in the PPMS vs. HS comparison, valine was enriched in the neurodegeneration of brain cells (p=0.05), and heptadecanoic acid, alpha-ketoisocaproic acid, and glycerol participated in inflammation in the CNS (p=0.03). Conclusion: Overall, our study suggested that RRMS and PPMS may contribute metabolic fingerprints in the form of unique altered metabolites for discriminating MS disease from HS, with the potential for constructing a metabolite panel for progressive autoimmune diseases such as MS.

Blood-based targeted metabolipidomics reveals altered omega fatty acid-derived lipid mediators in relapsing-remitting multiple sclerosis patients.

Unresolved and uncontrolled inflammation is considered a hallmark of pathogenesis in chronic inflammatory diseases like multiple sclerosis (MS), suggesting a defective resolution process. Inflammatory resolution is an active process partially mediated by endogenous metabolites of dietary polyunsaturated fatty acids (PUFA), collectively termed specialized pro-resolving lipid mediators (SPMs). Altered levels of resolution mediators have been reported in several inflammatory diseases and may partly explain impaired inflammatory resolution. Performing LC-MS/MS-based targeted lipid mediator profiling, we observed distinct changes in fatty acid metabolites in serum from 30 relapsing-remitting MS (RRMS) patients relative to 30 matched healthy subjects (HS). Robust linear regression revealed 12 altered lipid mediators after adjusting for confounders (p <0.05). Of these, 15d-PGJ2, PGE3, and LTB5 were increased in MS while PGF2a, 8,9-DiHETrE, 5,6-DiHETrE, 20-HETE, 15-HETE, 12-HETE, 12-HEPE, 14-HDoHE, and DHEA were decreased in MS compared to HS. In addition, 12,13-DiHOME and 12,13-DiHODE were positively correlated with expanded disability status scale values (EDSS). Using Partial Least Squares, we identified several lipid mediators with high VIP scores (VIP > 1: 32% - 52%) of which POEA, PGE3, DHEA, LTB5, and 12-HETE were top predictors for distinguishing between RRMS and HS (AUC =0.75) based on the XGBoost Classifier algorithm. Collectively, these findings suggest an imbalance between inflammation and resolution. Altogether, lipid mediators appear to have potential as diagnostic and prognostic biomarkers for RRMS.

Pyruvate Dehydrogenase-Dependent Metabolic Programming Affects the Oligodendrocyte Maturation and Remyelination.

The metabolic needs of the premature/premyelinating oligodendrocytes (pre-OLs) and mature oligodendrocytes (OLs) are distinct. The metabolic control of oligodendrocyte maturation from the pre-OLs to the OLs is not fully understood. Here, we show that the terminal maturation and higher mitochondrial respiration in the OLs is an integrated process controlled through pyruvate dehydrogenase complex (Pdh). Combined bioenergetics and metabolic studies show that OLs show elevated mitochondrial respiration than the pre-OLs. Our signaling studies show that the increased mitochondrial respiration activity in the OLs is mediated by the activation of Pdh due to inhibition of the pyruvate dehydrogenase kinase-1 (Pdhk1) that phosphorylates and inhibits Pdh activity. Accordingly, when Pdhk1 is directly expressed in the pre-OLs, they fail to mature into the OLs. While Pdh converts pyruvate into the acetyl-CoA by its oxidative decarboxylation, our study shows that Pdh-dependent acetyl-CoA generation from pyruvate contributes to the acetylation of the bHLH family transcription factor, oligodendrocyte transcription factor 1 (Olig1) which is known to be involved in the OL maturation. Pdh inhibition via direct expression of Pdhk1 in the pre-OLs blocks the Olig1-acetylation and OL maturation. Using the cuprizone model of demyelination, we show that Pdh is deactivated during the demyelination phase, which is however reversed in the remyelination phase upon cuprizone withdrawal. In addition, Pdh activity status correlates with the Olig1-acetylation status in the cuprizone model. Hence, the Pdh metabolic node activation allows a robust mitochondrial respiration and activation of a molecular program necessary for the terminal maturation of oligodendrocytes. Our findings open a new dialogue in the developmental biology that links cellular development and metabolism. These findings have far-reaching implications in the development of therapies for a variety of demyelinating disorders including multiple sclerosis.

Pro-resolution lipid mediator maresin-1 ameliorates inflammation, promotes neuroprotection, and prevents disease progression in experimental models of multiple sclerosis.

Multiple sclerosis (MS) is the most common inflammatory neurodegenerative disease in young adults, resulting in neurological defects and disability. The endogenous mechanisms to resolve inflammation are intact but become defective in patients, resulting in lack of resolution mediators and unresolved chronic inflammation. Docosahexaenoic acid (DHA) metabolism being impaired in MS, we hypothesize that supplementing its downstream metabolite maresin 1 (MaR1) will alleviate inflammation and demyelination in preclinical mouse model of MS; experimental allergic encephalomyelitis (EAE). Restoration of MaR1 by its exogenous administration in EAE mice propagated inflammatory resolution and had a protective effect on neurological deficits, prevented disease progression, and reduced disease severity by reducing immune cell infiltration (CD4+IL17+ and CD4+IFN-γ+) into the CNS. It significantly reduced the proinflammatory cytokine IL17 and promoted an anti-inflammatory response via IL10 and IL4. Neutralization of IL10 abolished the protective effect of MaR1 in EAE confirming IL10 is mediating MaR1 effect in EAE. Furthermore, it improved the pathophysiology and exerted neuroprotective effects by mitigating disease signs in EAE as evidenced by lower levels of NFL in the plasma of treated group compared to control and higher MBP expression in the brain from the MaR1 treated mice, decreased inflammatory infiltrates, and less demyelination and vacuolization in the spinal cord tissue sections of treated mice. SCENITH data confirmed that MaR1 maintains myelin by regulating oligodendrocyte metabolism. Also, it induces metabolic reprogramming in infiltrating CD4 cells and macrophages, which modulate their phenotype. Metabolic changes induced macrophages by MaR1 restores the impaired efferocytosis in EAE, promoting clearance of damaged myelin and dead cells; thereby lowering the disability with disease course. Overall, MaR1 supplementation has anti-inflammatory and neuroprotective effects in preclinical animal models and induces metabolic reprogramming in disease associated cell-types, promotes efferocytosis, implying that it could be a new therapeutic molecule in MS and other autoimmune diseases. Highlights: Inflammation is dysregulated in EAE due to impaired synthesis of DHA derived proresolving lipid mediator MaR1.Administration of the resolution agonist MaR1 propagates resolution processes and improves neurological outcome in RR model of EAE.MaR1 ameliorates clinical signs of EAE by attenuating pro-inflammatory cytokine IL17 mediated response and promoting anti-inflammatory response through IL10.MaR1 supplementation improves the pathophysiology in EAE and shows neuroprotection as indicated by the lower levels of NFL in the plasma and higher expression of MBP in the brain of treated mice.MaR1 induces metabolic reprogramming in disease-associated cell types.MaR1 promotes efferocytosis in EAE through metabolic reprogramming of macrophages. Significance: Inflammatory process is a protective response to several challenges like injury or infection. However, it must resolve over time to maintain tissue homeostasis. Impaired or delayed resolution leads to damaging effects, including chronic inflammation, tissue damage, and disease progression as occurs in multiple sclerosis (MS). We report that inflammation is dysregulated in preclinical animal model of MS, experimental autoimmune encephalomyelitis (EAE), partially due to impaired synthesis of proresolving lipid mediators. We show that the administration of the resolution agonist known as maresin 1 (MaR1) in EAE actively propagates resolution processes and improves neurological outcome. We conclude that MaR1 is a potential interventional candidate to attenuate dysregulated inflammation and to restore neurological deficits in EAE.

Clinical and diagnostic spectrum of optic neuritis: A single-center retrospective study of disorders associated with multiple sclerosis, anti-aquaporin-4 and anti-myelin oligodendrocyte glycoprotein antibodies.

OBJECTIVE: Optic neuritis (ON) is an immune-mediated optic neuropathy associated with multiple immune-mediated neurological conditions. Our aim was to characterize the clinical and diagnostic features of first or initial episodes of ON associated with multiple sclerosis (MS)-associated (typical) and antibody-related (atypical) ON. METHODS: Retrospective, single institution, medical record review. We analyzed demographic, clinical, laboratory, and radiographic findings of 139 patients who presented with first episodes of MS-associated ON (MS-ON), aquaporin 4 antibody-associated ON (AQP4-ON), and myelin oligodendrocyte glycoprotein antibody-associated ON (MOG-ON) between January 2015 and October 2019 without preceding diagnosis. Simple hypothesis testing assessed differences between groups were performed. RESULTS: Of 139 patients (109 [79 %] women; 29 [21 %] men; mean age 47 [SD, 14] years), 106 had MS-ON, 25 had AQP4-ON, and 8 had MOG-ON. Patients with MOG-ON had the highest recurrence rate (88 %) relative to MS-ON (28 %) and AQP4-ON (56 %) patients (P < .001). Patients with AQP4-ON had the highest mean visual functional system scores (4.3 [SD, 1.8]) relative to MS-ON (2.0 [SD, 1.9]) and MOG-ON patients (2.8 [SD, 2.0]) (P < .001). CONCLUSION: Patients presenting with initial episodes of ON exhibit a range radiographic and laboratory feature depending on the underlying associated disease. Understanding the variable characteristics of typical (MS-associated) and atypical (antibody-associated) ON may help physicians accurately diagnose and effectively treat ON.

Blood-based untargeted metabolomics in relapsing-remitting multiple sclerosis revealed the testable therapeutic target.

Metabolic aberrations impact the pathogenesis of multiple sclerosis (MS) and possibly can provide clues for new treatment strategies. Using untargeted metabolomics, we measured serum metabolites from 35 patients with relapsing-remitting multiple sclerosis (RRMS) and 14 healthy age-matched controls. Of 632 known metabolites detected, 60 were significantly altered in RRMS. Bioinformatics analysis identified an altered metabotype in patients with RRMS, represented by four changed metabolic pathways of glycerophospholipid, citrate cycle, sphingolipid, and pyruvate metabolism. Interestingly, the common upstream metabolic pathway feeding these four pathways is the glycolysis pathway. Real-time bioenergetic analysis of the patient-derived peripheral blood mononuclear cells showed enhanced glycolysis, supporting the altered metabolic state of immune cells. Experimental autoimmune encephalomyelitis mice treated with the glycolytic inhibitor 2-deoxy-D-glucose ameliorated the disease progression and inhibited the disease pathology significantly by promoting the antiinflammatory phenotype of monocytes/macrophage in the central nervous system. Our study provided a proof of principle for how a blood-based metabolomic approach using patient samples could lead to the identification of a therapeutic target for developing potential therapy.

Multi-omic evaluation of metabolic alterations in multiple sclerosis identifies shifts in aromatic amino acid metabolism.

The circulating metabolome provides unique insights into multiple sclerosis (MS) pathophysiology, but existing studies are relatively small or characterized limited metabolites. We test for differences in the metabolome between people with MS (PwMS; n = 637 samples) and healthy controls (HC; n = 317 samples) and assess the association between metabolomic profiles and disability in PwMS. We then assess whether metabolic differences correlate with changes in cellular gene expression using publicly available scRNA-seq data and whether identified metabolites affect human immune cell function. In PwMS, we identify striking abnormalities in aromatic amino acid (AAA) metabolites (p = 2.77E-18) that are also strongly associated with disability (p = 1.01E-4). Analysis of scRNA-seq data demonstrates altered AAA metabolism in CSF and blood-derived monocyte cell populations in PwMS. Treatment with AAA-derived metabolites in vitro alters monocytic endocytosis and pro-inflammatory cytokine production. We identify shifts in AAA metabolism resulting in the reduced production of immunomodulatory metabolites and increased production of metabotoxins in PwMS.

Review of the COVID-19 Risk in Multiple Sclerosis.

The ongoing pandemic of the novel coronavirus of 2019 (COVID-19) has resulted in over 1 million deaths, primarily affecting older patients with chronic ailments. Multiple sclerosis (MS) patients have been deemed particularly vulnerable given their high rates of disability and increased susceptibility to infections. There have also been concerns regarding disease-modifying therapy (DMT) during the pandemic as many DMTs may increase the risk of infection due to some of their immunosuppressive properties. Furthermore, due to MS-related chronic inflammatory damage within the central nervous system, there have been concerns for worsening neurological injury by COVID-19. This has resulted in an alarmingly high level of anxiety and stress among the MS community leading to a lack of compliance with medications and routine check-ups, and even failure to obtain treatment for relapse. However, there is currently substantial evidence that MS and most DMT usage is not associated with increased COVID-19 severity. MS patients who suffer worse outcomes were more likely to be older and suffer from significant disabilities and comorbid conditions, which would also be expected from those in the general population. Likewise, there is little if any evidence demonstrating an increased susceptibility of MS patients to COVID-19-related neurological complications. Therefore, we aim to summarize the most recent findings related to COVID-19 and MS demonstrating that MS and most DMTs do not appear as risk factors for severe COVID-19.

Impairments of white matter tracts and connectivity alterations in five cognitive networks of patients with multiple sclerosis.

INTRODUCTION: MS is associated with structural and functional brain alterations leading to cognitive impairments across multiple domains including attention, memory, and speed of information processing. Here, we analyzed the white matter damage and topological organization of white matter tracts in specific brain regions responsible for cognition in MS. METHODS: Brain DTI, rs-fMRI, T1, T2, and T2-FLAIR were acquired for 22 MS subjects and 22 healthy controls. Automatic brain parcellation was performed on T1-weighted images. Skull-stripped T1-weighted intensity inverted images were co-registered to the b0 image. Diffusion-weighted images were processed to perform whole brain tractography. The rs-fMRI data were processed, and the connectivity matrixes were analyzed to identify significant differences in the network of nodes between the two groups using NBS analysis. In addition, diffusion entropy maps were produced from DTI data sets using in-house software. RESULTS: MS subjects exhibited significantly reduced mean FA and entropy in 38 and 34 regions, respectively, out of a total of 54 regions. The connectivity values in both structural and functional analyses were decreased in most regions of the default mode network and in four other cognitive networks in MS subjects compared to healthy controls. MS also induced significant reduction in the normalized hippocampus and corpus callosum volumes; the normalized hippocampus volume was significantly correlated with EDSS scores. CONCLUSION: MS subjects have significant white matter damage and reduction of FA and entropy in various brain regions involved in cognitive networks. Structural and functional connectivity within the default mode network and an additional four cognitive networks exhibited significant changes compared with healthy controls.

COVID-19 in multiple sclerosis patients and risk factors for severe infection.

Multiple sclerosis (MS) patients have been considered a higher-risk population for COVID-19 due to the high prevalence of disability and disease-modifying therapy use; however, there is little data identifying clinical characteristics of MS associated with worse COVID-19 outcomes. Therefore, we conducted a multicenter prospective cohort study looking at the outcomes of 40 MS patients with confirmed COVID-19. Severity of COVID-19 infection was based on hospital course, where a mild course was defined as the patient not requiring hospital admission, moderate severity was defined as the patient requiring hospital admission to the general floor, and most severe was defined as requiring intensive care unit admission and/or death. 19/40(47.5%) had mild courses, 15/40(37.5%) had moderate courses, and 6/40(15%) had severe courses. Patients with moderate and severe courses were significantly older than those with a mild course (57[50-63] years old and 66[58.8-69.5] years old vs 48[40-51.5] years old, P = 0.0121, P = 0.0373). There was differing prevalence of progressive MS phenotype in those with more severe courses (severe:2/6[33.3%]primary-progressing and 0/6[0%]secondary-progressing, moderate:1/14[7.14%] and 5/14[35.7%] vs mild:0/19[0%] and 1/19[5.26%], P = 0.0075, 1 unknown). Significant disability was found in 1/19(5.26%) mild course-patients, but was in 9/15(60%, P = 0.00435) of moderate course-patients and 2/6(33.3%, P = 0.200) of severe course-patients. Disease-modifying therapy prevalence did not differ among courses (mild:17/19[89.5%], moderate:12/15[80%] and severe:3/6[50%], P = 0.123). MS patients with more severe COVID-19 courses tended to be older, were more likely to suffer from progressive phenotype, and had a higher degree of disability. However, disease-modifying therapy use was not different among courses.

The effect of race on clinical presentation and outcomes in neurosarcoidosis.

BACKGROUND: Nervous system is affected in 25% of patients with sarcoidosis. Current literature is largely limited to case reports with disproportionate Caucasian population. We aim to evaluate differences in presentation, management and outcomes by race in neurosarcoidosis. METHODS: Clinical and demographic data on consecutive patients fulfilling Zajicek criteria for neurosarcoidosis from 1995 to 2016 at Henry Ford Hospital were extracted. Disparities in clinical presentation, laboratory values, radiological features, treatment and outcomes, were compared between two groups: African Americans (AA) and non-AA using chi-squared tests, two sample t-test for age and Wilcoxon two sample tests. RESULTS: A total of 118 patients were included, of which 58% were female and 73% were AA. The diagnosis of neurosarcoidosis was noted to be definite (25%), probable (64%) and possible (11%). AA patients had a significantly higher rate of elevated erythrocyte sedimentation rate (62% vs 24%, P = .005) and had lower resolution of abnormalities on follow-up imaging (14% vs 41%, P = .017). There was no difference in disability on follow-up (25% vs 33%, P = .43) or mortality (13% vs 9%, P = .6). CONCLUSIONS: There were no differences in presentation, management and outcomes by race. Discordance in the clinical and radiological data by race has clinical implications and needs further investigation.

Tales of a department: how the COVID-19 pandemic transformed Detroit's Henry Ford Hospital, Department of Neurology-part I: the surge.

The COVID-19 pandemic has reshaped the way healthcare systems operate around the world. The major hurdles faced have been availability of personal protective equipment, intensive care unit beds, ventilators, treatments and medical personnel. Detroit, Michigan has been an epidemic 'hotspot' in the USA with Wayne County among the hardest hit counties in the nation. The Department of Neurology at Henry Ford Hospital, in the heart of Detroit, has responded effectively to the pandemic by altering many aspects of its operations. The rapid engagement of the department and enhanced utilisation of teleneurology were two of the pivotal elements in the successful response to the pandemic. In this review, we describe the transformation our department has undergone, as it relates to its infrastructure redesigning, coverage restructuring, redeployment strategies, medical education adaptations and novel research initiatives.

Resting state fMRI connectivity analysis as a tool for detection of abnormalities in five different cognitive networks of the brain in Multiple Sclerosis patients.

OBJECTIVES: Cognitive dysfunction is present in at least half of patients with Multiple Sclerosis. The purpose of this study was to examine functional connectivity abnormalities in patients with multiple sclerosis (MS) using resting state fMRI (rsfMRI). METHODS: Conventional MRI, rsfMRI and diffusion tensor imaging (DTI) data was acquired from 10 patients with relapsing-remitting multiple sclerosis (RRMS) and 20 healthy controls. Cross-correlation of the resting state average signal among the voxels in each brain region of the five cognitive networks: default mode network (DMN), attention, verbal memory, memory, and visuospatial working memory network, was calculated. Voxelwise analyses were used to investigate fractional anisotropy (FA) of white matter tracts. The normalized gray matter (GM), white matter and thalamus volumes were calculated. RESULTS: Compared to controls, significant deficit in MS patients at each of five networks, attention (p=0.026), DMN (p=0.004), verbal memory (p<0.001), memory (p=0.001), visuospatial working memory (p=0.003) was found. Significant reduction (p=0.034) in the normalized GM volume and asymmetry in thalamus volume (p=0.041) was detected in MS patients compared to controls. CONCLUSION: Wide spread of functional abnormalities are present within different cognitive networks in patients with RRMS, suggesting that DMN may not be sufficient for measurement of MS cognitive impairment. Larger and longitudinal studies should ascertain whether rsfMRI of cognitive networks and changes in GM and thalamus volume can be used as tools for assessment of cognition in clinical trials in MS.

Untargeted Plasma Metabolomics Identifies Endogenous Metabolite with Drug-like Properties in Chronic Animal Model of Multiple Sclerosis.

We performed untargeted metabolomics in plasma of B6 mice with experimental autoimmune encephalitis (EAE) at the chronic phase of the disease in search of an altered metabolic pathway(s). Of 324 metabolites measured, 100 metabolites that mapped to various pathways (mainly lipids) linked to mitochondrial function, inflammation, and membrane stability were observed to be significantly altered between EAE and control (p < 0.05, false discovery rate <0.10). Bioinformatics analysis revealed six metabolic pathways being impacted and altered in EAE, including α-linolenic acid and linoleic acid metabolism (PUFA). The metabolites of PUFAs, including ω-3 and ω-6 fatty acids, are commonly decreased in mouse models of multiple sclerosis (MS) and in patients with MS. Daily oral administration of resolvin D1, a downstream metabolite of ω-3, decreased disease progression by suppressing autoreactive T cells and inducing an M2 phenotype of monocytes/macrophages and resident brain microglial cells. This study provides a proof of principle for the application of metabolomics to identify an endogenous metabolite(s) possessing drug-like properties, which is assessed for therapy in preclinical mouse models of MS.

Longitudinal Follow-up of a Cohort of Patients with Incidental Abnormal Magnetic Resonance Imaging Findings at Presentation and Their Risk of Developing Multiple Sclerosis.

BACKGROUND: Magnetic resonance imaging (MRI) is widely used in clinical practice, and "abnormal brain MRI" findings often prompt assessment for multiple sclerosis (MS), even when there are no symptoms suggestive of the disease. Despite several studies involving individuals with "radiologically isolated syndrome" (RIS), little is known about what factors might predict future development of MS. The objective of this study was to longitudinally evaluate clinical and MRI characteristics of people who presented to an MS clinic because of incidental abnormal MRI findings but did not have typical symptoms of MS, in order to assess risk factors for developing MS. METHODS: Thirty consecutive patients presenting to an MS clinic for evaluation of abnormal MRI findings were enrolled in the study. Clinical and paraclinical data, including MRI results, were reviewed. Magnetic resonance imaging findings of T2 hyperintensities measuring more than 3 mm in diameter and fulfilling at least three out of four Barkhof criteria, with or without gadolinium-enhancing lesions, were considered to be suggestive of MS. RESULTS: The median follow-up time was 5.5 years. No participants without MRI findings suggestive of MS were diagnosed with MS (P = .005). Fifteen participants had MRI findings suggestive of MS. Seven of the 15 (47%) were diagnosed with MS on follow-up. Cerebrospinal fluid (CSF) testing results were available for 15 participants. Abnormal results were found in six participants, of whom five (83%) also had MRI findings suggestive of MS. Only two of the nine (22%) participants with normal CSF results (P = .04) had MRI findings suggestive of MS. CONCLUSIONS: In our cohort, none of the participants without MRI findings suggestive of MS developed MS. The participants with MRI findings suggestive of MS were more likely to develop symptoms and MRI changes typical of MS on follow-up.

Bilateral hearing loss heralding sporadic Creutzfeldt-Jakob disease: a case report and literature review.

OBJECTIVE: To report a case of sporadic Creutzfeldt-Jakob disease (CJD) with bilateral hearing loss at onset and literature review of the scarce cases of CJD with similar audiologic manifestations at presentation. CASE REPORT: A 67-yr-old man presented to the hospital for evaluation of rapid progression of behavioral decline, unsteady gait, and bilateral hearing loss. Three months before admission, he abruptly developed bilateral hypoacusis without associated tinnitus or vertigo. Shortly after, his family noted an ataxic gait and behavioral changes, for example, paranoid delusions. Initial workup, including a complete autoimmune panel and heavy metals, infectious, toxicology, and paraneoplastic panel (e.g., anti-Hu, anti-VGKC), was conducted. Electroencephalography revealed diffuse generalized slowing without periodic complexes. The presence of distortion product otoacoustic emissions bilaterally was consistent with normal cochlear function, suggesting a retrocochlear origin for symptoms of hearing loss. In the meantime, the patient developed startle myoclonus. The brain magnetic resonance imaging demonstrated asymmetric cortical ribbon along with T2 FLAIR signal hyperintensities of bilateral basal ganglia. Later on, the protein 14-3-3 in the cerebrospinal fluid came back positive, which supported the diagnosis of CJD. Only three cases of CJD with deafness at onset have been published: one sporadic, associated with symptoms suggestive of polyneuropathy; and the other two familial, with the E200K mutation. One presented with symptoms of polyneuropathy and the other with typical features. CONCLUSION: This case illustrates the phenotypic variability of presentation of CJD in a patient with hearing loss as the initial manifestation. In patients with subacute bilateral hypoacusis and signs of dementia, the differential diagnosis of CJD must be taken into consideration.

Perfusion and Diffusion Abnormalities of Multiple Sclerosis Lesions and Relevance of Classified Lesions to Disease Status.

OBJECTIVE: Hemodynamic abnormality and disruption of white matter (WM) integrity are significant components in the pathophysiology of multiple sclerosis (MS) lesions. However, the roles of stratified lesions with distinct degrees of hemodynamic and structural injury in disease states remain to be explored. We tested the hypothesis that hemodynamic and structural impairment, as assessed by cerebral blood volume (CBV) and fractional anisotropy (FA), respectively, characterizes the extent of tissue injury, and the load of lesion with substantial tissue destruction would reflect the disease status and therefore, would be related to clinical disability. METHODS: Seven relapsing-remitting MS patients and seven healthy controls underwent perfusion, diffusion and conventional MRI scans. Based on T2-FLAIR and T1-weighted image, WM plaques were classified. After image coregistration, values of CBV and FA were estimated in three distinct lesion types (active, T1-hypointense and T1-isointense lesion) and compared with those obtained in WM from controls. A total of 1135 lesions were evaluated. Brain volumetric measurement and correlative analysis between brain atrophy, lesion volume and clinical disability were also performed. RESULTS: Compared with normal WM, significantly reduced CBV and FA were present in the T1-hypointense lesion, while insignificant changes in both parameters were exhibited in the T1-isointense lesion. However, increased CBV but significantly decreased FA was detected in the active lesion. A close spatial relationship between active and T1-hypointense lesion was observed. Lesion load represented by T1-hypointense plus active lesion volume significantly correlated with brain atrophy, which, in turn, significantly correlated with the severity of clinical disability. CONCLUSION: A distinct combination of CBV and FA characterizes the status of a specific lesion type. A severe structural impairment does not solely occur in the T1-hypointense lesion, but is also associated with the active lesion. The burden of the lesion with extensive structural damage provides an image index, indicative of disease status.

Sexual dimorphism in the white matter of rodents.

Sexual dimorphism of astrocytes and neurons is well documented in many brain and spinal cord structures. Sexual dimorphism of oligodendrocytes (Olgs) and myelin has received less attention. We recently showed that density of Olgs in corpus callosum, fornix, and spinal cord of wild-type male rodents is more densely packed than in females; myelin proteins and myelin gene expression are likewise greater in males than in female rodents. However, glial cell proliferation and cell death were two times greater in female corpus callosum. Endogenous sex hormones, specifically lack of androgens, produce an Olg female phenotype in castrated male mouse. In vitro studies using Olgs culture also showed differences between males and females Olg survival and signaling pathways in response to sexual hormones. Sexual dimorphism of white matter tracts and glia in rodents indicates the necessity for controlling gender in the experimental studies of neurodegenerative disorders. Most importantly, our studies suggest that hormones may contribute to sexual dimorphism observed in certain human diseases including multiple sclerosis.

Measuring adherence and persistence to disease-modifying agents among patients with relapsing remitting multiple sclerosis.

OBJECTIVES: To measure disease-modifying agent adherence and persistence among patients with multiple sclerosis (MS). DESIGN: Retrospective cohort study. SETTING: Multispecialty, salaried group practice in southeast Michigan, between June 1, 2004, and June 30, 2006. PATIENTS: 224 insured adult patients with relapsing remitting MS with an outpatient visit. MAIN OUTCOME MEASURES: Medical record-documented receipt of medication recommendation and prescription. Pharmacy claims data-derived measures of dispensing and among patients with two or more dispensings, medication possession ratios (MPRs), and proportion of gap days were estimated. Among those initiating agent use, persistence was estimated. RESULTS: Mean cohort age was 47.6 years, while 77% of participants were women and 39% were black. Of patients, 81.8% had a recommendation for a disease-modifying agent, 75.0% had a prescription, and 66.5% had two or more dispensings. Among those with two or more dispensings, mean MPR between the first and last dispensing date was 83.8% (95% CI 80.8-86.8), while mean MPR for the entire 24-month period was 68.0% (64.4-71.7). MPR for the 24-month period decreased with increasing drug copayments and was lower among black patients, while MPR between the first and last dispensing date increased with increasing age. Among those initiating therapy, 43% were nonpersistent with medications within 14 months. CONCLUSION: Medication adherence and persistence among patients with relapsing remitting MS is far from monolithic. Measuring medication adherence and persistence among defined populations is useful for understanding the relationship between medication use and outcomes in practice and for targeting patients and programs to improve medication adherence.

Prolonged survival after multifocal brain radiation necrosis associated with whole brain radiation for brain metastases: case report.

Radiation necrosis of the brain is a well documented adverse effect of radiation therapy. The authors report an unusual case of relapsing multifocal radiation necrosis following whole brain radiation therapy (WBRT) for brain metastases from a systemic germ cell tumor. Anticoagulation with warfarin may have had therapeutic benefit. The patient is alive without a neurological deficit 10 years after the diagnosis of radiation necrosis.