Publications by authors named "Ari J Green"

78 Publications

Distinctive waves of innate immune response in the retina in experimental autoimmune encephalomyelitis.

JCI Insight 2021 Jun 8;6(11). Epub 2021 Jun 8.

Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco, San Francisco, California, USA.

Neurodegeneration mediates neurological disability in inflammatory demyelinating diseases of the CNS. The role of innate immune cells in mediating this damage has remained controversial with evidence for destructive and protective effects. This has complicated efforts to develop treatment. The time sequence and dynamic evolution of the opposing functions are especially unclear. Given limits of in vivo monitoring in human diseases such as multiple sclerosis (MS), animal models are warranted to investigate the association and timing of innate immune activation with neurodegeneration. Using noninvasive in vivo retinal imaging of experimental autoimmune encephalitis (EAE) in CX3CR1GFP/+-knock-in mice followed by transcriptional profiling, we are able to show 2 distinct waves separated by a marked reduction in the number of innate immune cells and change in cell morphology. The first wave is characterized by an inflammatory phagocytic phenotype preceding the onset of EAE, whereas the second wave is characterized by a regulatory, antiinflammatory phenotype during the chronic stage. Additionally, the magnitude of the first wave is associated with neuronal loss. Two transcripts identified - growth arrest-specific protein 6 (GAS6) and suppressor of cytokine signaling 3 (SOCS3) - might be promising targets for enhancing protective effects of microglia in the chronic phase after initial injury.
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http://dx.doi.org/10.1172/jci.insight.149228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262300PMC
June 2021

Retinal imaging demonstrates reduced capillary density in clinically unimpaired ε4 gene carriers.

Alzheimers Dement (Amst) 2021 11;13(1):e12181. Epub 2021 May 11.

Department of Ophthalmology USC Roski Eye Institute Keck School of Medicine of the University of Southern California Los Angeles California USA.

Introduction: Apolipoprotein E () ε4, the strongest non-Mendelian genetic risk factor for Alzheimer's disease (AD), has been shown to affect brain capillaries in mice, with potential implications for AD-related neurodegenerative disease. However, human brain capillaries cannot be directly visualized in vivo. We therefore used retinal imaging to test ε4 effects on human central nervous system capillaries.

Methods: We collected retinal optical coherence tomography angiography, cognitive testing, and brain imaging in research participants and built statistical models to test genotype-phenotype associations.

Results: Our analyses demonstrate lower retinal capillary densities in early disease, in cognitively normal ε4 gene carriers. Furthermore, through regression modeling with a measure of brain perfusion (arterial spin labeling), we provide support for the relevance of these findings to cerebral vasculature.

Discussion: These results suggest that ε4 affects capillary health in humans and that retinal capillary measures could serve as surrogates for brain capillaries, providing an opportunity to study microangiopathic contributions to neurodegenerative disorders directly in humans.
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http://dx.doi.org/10.1002/dad2.12181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111703PMC
May 2021

APOSTEL 2.0 Recommendations for Reporting Quantitative Optical Coherence Tomography Studies.

Neurology 2021 07 28;97(2):68-79. Epub 2021 Apr 28.

From the Department of Neurology, Medical Faculty (A.A., O.A., H.-P.H., O.M., S.M., M.R., P.A.), Heinrich-Heine University Düsseldorf, Germany; Department of Neurology (A.C.-H., A.J.G.), University of California San Francisco; Departments of Neurology, Population Health, and Ophthalmology (L.J.B., R.K.), NYU Grossman School of Medicine, New York, NY; Mulier Institute (L.B.), Centre for Research on Sports in Society, Utrecht, the Netherlands; Scientific Institute San Raffaele (P.B.), Milan, Italy; Centre for Public Health (A.A.B.), Queen's University Belfast, Northern Ireland, UK; Division of Neuroimmunology (P.A.C., S. Saidha), Johns Hopkins University, Baltimore, MD; Departments of Clinical Neurosciences and Surgery (F.C.), University of Calgary, Alberta, Canada; Institut d'Investigacións Biomediques August Pi iSunyer (IDIBAPS) and Hospital Clinic (B.S.-D., E.H.M.-L., P.V.), University of Barcelona, Spain; Bascom Palmer Eye Institute (D.C.D.), University of Miami Miller School of Medicine, FL; Department of Ophthalmology (N.F.), University Medical Center, Göttingen; Department of Ophthalmology (R.P.F., F.G.H.), University of Bonn, Germany; Department of Neurology (J.L.F., G.P.-J.), Rigshospitalet Glostrup and University of Copenhagen, Denmark; Laboratory of Neuroimmunology (E.F., T.F.), Stanford University School of Medicine, CA; Institute of Ophthalmology (D.G.-H.), National Institute for Health Research (NIHR) Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology (D.G.-H.), London, UK; Biocruces Bizkaia Health Research Institute (I.G.), Barakaldo, Spain; Department of Neurosciences (J.S.G.), University of California, San Diego; Brain and Mind Centre (H.-P.H.), University of Sydney, Australia; Department of Neurology (H.-P.H.), Medical University of Vienna, Austria; Institute of Clinical Neuroimmunology (J.H.), LMU Hospital, Ludwig-Maximilians Universität München, Germany; UConn Health Comprehensive MS Center, Division of Multiple Sclerosis and Neuroimmunology, Department of Neurology (J.I.), University of Connecticut School of Medicine, Farmington; Faculty of Medicine and Health Sciences (A.K.), Macquarie University, Sydney, Australia; Department of Neurology (B.K., T.K.), Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Germany; Department of Medicine and Radiology (S.K.), University of Melbourne, Australia; Department of Neurology with Institute of Translational Neurology (J.K.), University of Münster; Eye Center, Medical Center, Faculty of Medicine (W.A.L.), University of Freiburg, Germany; Experimental Neurophysiology Unit (L.L.), Institute of Experimental Neurology (INSPE), IRCCS San Raffaele, University Vita-Salute San Raffaele, Milan, Italy; Lille Neurosciences & Cognition (O.O.), Univ Lille, Inserm, CHU Lille, U1172-LilNCog (JPARC), France; Experimental and Clinical Research Center (F.P., H.G.Z., A.U.B.), Max Delbrück Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Germany; Moorfields Eye Hospital (A.P.), The National Hospital for Neurology and Neurosurgery, Queen Square, UCL Institute of Neurology, London, UK; Neuro-ophthalmology Expert Center (A.P.), Amsterdam UMC, the Netherlands; Department of Neurology, First Faculty of Medicine (J.L.P.), Charles University and General University Hospital in Prague, Czech Republic; Department of Ophthalmology (G.R.), Ramon y Cajal Hospital, Medicine University of Alcalá, Madrid, Spain; Department of Neurology (M.R.), Center for Neurology and Neuropsychiatry, LVR-Klinikum, Heinrich-Heine-University Düsseldorf, Germany; Department of Neurology (S. Schippling), University Hospital Zurich, Switzerland; Departments of Ophthalmology, Neuroscience, and Physiology (J.S.S.), NYU Langone Health, NYU Grossman School of Medicine, New York; Departments of Biomedical Engineering, Electrical and Computer Engineering (J.S.S.), NYU Tandon School of Engineering, Brooklyn, NY; Thomas Jefferson University Medical College (R.C.S.), Philadelphia, PA; Queen Square MS Centre, Department of Neuroinflammation (A.T.), UCL Institute of Neurology, University College London, UK; Departments of Ophthalmology and Clinical Research (S.W.), Bern University Hospital, University of Bern, Switzerland; Division of Neurology, Department of Pediatrics (E.A.Y.), Hospital for Sick Children, Division of Neurosciences and Mental Health SickKids Research Institute, University of Toronto, Canada; Department of Clinical Neurosciences (P.Y.-W.-M.), University of Cambridge; Moorfields Eye Hospital (P.Y.-W.-M.), London, UK; University of California (A.U.B.), Irvine; and IMSVISUAL (A.A., A.C.-H., O.A., L.J.B., L.B., P.A.C., F.C., J.L.F., E.F., T.F., I.G., J.S.G., A.J.G., H.-P.H., J.H., J.I., R.K., A.K., B.K., T.K., J.K., L.L., E.H.M.-L., S.M., O.O., F.P., A.P., G.P.-J., J.L.P., M.R., S. Saidha, S. Schippling, R.C.S., P.V., E.A.Y., H.G.Z., A.U.B., P.A.), International Multiple Sclerosis Visual System Consortium, Middleton, WI.

Objective: To update the consensus recommendations for reporting of quantitative optical coherence tomography (OCT) study results, thus revising the previously published Advised Protocol for OCT Study Terminology and Elements (APOSTEL) recommendations.

Methods: To identify studies reporting quantitative OCT results, we performed a PubMed search for the terms "quantitative" and "optical coherence tomography" from 2015 to 2017. Corresponding authors of the identified publications were invited to provide feedback on the initial APOSTEL recommendations via online surveys following the principle of a modified Delphi method. The results were evaluated and discussed by a panel of experts and changes to the initial recommendations were proposed. A final survey was recirculated among the corresponding authors to obtain a majority vote on the proposed changes.

Results: A total of 116 authors participated in the surveys, resulting in 15 suggestions, of which 12 were finally accepted and incorporated into an updated 9-point checklist. We harmonized the nomenclature of the outer retinal layers, added the exact area of measurement to the description of volume scans, and suggested reporting device-specific features. We advised to address potential bias in manual segmentation or manual correction of segmentation errors. References to specific reporting guidelines and room light conditions were removed. The participants' consensus with the recommendations increased from 80% for the previous APOSTEL version to greater than 90%.

Conclusions: The modified Delphi method resulted in an expert-led guideline (evidence Class III; Grading of Recommendations, Assessment, Development and Evaluations [GRADE] criteria) concerning study protocol, acquisition device, acquisition settings, scanning protocol, funduscopic imaging, postacquisition data selection, postacquisition analysis, nomenclature and abbreviations, and statistical approach. It will be essential to update these recommendations to new research and practices regularly.
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http://dx.doi.org/10.1212/WNL.0000000000012125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279566PMC
July 2021

Disability Outcomes in the N-MOmentum Trial of Inebilizumab in Neuromyelitis Optica Spectrum Disorder.

Neurol Neuroimmunol Neuroinflamm 2021 05 26;8(3). Epub 2021 Mar 26.

From the Service de Neurologie Sclérose en Plaques (R.M.), Pathologies de La Myéline et Neuro-inflammation, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, France; University of Colorado School of Medicine (J.L.B.), Anschutz Medical Campus, Aurora; Research Institute and Hospital of National Cancer Center (H.J.K.), Goyang, South Korea; Mayo Clinic (B.G.W., S.J.P.), Rochester, MN; Mayo Clinic (D.W.), Scottsdale, AZ; Department of Multiple Sclerosis Therapeutics (K.F.), Fukushima Medical University and Multiple Sclerosis and Neuromyelitis Optica Center, Southern Tohoku Research Institute for Neuroscience, Koriyama, Japan; Experimental and Clinical Research Center (F.P.), Max Delbrück Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, Germany; University of Alabama at Birmingham (G.R.C.); UCSF Weill Institute for Neurosciences (A.J.G.), Department of Neurology and Department of Ophthalmology, University of California San Francisco; Medical Faculty (O.A., H.-P.H.), Heinrich Heine University, Düsseldorf, Germany; Icahn School of Medicine at Mount Sinai (F.D.L.), New York; Oxford PharmaGenesis Ltd (I.M.W.), UK; Viela Bio (J.D., D.S., D.C., W.R., M.S., J.N.R., E.K.), Gaithersburg, MD; and UCSF Weill Institute for Neurosciences (B.A.C.C.), University of California San Francisco.

Objective: To assess treatment effects on Expanded Disability Status Scale (EDSS) score worsening and modified Rankin Scale (mRS) scores in the N-MOmentum trial of inebilizumab, a humanized anti-CD19 monoclonal antibody, in participants with neuromyelitis optica spectrum disorder (NMOSD).

Methods: Adults (N = 230) with aquaporin-4 immunoglobulin G-seropositive NMOSD or -seronegative neuromyelitis optica and an EDSS score ≤8 were randomized (3:1) to receive inebilizumab 300 mg or placebo on days 1 and 15. The randomized controlled period (RCP) was 28 weeks or until adjudicated attack, with an option to enter the inebilizumab open-label period. Three-month EDSS-confirmed disability progression (CDP) was assessed using a Cox proportional hazard model. The effect of baseline subgroups on disability was assessed by interaction tests. mRS scores from the RCP were analyzed by the Wilcoxon-Mann-Whitney odds approach.

Results: Compared with placebo, inebilizumab reduced the risk of 3-month CDP (hazard ratio [HR]: 0.375; 95% CI: 0.148-0.952; = 0.0390). Baseline disability, prestudy attack frequency, and disease duration did not affect the treatment effect observed with inebilizumab (HRs: 0.213-0.503; interaction tests: all > 0.05, indicating no effect of baseline covariates on outcome). Mean EDSS scores improved with longer-term treatment. Inebilizumab-treated participants were more likely to have a favorable mRS outcome at the end of the RCP (OR: 1.663; 95% CI: 1.195-2.385; = 0.0023).

Conclusions: Disability outcomes were more favorable with inebilizumab vs placebo in participants with NMOSD.

Classification Of Evidence: This study provides Class II evidence that for patients with NMOSD, inebilizumab reduces the risk of worsening disability. N-MOmentum is registered at ClinicalTrials.gov: NCT02200770.
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http://dx.doi.org/10.1212/NXI.0000000000000978DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054974PMC
May 2021

Sensitivity analysis of the primary endpoint from the N-MOmentum study of inebilizumab in NMOSD.

Mult Scler 2021 Feb 4:1352458521988926. Epub 2021 Feb 4.

Viela Bio, Gaithersburg, MD, USA.

Background: In the N-MOmentum trial, the risk of an adjudicated neuromyelitis optica spectrum disorder (NMOSD) attack was significantly reduced with inebilizumab compared with placebo.

Objective: To demonstrate the robustness of this finding, using pre-specified sensitivity and subgroup analyses.

Methods: N-MOmentum is a prospective, randomized, placebo-controlled, double-masked trial of inebilizumab, an anti-CD19 monoclonal B-cell-depleting antibody, in patients with NMOSD. Pre-planned and analyses were performed to evaluate the primary endpoint across a range of attack definitions and demographic groups, as well as key secondary endpoints.

Results: In the N-MOmentum trial (ClinicalTrials.gov: NCT02200770), 174 participants received inebilizumab and 56 received placebo. Attack risk for inebilizumab versus placebo was consistently and significantly reduced, regardless of attack definition, type of attack, baseline disability, ethnicity, treatment history, or disease course (all with hazard ratios < 0.4 favoring inebilizumab, < 0.05). Analyses of secondary endpoints showed similar trends.

Conclusion: N-MOmentum demonstrated that inebilizumab provides a robust reduction in the risk of NMOSD attacks regardless of attack evaluation method, attack type, patient demographics, or previous therapy.The N-MOmentum study is registered at ClinicalTrials.gov: NCT2200770.
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http://dx.doi.org/10.1177/1352458521988926DOI Listing
February 2021

Underutilization of physical therapy for symptomatic women with MS during and following pregnancy.

Mult Scler Relat Disord 2021 Feb 19;48:102703. Epub 2020 Dec 19.

Weill Institute for Neurosciences, MS and Neuroinflammation Clinic, University of California San Francisco, Department of Neurology. Electronic address:

Background: Many patients with MS continue to have symptoms of their disease even when inflammatory activity is reduced by DMTs. Although disease activity tends to be reduced during pregnancy - especially in the third trimester - women with MS can experience ongoing symptoms during pregnancy, or new ones in the immediate postpartum period, that degrade quality of life. While many MS-related and postpartum symptoms can be improved with physical therapy (PT), there are currently no guidelines on pregnancy-related rehabilitation in MS. In this analysis, we evaluated the prevalence of PT-amenable symptoms and patterns of PT referrals in a cohort of UCSF MS Clinic patients who became pregnant.

Methods: We extracted electronic medical records (EMR) data for the year before conception, during pregnancy, and year postpartum for women with MS cared for at UCSF between 09-2005 and 08-2019. This included clinical visits, MS therapies and symptoms (as defined by the National MS Society). PT and pelvic floor PT orders and notes were also extracted.

Results: We included 142 live birth pregnancies from 118 women. During the course of their pregnancy and within the year postpartum, 107 women (75.4%) reported at least one PT-amenable symptom. A total of 30 (28.0%) referrals were made to PT, with attendance confirmed for 10 (33.3% of referrals). Symptoms most commonly triggering a referral for PT evaluation were numbness and urinary incontinence. Falls were reported after 10 of the pregnancies; 4 resulted in a referral to PT. Forty-one women reported urinary incontinence: 11 (26.8%) were referred to PT, and 2 to pelvic floor PT. Nineteen women experienced a documented relapse during pregnancy and/or postpartum: 11 received a PT referral, and 4 attended PT.

Conclusions: While women with MS recorded at least 1 PT-amenable symptom during or following 75.4% of their pregnancies, only 28% of these were referred to PT - and only a third attended PT. Of significance was the 4.9% referral rate for pelvic floor PT in postpartum women with a record of urinary incontinence. Pelvic floor PT is a mainstay of general postpartum care in many European countries. These data illustrate critical gaps in rehabilitation referral, access and use at the intersection of neurological conditions and pregnancy in a large US-based MS clinic. They lend support for quality improvement efforts to improve care pathways and for telerehabilitation innovations to reduce barriers to access and improve synergistic care between PT, MD and urologic care.
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http://dx.doi.org/10.1016/j.msard.2020.102703DOI Listing
February 2021

Interocular Difference in Retinal Nerve Fiber Layer Thickness Predicts Optic Neuritis in Pediatric-Onset Multiple Sclerosis.

J Neuroophthalmol 2020 Oct 22. Epub 2020 Oct 22.

Division of Neurology (ATW, JRS, AML, GWL), Children's Hospital of Philadelphia and Departments of Neurology and Pediatrics (ATW), Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania; Departments of Neurology (LB) and Ophthalmology (GH), Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts; Division of Neuroimmunology and Glial Biology (AJG, EW), Department of Neurology, Weill Institute of Neurosciences, University of California San Francisco, San Francisco, California; Department of Neurology and Neurotherapeutics (DC, BG), University of Texas Southwestern Medical Center, Dallas, Texas; Department of Neurology, University of California San Diego, San Diego, California; and Department of Ophthalmology (AJG), University of California San Francisco, San Francisco, California.

Background: Optical coherence tomography (OCT) is capable of quantifying retinal damage. Defining the extent of anterior visual pathway injury is important in multiple sclerosis (MS) as a way to document evidence of prior disease, including subclinical injury, and setting a baseline for patients early in the course of disease. Retinal nerve fiber layer (RNFL) thickness is typically classified as low if values fall outside of a predefined range for a healthy population. In adults, an interocular difference (IOD) in RNFL thickness greater than 5 μm identified a history of unilateral optic neuritis (ON). Through our PERCEPTION (PEdiatric Research Collaboration ExPloring Tests in Ocular Neuroimmunology) study, we explored whether RNFL IOD informs on remote ON in a multicenter pediatric-onset MS (POMS) cohort.

Methods: POMS (defined using consensus criteria and first attack <18 years) patients were recruited from 4 academic centers. A clinical history of ON (>6 months prior to an OCT scan) was confirmed by medical record review. RNFL thickness was measured on Spectralis machines (Heidelberg, Germany). Using a cohort of healthy controls from our centers tested on the same machines, RNFL thickness <86 μm (<2 SDs below the mean) was defined as abnormal. Based on previously published findings in adults, an RNFL IOD >5 μm was defined as abnormal. The proportions of POMS participants with RNFL thinning (<86 μm) and abnormal IOD (>5 μm) were calculated. Logistic regression was used to determine whether IOD was associated with remote ON.

Results: A total of 157 participants with POMS (mean age 15.2 years, SD 3.2; 67 [43%] with remote ON) were enrolled. RNFL thinning occurred in 45 of 90 (50%) ON eyes and 24 of 224 (11%) non-ON eyes. An IOD >5 μm was associated with a history of remote ON (P < 0.001). An IOD >5 μm occurred in 62 participants, 40 (65%) with remote ON. Among 33 participants with remote ON but normal RNFL values (≥86 μm in both eyes), 14 (42%) were confirmed to have ON by IOD criteria (>5 μm).

Conclusions: In POMS, the diagnostic yield of OCT in confirming remote ON is enhanced by considering RNFL IOD, especially for those patients with RNFL thickness for each eye in the normal range. An IOD >5 μm in patients with previous visual symptoms suggests a history of remote ON.
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http://dx.doi.org/10.1097/WNO.0000000000001070DOI Listing
October 2020

Retinal INL Thickness in Multiple Sclerosis: A Mere Marker of Neurodegeneration?

Ann Neurol 2021 01 11;89(1):192-193. Epub 2020 Nov 11.

Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA.

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http://dx.doi.org/10.1002/ana.25933DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990472PMC
January 2021

A pathogenic and clonally expanded B cell transcriptome in active multiple sclerosis.

Proc Natl Acad Sci U S A 2020 09 28;117(37):22932-22943. Epub 2020 Aug 28.

Weill Institute for Neurosciences, University of California, San Francisco, CA 94158;

Central nervous system B cells have several potential roles in multiple sclerosis (MS): secretors of proinflammatory cytokines and chemokines, presenters of autoantigens to T cells, producers of pathogenic antibodies, and reservoirs for viruses that trigger demyelination. To interrogate these roles, single-cell RNA sequencing (scRNA-Seq) was performed on paired cerebrospinal fluid (CSF) and blood from subjects with relapsing-remitting MS (RRMS; = 12), other neurologic diseases (ONDs; = 1), and healthy controls (HCs; = 3). Single-cell immunoglobulin sequencing (scIg-Seq) was performed on a subset of these subjects and additional RRMS ( = 4), clinically isolated syndrome ( = 2), and OND ( = 2) subjects. Further, paired CSF and blood B cell subsets (RRMS; = 7) were isolated using fluorescence activated cell sorting for bulk RNA sequencing (RNA-Seq). Independent analyses across technologies demonstrated that nuclear factor kappa B (NF-κB) and cholesterol biosynthesis pathways were activated, and specific cytokine and chemokine receptors were up-regulated in CSF memory B cells. Further, SMAD/TGF-β1 signaling was down-regulated in CSF plasmablasts/plasma cells. Clonally expanded, somatically hypermutated IgM+ and IgG1+ CSF B cells were associated with inflammation, blood-brain barrier breakdown, and intrathecal Ig synthesis. While we identified memory B cells and plasmablast/plasma cells with highly similar Ig heavy-chain sequences across MS subjects, similarities were also identified with ONDs and HCs. No viral transcripts, including from Epstein-Barr virus, were detected. Our findings support the hypothesis that in MS, CSF B cells are driven to an inflammatory and clonally expanded memory and plasmablast/plasma cell phenotype.
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http://dx.doi.org/10.1073/pnas.2008523117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502747PMC
September 2020

Imaging correlates of visual function in multiple sclerosis.

PLoS One 2020 3;15(8):e0235615. Epub 2020 Aug 3.

Division of Neuroimmunology and Glial Biology UCSF, Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, San Francisco, CA, United States of America.

No single neuroimaging technique or sequence is capable of reflecting the functional deficits manifest in MS. Given the interest in imaging biomarkers for short- to medium-term studies, we aimed to assess which imaging metrics might best represent functional impairment for monitoring in clinical trials. Given the complexity of functional impairment in MS, however, it is useful to isolate a particular functionally relevant pathway to understand the relationship between imaging and neurological function. We therefore analyzed existing data, combining multiparametric MRI and OCT to describe MS associated visual impairment. We assessed baseline data from fifty MS patients enrolled in ReBUILD, a prospective trial assessing the effect of a remyelinating drug (clemastine). Subjects underwent 3T MRI imaging, including Neurite Orientation Dispersion and Density Imaging (NODDI), myelin content quantification, and retinal imaging, using OCT. Visual function was assessed, using low-contrast letter acuity. MRI and OCT data were studied to model visual function in MS, using a partial, least-squares, regression analysis. Measures of neurodegeneration along the entire visual pathway, described most of the observed variance in visual disability, measured by low contrast letter acuity. In those patients with an identified history of ON, however, putative myelin measures also showed correlation with visual performance. In the absence of clinically identifiable inflammatory episodes, residual disability correlates with neurodegeneration, whereas after an identifiable exacerbation, putative measures of myelin content are additionally informative.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0235615PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7398529PMC
September 2020

Importance of Not MSing Cerebral White Matter Disease in Patients with Inflammatory Bowel Disease.

Dig Dis Sci 2020 09;65(9):2527-2532

Division of Gastroenterology, Department of Medicine, University of California, 513 Parnassus Ave, S-357, San Francisco, CA, 94143-0451, USA.

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http://dx.doi.org/10.1007/s10620-020-06449-2DOI Listing
September 2020

Protective effects of 4-aminopyridine in experimental optic neuritis and multiple sclerosis.

Brain 2020 04;143(4):1127-1142

NeuroCure Clinical Research Center and Experimental and Clinical Research Center, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health and Max Delbrueck Center for Molecular Medicine, Berlin, Germany.

Chronic disability in multiple sclerosis is linked to neuroaxonal degeneration. 4-aminopyridine (4-AP) is used and licensed as a symptomatic treatment to ameliorate ambulatory disability in multiple sclerosis. The presumed mode of action is via blockade of axonal voltage gated potassium channels, thereby enhancing conduction in demyelinated axons. In this study, we provide evidence that in addition to those symptomatic effects, 4-AP can prevent neuroaxonal loss in the CNS. Using in vivo optical coherence tomography imaging, visual function testing and histologic assessment, we observed a reduction in retinal neurodegeneration with 4-AP in models of experimental optic neuritis and optic nerve crush. These effects were not related to an anti-inflammatory mode of action or a direct impact on retinal ganglion cells. Rather, histology and in vitro experiments indicated 4-AP stabilization of myelin and oligodendrocyte precursor cells associated with increased nuclear translocation of the nuclear factor of activated T cells. In experimental optic neuritis, 4-AP potentiated the effects of immunomodulatory treatment with fingolimod. As extended release 4-AP is already licensed for symptomatic multiple sclerosis treatment, we performed a retrospective, multicentre optical coherence tomography study to longitudinally compare retinal neurodegeneration between 52 patients on continuous 4-AP therapy and 51 matched controls. In line with the experimental data, during concurrent 4-AP therapy, degeneration of the macular retinal nerve fibre layer was reduced over 2 years. These results indicate disease-modifying effects of 4-AP beyond symptomatic therapy and provide support for the design of a prospective clinical study using visual function and retinal structure as outcome parameters.
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http://dx.doi.org/10.1093/brain/awaa062DOI Listing
April 2020

Transcriptional profiling and therapeutic targeting of oxidative stress in neuroinflammation.

Nat Immunol 2020 05 13;21(5):513-524. Epub 2020 Apr 13.

Gladstone Institutes, San Francisco, CA, USA.

Oxidative stress is a central part of innate immune-induced neurodegeneration. However, the transcriptomic landscape of central nervous system (CNS) innate immune cells contributing to oxidative stress is unknown, and therapies to target their neurotoxic functions are not widely available. Here, we provide the oxidative stress innate immune cell atlas in neuroinflammatory disease and report the discovery of new druggable pathways. Transcriptional profiling of oxidative stress-producing CNS innate immune cells identified a core oxidative stress gene signature coupled to coagulation and glutathione-pathway genes shared between a microglia cluster and infiltrating macrophages. Tox-seq followed by a microglia high-throughput screen and oxidative stress gene network analysis identified the glutathione-regulating compound acivicin, with potent therapeutic effects that decrease oxidative stress and axonal damage in chronic and relapsing multiple sclerosis models. Thus, oxidative stress transcriptomics identified neurotoxic CNS innate immune populations and may enable discovery of selective neuroprotective strategies.
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http://dx.doi.org/10.1038/s41590-020-0654-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523413PMC
May 2020

The Spectrum of Neurologic Disease in the Severe Acute Respiratory Syndrome Coronavirus 2 Pandemic Infection: Neurologists Move to the Frontlines.

JAMA Neurol 2020 06;77(6):679-680

Deparment of Neurology and Weill Institute for Neuroscience, University of California, San Francisco.

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http://dx.doi.org/10.1001/jamaneurol.2020.1065DOI Listing
June 2020

Fixational microsaccades: A quantitative and objective measure of disability in multiple sclerosis.

Mult Scler 2020 03 7;26(3):343-353. Epub 2020 Feb 7.

Department of Neurology, University of California, San Francisco, San Francisco, CA, USA/Department of Ophthalmology, University of California, San Francisco, San Francisco, CA, USA.

Background: Objective tools for prognosis and disease progression monitoring in multiple sclerosis (MS) are lacking. The visuomotor system could be used to track motor dysfunction at the micron scale through the monitoring of fixational microsaccades.

Aims: The aim of this study was to evaluate whether microsaccades are correlated with standard MS disability metrics and to assess whether these methods play a predictive role in MS disability.

Method: We used a custom-built retinal eye tracker, the tracking scanning laser ophthalmoscope (TSLO), to record fixation in 111 participants with MS and 100 unaffected controls.

Results: In MS participants, a greater number of microsaccades showed significant association with higher Expanded Disability Status Scale score (EDSS,  < 0.001), nine-hole peg test (non-dominant:  = 0.006), Symbol Digit Modalities Test (SMDT,  = 0.014), and Functional Systems Scores (FSS) including brainstem ( = 0.005), cerebellar ( = 0.011), and pyramidal ( = 0.009). Both brainstem FSS and patient-reported fatigue showed significant associations with microsaccade number, amplitude, and peak acceleration. Participants with MS showed a statistically different average number ( = 0.020), peak vertical acceleration ( = 0.003), and vertical amplitude ( < 0.001) versus controls. Logistic regression models for MS disability were created using TSLO microsaccade metrics and paraclinical tests with ⩾80% accuracy.

Conclusion: Microsaccades provide objective measurements of MS disability level and disease worsening.
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http://dx.doi.org/10.1177/1352458519894712DOI Listing
March 2020

Monitoring retinal changes with optical coherence tomography predicts neuronal loss in experimental autoimmune encephalomyelitis.

J Neuroinflammation 2019 Nov 4;16(1):203. Epub 2019 Nov 4.

Division of Neuroimmunology and Glial Biology, Department of Neurology, University of California, San Francisco, San Francisco, USA.

Background: Retinal optical coherence tomography (OCT) is a clinical and research tool in multiple sclerosis, where it has shown significant retinal nerve fiber (RNFL) and ganglion cell (RGC) layer thinning, while postmortem studies have reported RGC loss. Although retinal pathology in experimental autoimmune encephalomyelitis (EAE) has been described, comparative OCT studies among EAE models are scarce. Furthermore, the best practices for the implementation of OCT in the EAE lab, especially with afoveate animals like rodents, remain undefined. We aimed to describe the dynamics of retinal injury in different mouse EAE models and outline the optimal experimental conditions, scan protocols, and analysis methods, comparing these to histology to confirm the pathological underpinnings.

Methods: Using spectral-domain OCT, we analyzed the test-retest and the inter-rater reliability of volume, peripapillary, and combined horizontal and vertical line scans. We then monitored the thickness of the retinal layers in different EAE models: in wild-type (WT) C57Bl/6J mice immunized with myelin oligodendrocyte glycoprotein peptide (MOG) or with bovine myelin basic protein (MBP), in TCR mice immunized with MOG, and in SJL/J mice immunized with myelin proteolipid lipoprotein (PLP). Strain-matched control mice were sham-immunized. RGC density was counted on retinal flatmounts at the end of each experiment.

Results: Volume scans centered on the optic disc showed the best reliability. Retinal changes during EAE were localized in the inner retinal layers (IRLs, the combination of the RNFL and the ganglion cell plus the inner plexiform layers). In WT, MOG EAE, progressive thinning of IRL started rapidly after EAE onset, with 1/3 of total loss occurring during the initial 2 months. IRL thinning was associated with the degree of RGC loss and the severity of EAE. Sham-immunized SJL/J mice showed progressive IRL atrophy, which was accentuated in PLP-immunized mice. MOG-immunized TCR mice showed severe EAE and retinal thinning. MBP immunization led to very mild disease without significant retinopathy.

Conclusions: Retinal neuroaxonal damage develops quickly during EAE. Changes in retinal thickness mirror neuronal loss and clinical severity. Monitoring of the IRL thickness after immunization against MOG in C57Bl/6J mice seems the most convenient model to study retinal neurodegeneration in EAE.
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http://dx.doi.org/10.1186/s12974-019-1583-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6827223PMC
November 2019

Inebilizumab for the treatment of neuromyelitis optica spectrum disorder (N-MOmentum): a double-blind, randomised placebo-controlled phase 2/3 trial.

Lancet 2019 10 5;394(10206):1352-1363. Epub 2019 Sep 5.

Viela Bio, Gaithersburg, MD, USA.

Background: No approved therapies exist for neuromyelitis optica spectrum disorder (NMOSD), a rare, relapsing, autoimmune, inflammatory disease of the CNS that causes blindness and paralysis. We aimed to assess the efficacy and safety of inebilizumab, an anti-CD19, B cell-depleting antibody, in reducing the risk of attacks and disability in NMOSD.

Methods: We did a multicentre, double-blind, randomised placebo-controlled phase 2/3 study at 99 outpatient specialty clinics or hospitals in 25 countries. Eligible participants were adults (≥18 years old) with a diagnosis of NMOSD, an Expanded Disability Status Scale score of 8·0 or less, and a history of at least one attack requiring rescue therapy in the year before screening or at least two attacks requiring rescue therapy in the 2 years before screening. Participants were randomly allocated (3:1) to 300 mg intravenous inebilizumab or placebo with a central interactive voice response system or interactive web response system and permuted block randomisation. Inebilizumab or placebo was administered on days 1 and 15. Participants, investigators, and all clinical staff were masked to the treatments, and inebilizumab and placebo were indistinguishable in appearance. The primary endpoint was time to onset of an NMOSD attack, as determined by the adjudication committee. Efficacy endpoints were assessed in all randomly allocated patients who received at least one dose of study intervention, and safety endpoints were assessed in the as-treated population. The study is registered with ClinicalTrials.gov, number NCT02200770.

Findings: Between Jan 6, 2015, and Sept 24, 2018, 230 participants were randomly assigned to treatment and dosed, with 174 participants receiving inebilizumab and 56 receiving placebo. The randomised controlled period was stopped before complete enrolment, as recommended by the independent data-monitoring committee, because of a clear demonstration of efficacy. 21 (12%) of 174 participants receiving inebilizumab had an attack versus 22 (39%) of 56 participants receiving placebo (hazard ratio 0·272 [95% CI 0·150-0·496]; p<0·0001). Adverse events occurred in 125 (72%) of 174 participants receiving inebilizumab and 41 (73%) of 56 participants receiving placebo. Serious adverse events occurred in eight (5%) of 174 participants receiving inebilizumab and five (9%) of 56 participants receiving placebo.

Interpretation: Compared with placebo, inebilizumab reduced the risk of an NMOSD attack. Inebilizumab has potential application as an evidence-based treatment for patients with NMOSD.

Funding: MedImmune and Viela Bio.
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http://dx.doi.org/10.1016/S0140-6736(19)31817-3DOI Listing
October 2019

Early complement genes are associated with visual system degeneration in multiple sclerosis.

Brain 2019 09;142(9):2722-2736

Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA.

Multiple sclerosis is a heterogeneous disease with an unpredictable course and a wide range of severity; some individuals rapidly progress to a disabled state whereas others experience only mild symptoms. Though genetic studies have identified variants that are associated with an increased risk of developing multiple sclerosis, no variants have been consistently associated with multiple sclerosis severity. In part, the lack of findings is related to inherent limitations of clinical rating scales; these scales are insensitive to early degenerative changes that underlie disease progression. Optical coherence tomography imaging of the retina and low-contrast letter acuity correlate with and predict clinical and imaging-based outcomes in multiple sclerosis. Therefore, they may serve as sensitive phenotypes to discover genetic predictors of disease course. We conducted a set of genome-wide association studies of longitudinal structural and functional visual pathway phenotypes in multiple sclerosis. First, we assessed genetic predictors of ganglion cell/inner plexiform layer atrophy in a discovery cohort of 374 patients with multiple sclerosis using mixed-effects models adjusting for age, sex, disease duration, optic neuritis and genetic ancestry and using a combination of single-variant and network-based analyses. For candidate variants identified in discovery, we conducted a similar set of analyses of ganglion cell/inner plexiform layer thinning in a replication cohort (n = 376). Second, we assessed genetic predictors of sustained loss of 5-letters in low-contrast letter acuity in discovery (n = 582) using multivariable-adjusted Cox proportional hazards models. We then evaluated candidate variants/pathways in a replication cohort. (n = 253). Results of both studies revealed novel subnetworks highly enriched for connected genes in early complement activation linked to measures of disease severity. Within these networks, C3 was the gene most strongly associated with ganglion cell/inner plexiform layer atrophy (P = 0.004) and C1QA and CR1 were top results in analysis of sustained low-contrast letter acuity loss. Namely, variant rs158772, linked to C1QA, and rs61822967, linked to CR1, were associated with 71% and 40% increases in risk of sustained LCLA loss, respectively, in meta-analysis pooling discovery and replication cohorts (rs158772: hazard ratio: 1.71; 95% confidence interval 1.30-2.25; P = 1.3 × 10-4; rs61822967: hazard ratio: 1.40; 95% confidence interval: 1.16-1.68; P = 4.1 × 10-4). In conclusion, early complement pathway gene variants were consistently associated with structural and functional measures of multiple sclerosis severity. These results from unbiased analyses are strongly supported by several prior reports that mechanistically implicated early complement factors in neurodegeneration.
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http://dx.doi.org/10.1093/brain/awz188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6776113PMC
September 2019

Lessons from an unsuccessful therapeutic trial.

Authors:
Ari J Green

Lancet Neurol 2019 09 5;18(9):808-810. Epub 2019 Jul 5.

University of California at San Francisco (UCSF) Weill Institute for Neurosciences, Department of Neurology, Division of Neuroimmunology and Glial Biology, San Francisco, CA 94143, USA; UCSF Department of Ophthalmology, Division of Neuro-Ophthalmology, San Francisco, CA, USA. Electronic address:

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http://dx.doi.org/10.1016/S1474-4422(19)30274-1DOI Listing
September 2019

Personalizing medical care for patients with MS: Monitoring brainstem damage by infrared oculography.

Neurology 2019 05 19;92(20):929-930. Epub 2019 Apr 19.

From Stanford University (P.V.), CA; Institut d'Investigacions Biomèdiques August Pi Sunyer (P.V.), Barcelona, Spain; Weill Institute for Neurosciences (A.J.G.), Division of Neuroimmunology and Glial Biology, Department of Neurology, University of California, San Francisco; Department of Ophthalmology (A.J.G.), UCSF; and New York University (S.G.), NY.

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http://dx.doi.org/10.1212/WNL.0000000000007493DOI Listing
May 2019

Association of Continuous Assessment of Step Count by Remote Monitoring With Disability Progression Among Adults With Multiple Sclerosis.

JAMA Netw Open 2019 03 1;2(3):e190570. Epub 2019 Mar 1.

Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco.

Importance: Disability measures in multiple sclerosis (MS) fail to capture potentially important variability in walking behavior. More sensitive and ecologically valid outcome measures are needed to advance MS research.

Objectives: To assess continuous step count activity remotely among individuals with MS for 1 year and determine how average daily step count is associated with other measures of MS disability.

Design, Setting, And Participants: In a prospective longitudinal observational cohort study, 95 adults with relapsing or progressive MS who were able to walk more than 2 minutes with or without an assistive device were recruited between June 15, 2015, and August 8, 2016, and remotely monitored in their natural environment for 1 year. Patients were excluded if they had a clinical relapse within 30 days or comorbidity contributing to ambulatory impairment. Longitudinal analysis was performed from October 2017 to March 2018. Revised analysis was performed in December 2018.

Intervention: Activity monitoring of step count using a wrist-worn accelerometer.

Main Outcomes And Measures: Average daily step count compared with in-clinic assessments and patient-reported outcomes.

Results: Of the 95 participants recruited (59 women and 36 men; mean [SD] age, 49.6 [13.6] years [range, 22.0-74.0 years]), 35 (37%) had progressive MS, and the median baseline Expanded Disability Status Scale score was 4.0 (range, 0-6.5). At 1 year, 79 participants completed follow-up (83% retention). There was a modest reduction in accelerometer use during the 1 year of the study. A decreasing average daily step count during the study was associated with worsening of clinic-based outcomes (Timed 25-Foot Walk, β = -13.09; P < .001; Timed-Up-and-Go, β = -9.25; P < .001) and patient-reported outcomes (12-item Multiple Sclerosis Walking Scale, β = -17.96; P < .001). A decreasing average daily step count occurred even when the Expanded Disability Status Scale score remained stable, and 12 of 25 participants (48%) with a significant decrease in average daily step count during the study did not have a reduction on other standard clinic-based metrics. Participants with a baseline average daily step count below 4766 (cohort median) had higher odds of clinically meaningful disability (Expanded Disability Status Scale score) worsening at 1 year, adjusting for age, sex, and disease duration (odds ratio, 4.01; 95% CI, 1.17-13.78; P = .03).

Conclusions And Relevance: Continuous remote activity monitoring of individuals with MS for 1 year appears to be feasible. In this study, a decreasing average daily step count during a 1-year period was associated with worsening of standard ambulatory measures but could also occur even when traditional disability measures remained stable. These results appear to support the prospect of using the average daily step count as a sensitive longitudinal outcome measure in MS and as a clinically relevant metric for targeted intervention.
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http://dx.doi.org/10.1001/jamanetworkopen.2019.0570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6484622PMC
March 2019

Silent progression in disease activity-free relapsing multiple sclerosis.

Ann Neurol 2019 05 30;85(5):653-666. Epub 2019 Mar 30.

UCSF Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, San Francisco, CA.

Objective: Rates of worsening and evolution to secondary progressive multiple sclerosis (MS) may be substantially lower in actively treated patients compared to natural history studies from the pretreatment era. Nonetheless, in our recently reported prospective cohort, more than half of patients with relapsing MS accumulated significant new disability by the 10th year of follow-up. Notably, "no evidence of disease activity" at 2 years did not predict long-term stability. Here, we determined to what extent clinical relapses and radiographic evidence of disease activity contribute to long-term disability accumulation.

Methods: Disability progression was defined as an increase in Expanded Disability Status Scale (EDSS) of 1.5, 1.0, or 0.5 (or greater) from baseline EDSS = 0, 1.0-5.0, and 5.5 or higher, respectively, assessed from baseline to year 5 (±1 year) and sustained to year 10 (±1 year). Longitudinal analysis of relative brain volume loss used a linear mixed model with sex, age, disease duration, and HLA-DRB1*15:01 as covariates.

Results: Relapses were associated with a transient increase in disability over 1-year intervals (p = 0.012) but not with confirmed disability progression (p = 0.551). Relative brain volume declined at a greater rate among individuals with disability progression compared to those who remained stable (p < 0.05).

Interpretation: Long-term worsening is common in relapsing MS patients, is largely independent of relapse activity, and is associated with accelerated brain atrophy. We propose the term silent progression to describe the insidious disability that accrues in many patients who satisfy traditional criteria for relapsing-remitting MS. Ann Neurol 2019;85:653-666.
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http://dx.doi.org/10.1002/ana.25463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518998PMC
May 2019

Clinic to in-home telemedicine reduces barriers to care for patients with MS or other neuroimmunologic conditions.

Neurol Neuroimmunol Neuroinflamm 2018 Nov 2;5(6):e505. Epub 2018 Oct 2.

Division of Neuroinflammation and Glial Biology (R.B., P.G., C.J.B., E.C-H., A.J.G., J.M.G.), Department of Neurology, Weill Institute for the Neurosciences, UCSF MS and Neuroinflammation Center, University of California; and Neuro-ophthalmology Division (A.J.G.), Department of Ophthalmology, University of California, San Francisco.

Objective: To describe the routine use of telemedicine-enabled neurologic care in an academic outpatient MS and neuroimmunology clinic and quantify its role in reducing patient burden.

Methods: Between January 2017 and December 2017, we surveyed patients and MS neurologists after 50 consecutive routinely scheduled televideo visits and a convenience sample of 100 in-clinic visits. Summary statistics were calculated and comparisons performed.

Results: Overall, 98% televideo participants found the technology easy to use, and only 17% believed that an in-person examination would have more effectively addressed their needs for the visit. MS neurologists reported achieving their clinical goals in 47/48 (98%) of televideo visits and an adequate physical examination with 2 exceptions (possible cauda equina syndrome and visual field loss). Three emergency department referrals were avoided due to televideo availability. Telemedicine reduced travel burden, including a mean (±SD) travel distance of 160 (±196) miles and avoiding overnight lodging and air travel. Telemedicine also reduced indirect costs, including time off work (65% of employed patients) and caregiver burden (30% avoided caregiver time off from work/obligations). Across 8 domains of provider interpersonal communication skills, telemedicine and in-clinic participants rated only 1 domain to be different (eye contact), and overall, 96% of in-clinic and 100% of telemedicine participants agreed/strongly agreed that their clinical goals had been met.

Conclusions: When incorporated as part of the continuum of MS/neuroimmunology care, clinic to in-home telemedicine reduces travel and caregiver burden and enables efficient, convenient, and effective follow-up.
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http://dx.doi.org/10.1212/NXI.0000000000000505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6354660PMC
November 2018

pRNFL as a marker of disability worsening in the medium/long term in patients with MS.

Neurol Neuroimmunol Neuroinflamm 2019 03 21;6(2):e533. Epub 2018 Dec 21.

Department of Neurology (C.C., M.D., V.D., D.B., S.L.H., B.A.C.C., J.M.G., A.J.G.), UCSF Weill Institute for Neurosciences, University of California, San Francisco, CA; and Department of Neurology (B.N.), Johns Hopkins University School of Medicine, Baltimore, MD.

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http://dx.doi.org/10.1212/NXI.0000000000000533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6340330PMC
March 2019

Selective Estrogen Receptor Modulators Enhance CNS Remyelination Independent of Estrogen Receptors.

J Neurosci 2019 03 29;39(12):2184-2194. Epub 2019 Jan 29.

Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, California 94143, and

A significant unmet need for patients with multiple sclerosis (MS) is the lack of U.S. Food and Drug Administration (FDA)-approved remyelinating therapies. We have identified a compelling remyelinating agent, bazedoxifene (BZA), a European Medicines Agency (EMA)-approved (and FDA-approved in combination with conjugated estrogens) selective estrogen receptor (ER) modulator (SERM) that could move quickly from bench to bedside. This therapy stands out as a tolerable alternative to previously identified remyelinating agents and other candidates within this family. Using an unbiased high-throughput screen, with subsequent validation in both murine and human oligodendrocyte precursor cells (OPCs) and coculture systems, we find that BZA enhances differentiation of OPCs into functional oligodendrocytes. Using an murine model of focal demyelination, we find that BZA enhances OPC differentiation and remyelination. Of critical importance, we find that BZA acts independently of its presumed target, the ER, in both and systems. Using a massive computational data integration approach, we independently identify six possible candidate targets through which SERMs may mediate their effect on remyelination. Of particular interest, we identify EBP (encoding 3β-hydroxysteroid-Δ8,Δ7-isomerase), a key enzyme in the cholesterol biosynthesis pathway, which was previously implicated as a target for remyelination. These findings provide valuable insights into the implications for SERMs in remyelination for MS and hormonal research at large. Therapeutics targeted at remyelination failure, which results in axonal degeneration and ultimately disease progression, represent a large unmet need in the multiple sclerosis (MS) population. Here, we have validated a tolerable European Medicines Agency-approved (U.S. Food and Drug Administration-approved in combination with conjugated estrogens) selective estrogen receptor (ER) modulator (SERM), bazedoxifene (BZA), as a potent agent of oligodendrocyte precursor cell (OPC) differentiation and remyelination. SERMs, which were developed as nuclear ER-α and ER-β agonists/antagonists, have previously been implicated in remyelination and neuroprotection, following a heavy focus on estrogens with underwhelming and conflicting results. We show that nuclear ERs are not required for SERMs to mediate their potent effects on OPC differentiation and remyelination and highlight EBP, an enzyme in the cholesterol biosynthesis pathway that could potentially act as a target for SERMs.
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http://dx.doi.org/10.1523/JNEUROSCI.1530-18.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6433770PMC
March 2019

Potential Benefits of Early Aggressive Treatment in Multiple Sclerosis.

Authors:
Ari J Green

JAMA Neurol 2019 03;76(3):254-256

Department of Neurology, University of California, San Francisco Weill Institute for Neurosciences.

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http://dx.doi.org/10.1001/jamaneurol.2018.4932DOI Listing
March 2019

Prion Seeds Distribute throughout the Eyes of Sporadic Creutzfeldt-Jakob Disease Patients.

mBio 2018 11 20;9(6). Epub 2018 Nov 20.

Department of Pathology, University of California, San Diego, La Jolla, California, USA

Sporadic Creutzfeldt-Jakob disease (sCJD) is the most common prion disease in humans and has been iatrogenically transmitted through corneal graft transplantation. Approximately 40% of sCJD patients develop visual or oculomotor symptoms and may seek ophthalmological consultation. Here we used the highly sensitive real-time quaking-induced conversion (RT-QuIC) assay to measure postmortem prion seeding activities in cornea, lens, ocular fluid, retina, choroid, sclera, optic nerve, and extraocular muscle in the largest series of sCJD patient eyes studied by any assay to date. We detected prion seeding activity in 100% of sCJD eyes, representing three common sCJD subtypes, with levels varying by up to 4 log-fold among individuals. The retina consistently showed the highest seed levels, which in some cases were only slightly lower than brain. Within the retina, prion deposits were detected by immunohistochemistry (IHC) in the retinal outer plexiform layer in most sCJD cases, and in some eyes the inner plexiform layer, consistent with synaptic prion deposition. Prions were not detected by IHC in any other eye region. With RT-QuIC, prion seed levels generally declined in eye tissues with increased distance from the brain, and yet all corneas had prion seeds detectable. Prion seeds were also present in the optic nerve, extraocular muscle, choroid, lens, vitreous, and sclera. Collectively, these results reveal that sCJD patients accumulate prion seeds throughout the eye, indicating the potential diagnostic utility as well as a possible biohazard. Cases of iatrogenic prion disease have been reported from corneal transplants, yet the distribution and levels of prions throughout the eye remain unknown. This study probes the occurrence, level, and distribution of prions in the eyes of patients with sporadic Creutzfeldt-Jakob disease (sCJD). We tested the largest series of prion-infected eyes reported to date using an ultrasensitive technique to establish the prion seed levels in eight regions of the eye. All 11 cases had detectable prion seeds in the eye, and in some cases, the seed levels in the retina approached those in brain. In most cases, prion deposits could also be seen by immunohistochemical staining of retinal tissue; other ocular tissues were negative. Our results have implications for estimating the risk for iatrogenic transmission of sCJD as well as for the development of antemortem diagnostic tests for prion diseases.
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http://dx.doi.org/10.1128/mBio.02095-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6247090PMC
November 2018

Methods to Assess Ocular Motor Dysfunction in Multiple Sclerosis.

J Neuroophthalmol 2018 12;38(4):488-493

Department of Neurology (CKS, AB-R, JHS, AJG), University of California, San Francisco, San Francisco, California; School of Medicine (AB-R), University of Ottawa, Ottawa, Ontario, Canada; School of Optometry (EB, JT), University of California, Berkeley, Berkeley, California; Vision Science Graduate Group (EB), University of California, Berkeley, Berkeley, California; and Department of Ophthalmology (AJG), University of California, San Francisco, San Francisco, California.

: BACKGROUND:: Multiple sclerosis (MS) is an inflammatory disease of the central nervous system causing the immune-mediated demyelination of the brain, optic nerve, and spinal cord and resulting in ultimate axonal loss and permanent neurological disability. Ocular motor dysfunction is commonly observed in MS but can be frequently overlooked or underappreciated by nonspecialists. Therefore, detailed and quantitative assessment of eye movement function has significant potential for optimization of patient care, especially for clinicians interested in treating visual symptoms or tracking disease progression. METHODS:: A brief history of eye tracking technology followed by a contextualized review of the methods that can be used to assess ocular motor dysfunction in MS-including a discussion of each method's strengths and limitations. We discuss the rationale for interest in this area and describe new tools capable of tracking eye movements as a possible means of monitoring disease. RESULTS/CONCLUSIONS:: This overview should inform clinicians working with patients with MS of how ocular motor deficits can best be assessed and monitored in this population. It also provides a rationale for interest in this field with insights regarding which techniques should be used for studying which classes of eye movements and related dysfunction in the disease.
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http://dx.doi.org/10.1097/WNO.0000000000000734DOI Listing
December 2018

Oligodendrocyte-encoded Kir4.1 function is required for axonal integrity.

Elife 2018 09 11;7. Epub 2018 Sep 11.

Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, California, United States.

Glial support is critical for normal axon function and can become dysregulated in white matter (WM) disease. In humans, loss-of-function mutations of which encodes the inward-rectifying potassium channel KIR4.1, causes seizures and progressive neurological decline. We investigated Kir4.1 functions in oligodendrocytes (OLs) during development, adulthood and after WM injury. We observed that Kir4.1 channels localized to perinodal areas and the inner myelin tongue, suggesting roles in juxta-axonal K removal. Conditional knockout (cKO) of OL- resulted in late onset mitochondrial damage and axonal degeneration. This was accompanied by neuronal loss and neuro-axonal dysfunction in adult OL- cKO mice as shown by delayed visual evoked potentials, inner retinal thinning and progressive motor deficits. Axon pathologies in OL- cKO were exacerbated after WM injury in the spinal cord. Our findings point towards a critical role of OL-Kir4.1 for long-term maintenance of axonal function and integrity during adulthood and after WM injury.
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http://dx.doi.org/10.7554/eLife.36428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6167053PMC
September 2018