Publications by authors named "Daniel Ontaneda"

87 Publications

Vitamin D Levels and Visual System Measurements in Progressive Multiple Sclerosis: A Cross-sectional Study.

Int J MS Care 2021 Mar-Apr;23(2):53-58. Epub 2020 Apr 28.

Background: Vitamin D deficiency is associated with increased disease activity in multiple sclerosis (MS), but its role in progressive MS has not been elucidated. The objective was to determine the correlation between vitamin D levels and visual parameters in primary progressive MS (PPMS) and secondary progressive MS (SPMS).

Methods: Serum 25-hydroxyvitamin D (25[OH]D) and 25-hydroxyvitamin D (25[OH]D) levels were obtained from the Secondary and Primary Progressive Ibudilast NeuroNEXT Trial in MS (SPRINT-MS). Visual function measurements and vitamin D associations were determined using the Pearson correlation and the generalized linear mixed model.

Results: The analysis included 258 patients (mean ± SD age of 55.6 ± 7.3 years, 52.7% female, and 52.3% PPMS). Mean vitamin D values were above sufficiency and were similar between PPMS and SPMS ( = .47 and = .31). There was no association between 25(OH)D levels and any visual markers, including peripapillary retinal nerve fiber layer thickness (Spearman = -0.08), macular volume ( = -0.03), ganglion cell-inner plexiform layer ( = -0.07), and 2.5% low-contrast visual acuity test ( = -0.10). No statistically significant associations between vitamin D levels and visual system measurements were detected in the PPMS and SPMS subgroups.

Conclusions: Vitamin D levels were not associated with optical coherence tomography findings or low-contrast letter acuity in this group of patients with progressive MS.
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http://dx.doi.org/10.7224/1537-2073.2020-005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047686PMC
April 2020

Integrating patient-reported outcomes and quantitative timed tasks to identify relapsing remitting multiple sclerosis patient subgroups: a latent profile analysis.

Mult Scler Relat Disord 2021 Mar 18;51:102912. Epub 2021 Mar 18.

Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA; Center for Health Care Research and Policy, School of Medicine, Case Western Reserve University, Cleveland, OH, USA.

Background: Multiple sclerosis (MS) patients experience wide-ranging symptoms with varied severity, and approaches that integrate patient-reported outcomes and objective quantitative measures will present opportunities for advancing clinical profiling. The primary objective of the current study was to conduct exploratory data analysis using latent variable modeling to empirically identify clusters of relapsing remitting (RR) MS patients with shared impairment patterns across three patient-reported outcomes and two timed task measures.

Methods: Latent profile analyses and impairment data for 2,012 RRMS patients identified distinct patient clusters using timed task measures of upper and lower limb performance, and patient-reported outcomes measuring quality of life, depression symptom severity, and perceived global disability. Multinomial logistic regression models were used to characterize associations between socio-demographic attributes and assignment to the patient clusters.

Results: There were 6 distinct clusters of RRMS patients that differed by symptom patterns, and by their socio-demographic attributes. Most notable were were no differences in age, sex, or disease duration between the least and most impaired classes, representing 14% and 4% of patients, respectively. Patients in the most impaired class were much more likely to be Black American, have a history of smoking, have a higher body mass index, and be of lower socioeconomic status than the least impaired class. There were positive relationships between age and classification to clusters of increasing moderately severe impairment but not the most severe clusters.

Conclusion: We present a framework for discerning phenotypic impairment clusters in RRMS. The results demonstrate opportunities for advancing clinical profiling, which is necessary for optimizing personalized MS care models and clinical research.
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http://dx.doi.org/10.1016/j.msard.2021.102912DOI Listing
March 2021

Deep grey matter injury in multiple sclerosis: A NAIMS consensus statement.

Brain 2021 Mar 23. Epub 2021 Mar 23.

Department of Neurology, University of Southern California Keck School of Medicine, Los Angeles, CA, USA.

Although multiple sclerosis (MS) has traditionally been considered a white matter disease, extensive research documents the presence and importance of gray matter injury including cortical and deep regions. The deep gray matter (DGM) exhibits a broad range of pathology and is uniquely suited to study the mechanisms and clinical relevance of tissue injury in MS using magnetic resonance techniques. DGM injury has been associated with clinical and cognitive disability. Recently, MRI characterization of DGM properties, such as thalamic volume, have been tested as potential clinical trial endpoints associated with neurodegenerative aspects of MS. Given this emerging area of interest and its potential clinical trial relevance, the North American Imaging in MS (NAIMS) Cooperative held a workshop and reached consensus on imaging topics related to the DGM. Herein, we review current knowledge regarding DGM injury in MS from an imaging perspective, including insights from histopathology, image acquisition and post-processing for DGM. We discuss the clinical relevance of DGM injury and specific regions of interest within the DGM. We highlight unanswered questions and propose future directions, with the aim of focusing research priorities towards better methods, analysis, and interpretation of results.
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http://dx.doi.org/10.1093/brain/awab132DOI Listing
March 2021

Juxtacortical susceptibility changes in progressive multifocal leukoencephalopathy at the gray-white matter junction correlates with iron-enriched macrophages.

Mult Scler 2021 Mar 22:1352458521999651. Epub 2021 Mar 22.

Mellen Center for Multiple Sclerosis Treatment and Research, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA.

Objective: Describe magnetic resonance imaging (MRI) susceptibility changes in progressive multifocal leukoencephalopathy (PML) and identify neuropathological correlates.

Methods: PML cases and matched controls with primary central nervous system lymphoma (PCNSL) were retrospectively identified. MRI brain at 3 T and 7 T were reviewed. MRI-pathology correlations in fixed brain autopsy tissue were conducted in three subjects with confirmed PML.

Results: With PML ( = 26 total, = 5 multiple sclerosis natalizumab-associated), juxtacortical changes on susceptibility-weighted imaging (SWI) or gradient echo (GRE) sequences were noted in 3/3 cases on 7 T MRI and 14/22 cases (63.6%) on 1.5 T or 8/22 (36.4%) 3 T MRI. Similar findings were only noted in 3/25 (12.0%) of PCNSL patients (odds ratio (OR) 12.83, 95% confidence interval (CI), 2.9-56.7, < 0.001) on 1.5 or 3 T MRI. On susceptibility sequences available prior to diagnosis of PML, 7 (87.5%) had changes present on average 2.7 ± 1.8 months (mean ± SD) prior to diagnosis. Postmortem 7 T MRI showed SWI changes corresponded to areas of increased iron density along the gray-white matter (GM-WM) junction predominantly in macrophages.

Conclusion: Susceptibility changes in PML along the GM-WM junction can precede noticeable fluid-attenuated inversion recovery (FLAIR) changes and correlates with iron accumulation in macrophages.
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http://dx.doi.org/10.1177/1352458521999651DOI Listing
March 2021

Predicting disability worsening in relapsing and progressive multiple sclerosis.

Curr Opin Neurol 2021 Jun;34(3):312-321

Mellen Center for Multiple Sclerosis, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio, USA.

Purpose Of Review: Multiple sclerosis (MS) is a clinically heterogeneous disease, which complicates expectant management as well as treatment decisions. This review provides an overview of both well established and emerging predictors of disability worsening, including clinical factors, imaging factors, biomarkers and treatment strategies.

Recent Findings: In addition to well known clinical predictors (age, male sex, clinical presentation, relapse behaviour), smoking, obesity, vascular and psychiatric comorbidities are associated with subsequent disability worsening in persons with MS. A number of imaging features are predictive of disability worsening and are present to varying degrees in relapsing and progressive forms of MS. These include brain volumes, spinal cord atrophy, lesion volumes and optical coherence tomography features. Cerebrospinal and more recently blood biomarkers including neurofilament light show promise as more easily attainable biomarkers of future disability accumulation. Importantly, recent observational studies suggest that initiation of early-intensive therapy, as opposed to escalation based on breakthrough disease, is associated with decreased accumulation of disability overall, although randomized controlled trials investigating this question are underway.

Summary: Understanding risk factors associated with disability progression can help to both counsel patients and enhance the clinician's availability to provide evidence-based treatment recommendations.
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http://dx.doi.org/10.1097/WCO.0000000000000928DOI Listing
June 2021

Thalamic Injury and Cognition in Multiple Sclerosis.

Front Neurol 2020 5;11:623914. Epub 2021 Feb 5.

Mellen Center for Multiple Sclerosis Treatment and Research, Neurological Institute, Cleveland Clinic, Cleveland, OH, United States.

Multiple sclerosis (MS) produces demyelination and degeneration in both gray and white matter. Both cortical and deep gray matter injury is observed during the course of MS. Among deep gray matter structures, the thalamus has received special attention, as it undergoes volume loss in different MS subtypes and is involved in the earliest form of the disease, radiologically isolated syndrome. The thalamus plays an important role as an information relay center, and involvement of the thalamus in MS has been associated with a variety of clinical manifestations in MS, including fatigue, movement disorders, pain, and cognitive impairment (CI). Similar to thalamic volume loss, CI is seen from the earliest stages of MS and is potentially one of the most debilitating manifestations of the disease. The thalamus, particularly the dorsomedial nucleus as part of the basolateral limbic circuit and anterior thalamic nuclei through connections with the prefrontal cortex, has been shown to be involved in CI. Specifically, several cognitive performance measures such as processing speed and memory correlate with thalamic volume. Thalamic atrophy is one of the most important predictors of CI in MS, and both thalamic volume, diffusion tensor imaging measures, and functional activation correlate with the degree of CI in MS. Although the exact mechanism of thalamic atrophy is not well-understood, it is hypothesized to be secondary to degeneration following white matter injury resulting in secondary neurodegeneration and neuronal loss. The thalamus may represent an ideal biomarker for studies aiming to test neuroprotective or restorative therapies aimed at cognition.
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http://dx.doi.org/10.3389/fneur.2020.623914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892763PMC
February 2021

Comorbidity effect on processing speed test and MRI measures in multiple sclerosis patients.

Mult Scler Relat Disord 2020 Nov 21;46:102593. Epub 2020 Oct 21.

Mellen Center for Multiple Sclerosis Treatment and Research, Neurological Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.

Background: Comorbid conditions are known to affect the clinical course of multiple sclerosis (MS). Our objective was to determine the impact of comorbidities on the processing speed test (PST).

Methods: We conducted a retrospective, longitudinal analysis of all patients who completed PST testing from June 2015 - August 2019 at our center. Our electronic medical record was queried to determine the presence of the following comorbidities: diabetes mellitus (DM), hypertension (HTN), hyperlipidemia (HLD), coronary artery disease, and depression. To help address baseline PST performance and practice effect, patients were also divided into four quartiles by baseline PST scores. Brain MRIs obtained within a 90-day window from the initial clinical assessment were quantitatively analyzed via fully-automated methods to calculate whole brain fraction (WBF), T2 lesion volume (T2LV), gray matter fraction (GMF), and thalamic volume (TV). Univariable and multivariable linear regression models were used to determine the relationship between the comorbidities, PST performance and MRI metrics over time.

Results: A total of 4,344 patients (mean age 49.5 ± 12.4 years, 72.3% female, and 63.7% relapsing remitting MS) were included in the analysis with 13,375 individual patient encounters. Over half the cohort (52.4%) suffered from at least one comorbidity with the most common being depression (37.4%), HLD (20.9%), HTN (19.6%), and DM (6.4%). Patients with one or more comorbidity had lower baseline PST scores. Longitudinally, patients with two comorbidities lost 1.46 points on the PST per year relative to those with no comorbidities (95% CI -2.46 - -0.46, p = 0.004). Individuals with depression had lower PST scores than those without, and this difference persisted over time (β = -2.40, 95% CI -3.08 - -1.73, p < 0.001). At baseline, HLD patients had higher PST scores than non-HLD patients (β = 1.10, 95% CI 0.15 - 2.05, p = 0.022), but this difference did not remain over time. Individuals in the highest PST performance quartile were negatively impacted when diagnosed with depression, HTN, and DM relative to those without the comorbidities. There were no other correlations with PST scores and the remaining comorbidities. Depression was associated with lower baseline WBF (β = -0.0043, 95% CI -0.0084 - -0.0003, p = 0.033) and GMF (β = -0.0046, 95% CI -0.0078 - -0.0015, p = 0.004) along with larger T2LV (β = 0.1605, 95% CI 0.0082 - 0.3128, p = 0.039). HLD patients had more favorable baseline MRI measures, including higher WBF (β = 0.0076, 95% CI 0.0017 - 0.0135, p = 0.012) and TV (β = 0.0002, 95% CI 0.0000 - 0.0005, p = 0.041), with a lower T2LV (β = -0.2963, 95% CI -0.5219 - -0.0706, p = 0.010).

Conclusions: Comorbidities are common within a MS cohort and adversely impact processing speed. Depression adversely impacted PST scores with worse MRI outcomes. HLD was associated with lower longitudinal PST measures but favorable quantitative MRI metrics. MS patients with faster baseline processing speeds were most sensitive to comorbid conditions. Our findings suggest a complex interplay between cognition and comorbid conditions in MS patients.
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http://dx.doi.org/10.1016/j.msard.2020.102593DOI Listing
November 2020

Measures of Thalamic Integrity are Associated with Cognitive Functioning in Fingolimod-treated Multiple Sclerosis Patients.

Mult Scler Relat Disord 2021 Jan 22;47:102635. Epub 2020 Nov 22.

Mellen Center for Multiple Sclerosis Treatment and Research, Neurological Institute, Cleveland Clinic, 9500 Euclid Avenue / U10, Cleveland, OH, 44195, US.

Background: Cognitive impairment is common in relapsing-remitting multiple sclerosis (RRMS) and multiple domains are affected, including information processing speed, episodic memory, and executive function. Damage to the thalamus appears to be related to cognitive functioning in MS. Fingolimod is a disease-modifying therapy for RRMS, which has been shown to have a protective effect on thalamic volume.

Objective: To determine the relationship between cognitive measures and the thalamus in fingolimod-treated RRMS patients and healthy controls using ultra high-field magnetic resonance imaging (MRI).

Methods: Fingolimod-treated RRMS and healthy participants were recruited from a single center to undergo neuropsychological testing and 7 tesla MRI. These assessments were performed at baseline, 6 months, and 12 months. The neuropsychological testing included the Brief Visuospatial Memory Test-Revised (BVMTR), the Symbol Digit Modalities Test (SDMT), the Selective Reminding Test (SRT), and the Delis-Kaplan Executive Function System (DKEFS). MRI metrics included thalamic volume, thalamic myelin density, thalamic axon density, T2 lesion volume, brain parenchymal fraction, and cortical thickness. Mixed-effects linear regression was used to determine the relationship between MRI parameters and neuropsychological test performance over time. Rates of change in patients and controls were compared using two-sample t-tests.

Results: We enrolled 15 RRMS patients and 5 healthy controls. Controls performed better than patients at baseline, but this difference was only significant for the letter fluency subtest of the DKEFS and for long-term storage as assessed by the SRT. Thalamic volume and thalamic myelin density were significantly associated with visuospatial (BVMTR) and verbal memory (SRT). Thalamic volume alone was also associated with inhibitory control (Color word interference subtest of the DKEFS) and cognitive flexibility (Number letter switching subtest of the DKEFS), whereas thalamic myelin density alone was associated with semantic knowledge (Verbal fluency subtest of the DKEFS). There were no significant changes in the rates of change in neurometric test performance or MRI metrics between patients and controls from baseline to 6 months and baseline to 12 months.

Conclusions: Thalamic injury is associated with cognitive performance in several domains. Fingolimod-treated RRMS patients evolved similarly to healthy controls over one year with regards to neuropsychological test performance and changes on MRI.
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http://dx.doi.org/10.1016/j.msard.2020.102635DOI Listing
January 2021

Multiple sclerosis management during the COVID-19 pandemic.

Mult Scler 2020 09 10;26(10):1163-1171. Epub 2020 Aug 10.

Division of Neuroimmunology and Neurological Infections, Johns Hopkins University, Baltimore, MA, USA.

Background: People with multiple sclerosis (MS) may be at higher risk for complications from the 2019 coronavirus (COVID-19) pandemic due to use of immunomodulatory disease modifying therapies (DMTs) and greater need for medical services.

Objectives: To evaluate risk factors for COVID-19 susceptibility and describe the pandemic's impact on healthcare delivery.

Methods: Surveys sent to MS patients at Cleveland Clinic, Johns Hopkins, and Vall d'Hebron-Centre d'Esclerosi Múltiple de Catalunya in April and May 2020 collected information about comorbidities, DMTs, exposures, COVID-19 testing/outcomes, health behaviors, and disruptions to MS care.

Results: There were 3028/10,816 responders. Suspected or confirmed COVID-19 cases were more likely to have a known COVID-19 contact (odds ratio (OR): 4.38; 95% confidence interval (CI): 1.04, 18.54). In multivariable-adjusted models, people who were younger, had to work on site, had a lower education level, and resided in socioeconomically disadvantaged areas were less likely to follow social distancing guidelines. 4.4% reported changes to therapy plans, primarily delays in infusions, and 15.5% a disruption to rehabilitative services.

Conclusion: Younger people with lower socioeconomic status required to work on site may be at higher exposure risk and are potential targets for educational intervention and work restrictions to limit exposure. Providers should be mindful of potential infusion delays and MS care disruption.
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http://dx.doi.org/10.1177/1352458520948231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7424611PMC
September 2020

Achieving effective patient and public involvement in international clinical trials in neurology.

Neurol Clin Pract 2020 Jun;10(3):265-272

Department of Psychological Medicine and Clinical Neurosciences (ECT), Cardiff University; Department of Clinical Neurology (NE, CB), University of Nottingham, United Kingdom; Tulane University (BZC), New Orleans, LA; MS Society (UK) (EHG), London; National MS Society (NL), Waltham, MA; Dental Translational and Clinical Research Unit (SP), Division of Applied Health and Clinical Translation, University of Leeds, United Kingdom; Cleveland Clinic Lerner College of Medicine (DMM), OH; Cleveland Clinic Mellen Center (DMM, SMP, DO); and Centre for Health, Technologies & Social Practice (AM), School of Sociology & Social Policy, University of Leeds, United Kingdom.

There is a growing need for patient and public involvement (PPI) to inform the way that research is developed and performed. International randomized controlled trials are particularly likely to benefit from PPI, but guidance is lacking on how or when it should be incorporated. In this article, we describe the PPI process that occurred during the design and initiation of an international treatment clinical trial in MS. PPI was incorporated using a structured approach, aiming to minimize bias and achieve equivalence in study design, implementation, and interpretation. Methods included PPI representation within the study research team, and the use of focus groups, analyzed using thematic framework analysis. We report the outcomes of PPI and make recommendations on its use in other neurology clinical trials. By sharing our model for PPI, we aim to maximize effectiveness of future public involvement and to allow its effect to be better evaluated.
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http://dx.doi.org/10.1212/CPJ.0000000000000739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292561PMC
June 2020

Technology-enabled assessments to enhance multiple sclerosis clinical care and research.

Neurol Clin Pract 2020 Jun;10(3):222-231

Mellen Center for Multiple Sclerosis (GM, BPM, LEB, MW, MA, FB, AB, DC, DSC, CF, RJF, SG, BG, CH-C, KRM, MPM, DMM, MN, AR-G, MR, HY, MAW, DO, JAC, RAB), Neurological Institute, Cleveland Clinic Foundation; Department of Quantitative Health Sciences (HL), Cleveland Clinic; Schey Center for Cognitive Neuroimaging (SMR), Lou Ruvo Center for Brain Health, Neurological Institute, Cleveland Clinic Foundation; Department of Biomedical Engineering (DS, JLA), Lerner Research Institute, Cleveland Clinic Foundation, OH; and Epic Systems Corporation (NJ), Verona, WI.

Background: Comprehensive and efficient assessments are necessary for clinical care and research in chronic diseases. Our objective was to assess the implementation of a technology-enabled tool in MS practice.

Method: We analyzed prospectively collected longitudinal data from routine multiple sclerosis (MS) visits between September 2015 and May 2018. The MS Performance Test, comprising patient-reported outcome measures (PROMs) and neuroperformance tests (NPTs) self-administered using a tablet, was integrated into routine care. Descriptive statistics, Spearman correlations, and linear mixed-effect models were used to examine the implementation process and relationship between patient characteristics and completion of assessments.

Results: A total of 8022 follow-up visits from 4199 patients (median age 49.9 [40.2-58.8] years, 32.1% progressive course, and median disease duration 13.6 [5.9-22.3] years) were analyzed. By the end of integration, the tablet version of the Timed 25-Foot Walk was obtained in 89.0% of patients and the 9-Hole Peg Test in 94.8% compared with 74.2% and 64.3%, respectively before implementation. The greatest increase in data capture occurred in processing speed and low-contrast acuity assessments (0% prior vs 78.4% and 36.7%, respectively, following implementation). Four PROMs were administered in 41%-98% of patients compared with a single depression questionnaire with a previous capture rate of 70.6%. Completion rates and time required to complete each NPT improved with subsequent visits. Younger age and lower disability scores were associated with shorter completion time and higher completion rates.

Conclusions: Integration of technology-enabled data capture in routine clinical practice allows acquisition of comprehensive standardized data for use in patient care and clinical research.
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http://dx.doi.org/10.1212/CPJ.0000000000000710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292568PMC
June 2020

Teleneurology as a Solution for Outpatient Care During the COVID-19 Pandemic.

Telemed J E Health 2020 12 16;26(12):1537-1539. Epub 2020 Jun 16.

Cleveland Clinic, Cleveland, Ohio, USA.

The coronavirus disease of 2019 (COVID-19) pandemic and the need for social distancing have dramatically changed health care delivery. There is an urgent need to continue to deliver outpatient care for chronic neurological disease and teleneurology has the potential to fulfill this gap. This study reports the implementation and utilization of teleneurology across all neurological subspecilities during the COVID-19 pandemic. This is a retrospective observational study that identified all in-person and teleneurology outpatient nonprocedural visits from January 5 to April 4, 2020, across neurological specialties at a single academic center. Visit volumes were assessed weekly and practice patterns were compared before and after March 15, 2020, as this was the date of a major statewide stay-at-home order in Ohio. Before March 15 the mean in-person visit per week was 5129.4 and decreased to 866.7 after that date. The mean teleneurology visits per week increased from 209.1 to 2619.3 for the same time period. The overall teleneurology visit volume in the 3 weeks after March 15 increased by 533%. In a relatively short time frame of 3 weeks, a single academic center was able to dramatically increase teleneurology visits to provide outpatient neurological care. This study demonostrates that teleneruology can be a solution for outpatient neurological care in the context of COVID-19. The increased utilization of teleneurology during this crisis has the potential to expand teleneurology and improve access to neurological care in the future outside the pandemic setting.
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http://dx.doi.org/10.1089/tmj.2020.0137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757521PMC
December 2020

Keep the Worms in the Mud.

JAMA Neurol 2020 09;77(9):1066-1067

Mellen Center for Multiple Sclerosis, Department of Neurology, Neurological Institute, Cleveland Clinic, Cleveland, Ohio.

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http://dx.doi.org/10.1001/jamaneurol.2020.0519DOI Listing
September 2020

Imaging Mechanisms of Disease Progression in Multiple Sclerosis: Beyond Brain Atrophy.

J Neuroimaging 2020 05;30(3):251-266

Neuroimaging Unit, Neuroimmunology Division, Department of Neurology, Vanderbilt University Medical Center, Nashville, TN.

Clinicians involved with different aspects of the care of persons with multiple sclerosis (MS) and scientists with expertise on clinical and imaging techniques convened in Dallas, TX, USA on February 27, 2019 at a North American Imaging in Multiple Sclerosis Cooperative workshop meeting. The aim of the workshop was to discuss cardinal pathobiological mechanisms implicated in the progression of MS and novel imaging techniques, beyond brain atrophy, to unravel these pathologies. Indeed, although brain volume assessment demonstrates changes linked to disease progression, identifying the biological mechanisms leading up to that volume loss are key for understanding disease mechanisms. To this end, the workshop focused on the application of advanced magnetic resonance imaging (MRI) and positron emission tomography (PET) imaging techniques to assess and measure disease progression in both the brain and the spinal cord. Clinical translation of quantitative MRI was recognized as of vital importance, although the need to maintain a relatively short acquisition time mandated by most radiology departments remains the major obstacle toward this effort. Regarding PET, the panel agreed upon its utility to identify ongoing pathological processes. However, due to costs, required expertise, and the use of ionizing radiation, PET was not considered to be a viable option for ongoing care of persons with MS. Collaborative efforts fostering robust study designs and imaging technique standardization across scanners and centers are needed to unravel disease mechanisms leading to progression and discovering medications halting neurodegeneration and/or promoting repair.
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http://dx.doi.org/10.1111/jon.12700DOI Listing
May 2020

Determining the effectiveness of early intensive versus escalation approaches for the treatment of relapsing-remitting multiple sclerosis: The DELIVER-MS study protocol.

Contemp Clin Trials 2020 08 19;95:106009. Epub 2020 Apr 19.

Clinical Neurology, Division of Clinical Neuroscience, University of Nottingham, Nottingham, United Kingdom.

Multiple Sclerosis (MS) is a common cause of neurological disability among young adults and has a high economic burden. Currently there are 18 disease modifying agents for relapsing MS, which were tested in clinical trials versus placebo or an active comparator in a pairwise manner. However, there is currently no consensus on the fundamental principles of treatment approach and initial therapy selection. These factors result in variable use of disease modifying therapies. Here we describe the study protocol for Determining the Effectiveness of earLy Intensive Versus Escalation approaches for the Treatment of Relapsing-remitting Multiple Sclerosis (DELIVER-MS). The main objective of the study is to determine whether an early highly effective treatment approach, defined as use of one of four monoclonal antibodies as initial therapy, is more effective than an escalation treatment approach (any other approved medication as initial therapy with subsequent escalation to higher efficacy treatments guided by radiological and clinical evaluation). The primary endpoint of the study is reduction in normalized brain volume loss from baseline visit to month 36 visit using MRI. Brain volume loss was selected as the best short-term predictor of long-term clinical disability. A total of 400 participants will be randomized 1:1 using minimization to account for age and sex by site, and 400 will be enrolled into a parallel observational cohort. The study results will help guide overall treatment philosophy and will have important implications for patient choice, clinical practice, and treatment access.
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http://dx.doi.org/10.1016/j.cct.2020.106009DOI Listing
August 2020

Intrinsic and Extrinsic Mechanisms of Thalamic Pathology in Multiple Sclerosis.

Ann Neurol 2020 07 1;88(1):81-92. Epub 2020 May 1.

Mellen Center for MS Treatment and Research, Neurologic Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.

Objective: Thalamic atrophy is among the earliest brain changes detected in patients with multiple sclerosis (MS) and the degree of thalamic atrophy is a strong predictor of disability progression. The causes of thalamic atrophy are not fully understood. Here, we investigate the contributions of thalamic demyelinated lesions, thalamic neuronal loss, and cerebral white matter (WM) lesions to thalamic volume.

Methods: We used postmortem in situ magnetic resonance imaging (MRI) scans of 95 subjects with MS to correlate thalamic lesion volumes with global MRI metrics. We histologically characterized thalamic demyelination patterns and compared neuronal loss and neuritic pathology in the thalami with the extremes of volume.

Results: Grossly apparent thalamic discolorations in cm-thick brain slices were T2/fluid-attenuated inversion recovery (FLAIR) hyperintense, T1-hypointense, and appeared as perivascular demyelinated lesions with dystrophic neurons/axons. Subependymal demyelinated lesions with axonal loss and microglial/macrophage activation were also observed. The 12 subjects with the least thalamic volume had a 17.6% reduction of median neuronal density in the dorsomedial/ventrolateral and pulvinar nuclei compared with the 14 subjects with the greatest thalamic volume (p = 0.03). After correcting for age, disease duration, sex, and T2 lesion volume, the total (p = 0.20), ovoid (p = 0.31), or subependymal (p = 0.44) MRI thalamic lesion volumes correlated with thalamic volume. Thalamic volume correlated with cerebral T2 lesion volume (Spearman's rho = -0.65, p < 0.001; p < 0.0001 after correcting for age, disease duration, and sex).

Interpretation: Our findings suggest the degeneration of efferent/afferent thalamic projections and/or a neurodegenerative process as greater contributors to thalamic atrophy than thalamic demyelinating lesions. ANN NEUROL 2020 ANN NEUROL 2020;88:81-92.
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http://dx.doi.org/10.1002/ana.25743DOI Listing
July 2020

Fourteen-year serial MRIs of patients with mild and severe courses of MS.

Neurol Clin Pract 2020 Feb;10(1):e5-e6

Department of Biomedical Engineering (KN, EF), Lerner Research Institute, Cleveland Clinic; Mellen Center for Multiple Sclerosis Treatment and Research (RAR, DO, RJF), Neurological Institute, Cleveland Clinic; and Department of Neurosciences (BDT), Lerner Research Institute, Cleveland Clinic, OH. Dr. Rudick is now with Biogen, Cambridge, MA.

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http://dx.doi.org/10.1212/CPJ.0000000000000695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057063PMC
February 2020

Primary CNS lymphoma initially diagnosed as vasculitis.

Neurol Clin Pract 2020 Feb;10(1):84-88

Neurological Institute, Cleveland Clinic, OH.

Purpose Of Review: A vasculitic pattern of injury seen on brain biopsy can be attributed to a multitude of primary or secondary disorders, leading to diagnostic challenges for clinicians.

Recent Findings: This report describes the clinical presentation and histopathologic findings in 2 patients who initially received a diagnosis of primary CNS vasculitis, but did not show long-term response to treatment. In both cases, a second biopsy was performed, and the final diagnosis was primary CNS lymphoma (PCNSL).

Summary: Analyzing diagnostically challenging cases can increase recognition of PCNSL and improve outcomes in this rare condition.
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http://dx.doi.org/10.1212/CPJ.0000000000000693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057073PMC
February 2020

Clinical observation during alemtuzumab administration.

Mult Scler Relat Disord 2020 01 25;37:101412. Epub 2019 Sep 25.

Neurology Group, Division of Clinical Neuroscience, University of Nottingham, C Floor, South Block, Queen's Medical Centre, Nottingham, NG7 2UH, United Kingdom.

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http://dx.doi.org/10.1016/j.msard.2019.101412DOI Listing
January 2020

Detection of central vein should be part of MS diagnostic criteria - Yes.

Mult Scler 2020 04 3;26(4):405-406. Epub 2020 Mar 3.

Mellen Center for Multiple Sclerosis, Cleveland Clinic, Cleveland, OH, USA.

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http://dx.doi.org/10.1177/1352458520908176DOI Listing
April 2020

Controversial association between leptomeningeal enhancement and demyelinated cortical lesions in multiple sclerosis.

Mult Scler 2020 02;26(2):135-136

Cleveland Clinic, Mellen Center for Multiple Sclerosis, Cleveland, OH, USA.

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http://dx.doi.org/10.1177/1352458519892186DOI Listing
February 2020

Palatal myoclonus, abnormal eye movements, and olivary hypertrophy in GAD65-related disorder.

Neurology 2020 02 31;94(6):273-275. Epub 2019 Dec 31.

From the Mellen Center for Multiple Sclerosis Treatment and Research (G.M., M.A.W., D.O., J.A.C.), Neurological Institute, Cleveland Clinic; Center for Neurorestoration (H.F.), Neurological Institute, Cleveland Clinic; Neuroradiology Department (S.K., S.E.J.), Imaging Institute, Cleveland Clinic; and Neuromuscular Center (E.P.P.), Neurological Institute, Cleveland Clinic, OH.

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http://dx.doi.org/10.1212/WNL.0000000000008926DOI Listing
February 2020

Pregnancy and multiple sclerosis: Risk of unplanned pregnancy and drug exposure in utero.

Mult Scler J Exp Transl Clin 2019 Oct-Dec;5(4):2055217319891744. Epub 2019 Dec 12.

Mellen Center for MS Treatment and Research, Cleveland Clinic, United States of America.

Background: Multiple sclerosis is a central nervous system demyelinating disease that affects women of reproductive potential. It is important to identify the frequency and risk factors of unplanned or disease-modifying therapy-exposed pregnancies to create interventions to reduce these.

Methods: This retrospective, single-center, observational chart review study aims to identify risk factors for unplanned pregnancy to identify a target population for family counseling.

Results: In total, 63 live births in 45 patients (20 unplanned and 43 planned) were analyzed. The percentage of unplanned pregnancy was 32%. The proportion of those receiving family planning counseling was lower in the patients with unplanned pregnancies ( < 0.001). The main risk factors for unplanned pregnancy were younger age ( = 0.004), disease-modifying therapy exposure ( < 0.001), and being unmarried ( < 0.001). Overall, 16 pregnancies had disease-modifying therapy exposure and in a subsequent study the risk for disease-modifying therapy exposure was unplanned status ( < 0.001). Birth outcomes were not different between groups. There were more enhancing lesions in the post-partum magnetic resonance imaging of women with planned pregnancy ( < 0.04).

Conclusion: Prevention of unplanned pregnancy could lead to less disease-modifying therapy exposed pregnancies. This study suggests a targeted intervention of family planning counseling in younger, unmarried multiple sclerosis patients could potentially lead to less unintended in utero disease-modifying therapy exposure.
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http://dx.doi.org/10.1177/2055217319891744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6909269PMC
December 2019

Technology-enabled comprehensive characterization of multiple sclerosis in clinical practice.

Mult Scler Relat Disord 2020 Feb 14;38:101525. Epub 2019 Nov 14.

Mellen Center for Multiple Sclerosis, Cleveland Clinic, Cleveland, OH, United States. Electronic address:

Background: Objective and longitudinal measurements of disability in patients with multiple sclerosis (MS) are desired in order to monitor disease status and response to disease-modifying and symptomatic therapies. Technology-enabled comprehensive assessment of MS patients, including neuroperformance tests (NPTs), patient-reported outcome measures (PROMs), and MRI, is incorporated into clinical care at our center. The relationships of each NPT with PROMs and MRI measures in a real-world setting are incompletely studied, particularly in larger datasets.

Objectives: To demonstrate the utility of comprehensive neurological assessment and determine the association between NPTs, PROMs, and quantitative MRI measures in a large MS clinical cohort.

Methods: NPTs (processing speed [PST], contrast sensitivity [CST], manual dexterity [MDT], and walking speed [WST]) and physical disability-related PROMs (Quality of Life in Neurological Disorders [Neuro-QoL], Patient Determined Disease Steps [PDDS], and Patient-Reported Outcomes Measurement Information System Global-10 [PROMIS-10] physical) were collected as part of routine clinical care. Fully-automated MRI analysis calculated T2-lesion volume (T2LV), whole brain fraction (WBF), thalamic volume (TV), and cervical spinal cord cross-sectional area (CA) for brain MRIs completed within 3 months of a clinic visit during which NPTs and PROMs were assessed. Spearman's rank correlation coefficients evaluated the cross-sectional associations of NPTs with PROMs and MRI measures. Linear regression was utilized to determine which combination of clinical characteristics, patient demographics, MRI measures, and PROMs best cross-sectionally explained each NPT result.

Results: 997 unique patients (age 47.7 ± 11.4 years, 71.8% female) who underwent assessments over a 2-year period were included. Correlations among NPTs and PROMs were moderate. PST correlations were strongest for Neuro-QoL upper extremity (NQ-UE) (Spearman's rho = 0.43) and lower extremity (NQ-LE) (0.47). CST correlations were strongest for NQ-UE (0.33), NQ-LE (0.36), and PDDS (-0.31). MDT correlations were strongest for NQ-UE (-0.53), NQ-LE (-0.54), and PDDS (0.53). WST correlations were strongest for PDDS (0.64) and NQ-LE (-0.65). NPTs also had moderate correlations with MRI metrics, the strongest of which were observed with PST (with T2LV (-0.44) and WBF (0.49)). Spearman's rho for other NPT-MRI correlations ranged from 0.23 to 0.36. Linear regression identified age, disease duration, PROMIS-10 physical, NQ-UE, NQ-LE, T2LV and WBF as significant cross-sectional explanatory variables for PST (adjusted R=0.46). For CST, significant variables included age and NQ-LE (adjusted R = 0.30). For MDT, significant variables included PDDS, PROMIS-10 physical, NQ-UE, NQ-LE, T2LV, and WBF (adjusted R=0.37). For WST, significant variables included sex, PDDS, NQ-LE, T2LV, and CA (adjusted R=0.39).

Conclusions: Impaired performance on NPTs correlated with worse physical disability-related PROMs and MRI disease severity, but the strongest cross-sectional explanatory variables for each NPT component varied. This study supports the use of comprehensive, objective quantification of MS status in clinical and research settings. Future longitudinal analyses can determine predictors of treatment response and disability worsening.
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http://dx.doi.org/10.1016/j.msard.2019.101525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943942PMC
February 2020

Serum neurofilament light chain concentration in a phase 1/2 trial of autologous mesenchymal stem cell transplantation.

Mult Scler J Exp Transl Clin 2019 Oct-Dec;5(4):2055217319887198. Epub 2019 Nov 5.

Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, USA.

Background: Serum neurofilament light chain concentration is a proposed biomarker of axonal injury in multiple sclerosis. Mesenchymal stem cells have anti-inflammatory and repair-promoting activities, making them of interest for potential multiple sclerosis treatment.

Objectives: The purpose of this study was to assess correlation of serum neurofilament light chain concentration and measures of multiple sclerosis disease activity/severity, longitudinal stability of serum neurofilament light chain concentration, and treatment effect of mesenchymal stem cell transplantation on serum neurofilament light chain concentration.

Methods: Twenty-four multiple sclerosis patients underwent intravenous infusion of autologous mesenchymal stem cells. Clinical assessments, serum collection, and brain magnetic resonance imaging were performed at months -1, 0 (transplant), 1, 3, and 6. Matched control serum was collected once ( = 10). Serum neurofilament light chain concentration was measured by single-molecule array. Serum neurofilament light chain concentration correlations with disease measures were analyzed by Spearman correlations and linear mixed effect models. Pre-post transplant serum neurofilament light chain concentration was compared by Wilcoxon signed rank testing.

Results: There were significant (<0.01) correlations between serum neurofilament light chain concentration and gadolinium-enhancing lesion number (rho = 0.55) and volume (rho = 0.65), and new/enlarging T2 lesions (rho = 0.65). Patients without disease activity had lower fluctuation in serum neurofilament light chain concentration ( = 0.01). Mean pre- versus post-treatment serum neurofilament light chain concentration values were not significantly different.

Conclusions: Serum neurofilament light chain concentration correlated with magnetic resonance imaging measures of disease activity cross sectionally and longitudinally, and was stable in patients without disease activity. There was no clear treatment effect of mesenchymal stem cell transplantation on serum neurofilament light chain concentration.
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http://dx.doi.org/10.1177/2055217319887198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6831979PMC
November 2019

Pragmatic clinical trials for treating relapsing multiple sclerosis.

Lancet Neurol 2019 12;18(12):1075

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.

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http://dx.doi.org/10.1016/S1474-4422(19)30386-2DOI Listing
December 2019

Prevalence of multiple sclerosis in Cuenca, Ecuador.

Mult Scler J Exp Transl Clin 2019 Oct-Dec;5(4):2055217319884952. Epub 2019 Oct 30.

Department of Neurology, Carlos Andrade Marín Hospital, Ecuador.

Background: Cuenca, a city in the Andean Region of southern Ecuador, has 591,996 inhabitants. A decade-old study showed the prevalence of multiple sclerosis in Cuenca was 0.75 cases per 100,000 inhabitants but no new epidemiological studies in this city have been performed since then. The aim of this study, conducted in 2016, was to update the prevalence records of multiple sclerosis in Cuenca.

Methods: We performed a descriptive cross-sectional study in which we investigated prevalence rates in November of 2016. We estimated the prevalence of multiple sclerosis by cross-matching registries from the two neurological referral hospitals in Cuenca.

Results: A total of 23 records were obtained from the two sources. The estimated prevalence was 3.88 per 100,000 inhabitants (95% confidence interval: 3.83-3.94). The disease was predominant among women (60%). The mean age of this cohort was 37 years (standard deviation ±12.4). Of the cases, 78% were relapsing-remitting multiple sclerosis. The mean Expanded Disability Status Scale score was 2.5.

Conclusions: This study is an update to the first study conducted 10 years ago and shows the prevalence of multiple sclerosis in Cuenca has increased. However, the prevalence of multiple sclerosis is still low and very similar to that reported in neighbouring countries.
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http://dx.doi.org/10.1177/2055217319884952DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6822194PMC
October 2019

Comparative discontinuation, effectiveness, and switching practices of dimethyl fumarate and fingolimod at 36-month follow-up.

J Neurol Sci 2019 Dec 15;407:116498. Epub 2019 Oct 15.

Lou Ruvo Center for Brain Health, Cleveland Clinic, Las Vegas, NV, United States. Electronic address:

Background: Dimethyl fumarate (DMF) and fingolimod (FTY) are approved oral disease modifying therapies (DMTs) for relapsing multiple sclerosis (MS). There are currently no known head-to-head studies comparing DMF and FTY over 36 months, which leaves their relative effectiveness unknown.

Objective: To assess real-world discontinuation, effectiveness, and switching practices of DMF and FTY over 36 months along with disease activity after switching DMT.

Methods: Patients prescribed DMF (n = 737) and FTY (n = 535) from two academic MS centers were retrospectively reviewed. Discontinuation and effectiveness outcomes were assessed using propensity score (PS) weighting. PS model covariates included sociodemographics and clinical and MRI characteristics.

Results: Discontinuation was more common in DMF (58.3%) versus FTY (45.2%) over 36 months [OR = 1.81, 95% CI (1.41-2.31), p < .001], largely driven by intolerance [OR = 1.63, 95% CI (1.18-1.73), p < .001]. There were no differences in clinical relapses [OR = 1.27, 95% CI (0.90-1.79), p = .17], gadolinium-enhancing (GdE) lesions [OR = 1.25, 95% CI (0.85-1.84), p = .26], or new T2-hyperintense lesions [OR = 0.99, 95% CI (0.74-1.32), p = .93]. Within 12 months of DMF/FTY discontinuation, switchers to highly effective therapy (HET) versus other DMTs (injectables/orals) had fewer relapses (DMF/HET, 5.9% versus DMF/Other, 14.2%, p = .03; FTY/HET, 11.6% versus FTY/Other, 18.0%, p = .04) and fewer GdE lesions post-FTY (DMF/HET, 10.3% versus DMF/Other, 14.3%, p = .36; FTY/HET, 11.9% versus FTY/Other, 21.5%, p = .04).

Conclusion: This combined analysis showed similar effectiveness for DMF and FTY over 36 months with higher DMF discontinuations. Disease activity was lower in switchers to HET versus injectable/oral therapies after DMF/FTY cessation.
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http://dx.doi.org/10.1016/j.jns.2019.116498DOI Listing
December 2019

Tuberculosis screening in multiple sclerosis: effect of disease-modifying therapies and lymphopenia on the prevalence of indeterminate TB screening results in the clinical setting.

Mult Scler J Exp Transl Clin 2019 Jul-Sep;5(3):2055217319875467. Epub 2019 Sep 11.

Mellen Center for Multiple Sclerosis, Cleveland Clinic, USA.

Background: Tuberculosis screening is recommended in multiple sclerosis patients starting certain disease-modifying therapies. Disease-modifying therapies may affect interferon-gamma release assay results.

Objective: To determine the effects of multiple sclerosis disease-modifying therapies on interferon-gamma release assay results.

Methods: Indeterminate interferon-gamma release assay results among multiple sclerosis patients were compared across disease-modifying therapies by Fisher's exact test. Logistic regression evaluated the effects of lymphopenia on interferon-gamma release assay results.

Results: A total of 1058 patients underwent interferon-gamma release assay: 2.0% (21) positive, 6.1% (65) indeterminate, with 59.4% (628) on disease-modifying therapies. Results were significantly different across disease-modifying therapies ( = 0.002). Absolute lymphocyte count less than 0.5 k/μL had 9.39 times (95% confidence interval 5.2-17.0) increased odds of indeterminate interferon-gamma release assay results.

Conclusions: Disease-modifying therapies affecting lymphocytes had a higher risk of indeterminate interferon-gamma release assay results.
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http://dx.doi.org/10.1177/2055217319875467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6740049PMC
September 2019

Vitamin D and MRI measures in progressive multiple sclerosis.

Mult Scler Relat Disord 2019 Oct 13;35:276-282. Epub 2019 Aug 13.

Mellen Center for Multiple Sclerosis, Cleveland Clinic Foundation, Cleveland, OH, USA. Electronic address:

Background: Vitamin D deficiency is a proposed risk factor for multiple sclerosis (MS), but its role in progressive MS is not well understood.

Objective: To examine the association between vitamin D levels and MRI features in primary progressive (PPMS) and secondary progressive MS (SPMS).

Methods: Serum 25-hydroxyvitamin D (25[OH]D) and 25-hydroxyvitamin D (25[OH]D) levels were obtained from 267 subjects enrolled into the Secondary and Primary Progressive Ibudilast NeuroNEXT Trial in Multiple Sclerosis (SPRINT-MS). Associations between imaging data and vitamin D levels was determined using Pearson or Spearman correlation and multivariate regression analyses.

Results: 267 patients (age 55.6 ± 7.4, 47.2% male, and 51.3% PPMS) were evaluated with quantitative MRI and vitamin D levels. 25(OH)D and 25(OH)D were similar between PPMS and SPMS. There was no significant association between vitamin D and T1/2 lesion volume and brain parenchymal fraction. Modest associations were found between 25(OH)D and whole brain-magnetization transfer ratio (WB-MTR, r = 0.17, p = 0.007) and normal appearing grey matter MTR (NAGM-MTR, r = 0.15, p = 0.02).

Conclusions: 25(OH)D levels were not associated with brain volume or lesional measures in progressive MS contrary to what has been described in relapsing remitting MS. An association between WB-MTR and NAGM-MTR suggest higher vitamin D levels may exert a protective role on myelin content in progressive MS.
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http://dx.doi.org/10.1016/j.msard.2019.08.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6830523PMC
October 2019