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The University of California, San Diego Brief Assessment of Capacity to Consent (UBACC) is a tool to assess the capacity of participants to consent in psychiatric research. However, little is known about the psychometric properties in low and middle-income countries. This study aimed to examine the psychometric properties of the UBACC. We examined the reliability, latent factor structure, and item response of the first attempt of the UBACC items in a sample of 32,208 adults (16,467 individuals with psychosis and 15,741 controls) in Ethiopia, Kenya, South Africa, and Uganda; exploring these properties in the full sample and stratified by country, diagnostic status, sex, and ethnolinguistic language groups. Exploratory factor analysis (EFA) suggested a two-factor model for the overall sample. However, a three-factor model was more appropriate when examining the latent structure across country, language, and sex. Confirmatory factor analyses (CFA) revealed an adequately fitting three-factor model for the full sample and across country, sex, and language. A two-factor model, however, was more appropriate for English and Amharic languages. Across all groups, the internal consistency of the UBACC was low, indicating below-threshold reliability (Cronbach's α (95 % CI = 0.58 (0.57–0.59). Using a multidimensional item-response theory framework for the full sample revealed that UBACC item 8, measuring understanding of the benefits of study participation, was the most discriminating item. Many of the other items had below-threshold discriminating characteristics. EFA and CFA converged towards a two and three-dimensional structure for the UBACC, in line with the developers of the original scale. The differences in properties between populations and language groups, low internal consistency, and below-threshold item functioning suggest that investigations into the cultural and linguistic nuances are still warranted. Understanding the utility of consent tools, such as the UBACC, in underrepresented populations will be a part of the larger process which ensures that research participants are adequately protected. • This study assessed the UBACC tool's psychometric properties for consent capacity in psychiatric research. • The study included 32,208 adults from Ethiopia, Kenya, South Africa, and Uganda. • Results indicated low internal consistency across groups, even after removing non-salient items. • Exploratory and confirmatory factor analyses revealed varying structures, with an acceptable two-factor model overall. • Item analysis highlighted the need for cultural and linguistic considerations in consent tools for diverse populations. [ABSTRACT FROM AUTHOR]

Background: Genome‐wide association studies (GWAS) of Alzheimer's disease (AD) have implicated microglia in AD pathogenesis, and microglia is a promising cellular therapeutic target in AD. However, it remains unclear when and how AD genetic risk localizing to microglia contributes to AD pathophysiology. Method: Participants are from two community‐based cohorts (Religious Orders Study, the Rush Memory and Aging Project [ROSMAP]; n = 299 deceased; age 88.9±7.1, female 67%) and the screening phase of an AD prevention trial (the Anti‐Amyloid Treatment in Asymptomatic Alzheimer's study [A4]; n = 2919 cognitively unimpaired; age 71.4±4.8, female 60%). We quantified post‐mortem Aβ and tau in ROSMAP, and used PET to quantify Aβ (florbetapir cortical composite standardized uptake value ratio [SUVR]) and tau (flortaucipir temporal composite SUVR; subset n = 302) in A4. In a subset of ROSMAP participants (n = 31), we evaluated the proportion of activated microglia (PAM) in post‐mortem neocortex. We combined AD GWAS summary statistics with cellular gene expression profiles from human brain single nucleus sequencing, to derive cell‐type‐specific ADPRS (excluding APOE region) in ROSMAP and A4. We assessed the association of each (standardized) cell‐type‐specific ADPRS with AD pathology (linear regression; adjusting for APOE genotypes, age, sex, and first 10 genotype principal components), and examined the correlation between the microglial ADPRS and PAM (Pearson's correlation). We used Bonferroni‐corrected p‐value threshold, p<6.25×10−3. Result: Microglial, astrocytic, and endothelial ADPRS were associated with higher Aβ and tau in ROSMAP (Figure 1A‐B). In A4, microglial ADPRS showed the strongest association with Aβ (beta = 0.017, p = 1.6×10−7; Figure 1C), while the association of all other cell‐type‐specific ADPRS with Aβ were no longer significant once adjusted for microglial ADPRS (all p>0.05). Microglial ADPRS showed a suggestive association with temporal composite tau (beta = 0.033, p = 0.012; Figure 1D), even after additionally adjusting for Aβ (beta = 0.024, p = 0.048). Microglial ADPRS was positively correlated with PAM in ROSMAP (Figure 2). Conclusion: Genetic risk of AD localizing to microglial genes may contribute to Aβ and tau accumulation and microglial activation, likely starting from the preclinical (cognitively unimpaired) stage. These findings directly connect aggregate microglial AD genetic risk with Aβ and tau accumulation, and provide a genetic rationale to test microglia‐specific interventions in AD prevention trials. [ABSTRACT FROM AUTHOR]

Background: Posttraumatic stress disorder (PTSD) is associated with higher risk of certain chronic diseases, including ovarian cancer, but underlying mechanisms remain unclear. Although prior work has linked menopausal hormone therapy (MHT) use with elevated ovarian cancer risk, little research considers PTSD to likelihood of MHT use. We examined whether PTSD was prospectively associated with greater likelihood of initiating MHT use over 26 years. Methods: Using data from the Nurses' Health Study II, with trauma and PTSD (symptoms and onset date) assessed by screener in 2008 and MHT assessed via biennial survey (from 1989), we performed Cox proportional regression models with women contributing person-years from age 36 years. Relevant covariates were assessed at biennial surveys. We considered potential effect modification by race/ethnicity, age at baseline, and period (1989-2002 vs. 2003-2015). Results: Over follow-up, 22,352 of 43,025 women reported initiating MHT use. For example, compared with women with no trauma, the HR for initiating MHT was 1.18 for those with trauma/1-3 PTSD symptoms [95% confidence interval (CI), 1.13-1.22] and 1.31 for those with trauma/4-7 PTSD symptoms (95% CI, 1.25-1.36; P trend < 0.001), adjusting for sociodemographic factors. Associations were maintained when adjusting for reproductive factors and health conditions. We found evidence of effect modification by age at baseline. Conclusions: Trauma and number of PTSD symptoms were associated with greater likelihood of initiating MHT use in a dose-response manner. [ABSTRACT FROM AUTHOR]

Introduction The brain-derived neurotrophic factor (BDNF) interacts with important genetic Alzheimer's disease (AD) risk factors. Specifically, variants within the SORL1 gene determine BDNF's ability to reduce amyloid β (Aβ) in vitro. We sought to test whether functional BDNF variation interacts with SORL1 genotypes to influence expression and downstream AD-related processes in humans. Methods We analyzed postmortem brain RNA sequencing and neuropathological data for 441 subjects from the Religious Orders Study/Memory and Aging Project and molecular and structural neuroimaging data for 1285 subjects from the Alzheimer's Disease Neuroimaging Initiative. Results We found one SORL1 RNA transcript strongly regulated by SORL1 - BDNF interactions in elderly without pathological AD and showing stronger associations with diffuse than neuritic Aβ plaques. The same SORL1 - BDNF interactions also significantly influenced Aβ load as measured with [ 18 F]Florbetapir positron emission tomography. Discussion Our results bridge the gap between risk and resilience factors for AD, demonstrating interdependent roles of established SORL1 and BDNF functional genotypes. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's Disease (AD) affects millions globally, but therapy development is lagging. The dearth of new therapies requires a reconsideration of pre‐clinical models of AD to facilitate the discovery of efficacious treatments. Ideally, such models would allow for monitoring the functional behavior of neurons in conditions approximating the AD brain. Methods: Towards the goal of developing more representative, pre‐clinical AD models, we employ multiple‐electrode arrays (MEAs) and live‐cell imaging for assessing neuronal firing and neurite integrity (NI), respectively. We use this system to examine changes in neuronal activity and neurite integrity following treatment with TBS‐soluble human brain extract from a panel of 43 individuals comprised of AD patients, unaffected persons not exhibiting AD pathology nor cognitively impaired, and individuals not cognitively impaired but exhibited AD‐related postmortem pathology. To determine the molecular etiology of these functional changes in an unbiased manner, we perform label‐free proteomic analyses on the panel of 43 brain extracts. Results: Amyloid‐β (Aβ) and tau accumulate in the AD brain, and specific forms of each of these proteins have shown neurotoxic properties. We observe associations between spontaneous activity and Aβ42:40 levels, and between neurite integrity and oligomeric Aβ or tau containing N inserts. Additionally, the proteomic analyses reveal several candidates whose expression correlated with changes in neuronal structure and activity. Proteins associated with neurotoxic activities in MEA and NI assays are enriched in proteins implicated in lysosomal storage disorders, while proteins associated with neuroprotective properties are enriched in proteins of the WAVE regulatory complex that are involved in the regulation of actin polymerization. We further show that elevated GM2A in the AD brain and AD CSF is associated with reductions in both neurite integrity and MEA activity. Applying cell derived GM2A in the absence of brain extract is sufficient to induce a subtle but significant loss of neurite integrity. Conclusion: The techniques and data herein introduce a system for modeling neuronal vulnerability in response to factors present in the aged human brain and provide insights into proteins potentially contributing to AD pathogenesis. [ABSTRACT FROM AUTHOR]

Introduction We investigated the change in DNA methylation in peripheral blood CD4+ lymphocytes over time, examined the relation between CD4+ lymphocytes and brain methylation, and compared their associations with AD pathology. Methods Genome-wide methylation was measured three times in 41 older persons using Illumina Infinium HumanMethylation450 array. The two CD4+ lymphocytes measures were at study baseline and proximate to death. Brain tissue came from frozen dorsolateral prefrontal cortex. Results Global methylation features were conserved across tissue. At individual CpG sites, methylation level was concordant between the two CD4+ lymphocytes but more diffuse between CD4+ lymphocytes and brain. Previous associations of brain methylation with neuritic plaques at target methylation sites were not replicated in CD4+ lymphocytes. Discussion There is no strong evidence of change in CD4+ lymphocytes methylation among older persons over an average of 7.5 years. Methylation associations with AD pathology found in neocortex are not directly reflected in CD4+ lymphocytes. [ABSTRACT FROM AUTHOR]

Background: Conventional polygenic risk score (PRS) summarizes genetic risk throughout the genome and lacks biological specificity. Here, leveraging human brain single nucleus RNA sequencing (sNuc‐Seq) data, we introduce a new method to capture cell‐type specific Alzheimer's disease (AD) PRS, and implicate different cell types in distinct disease processes in preclinical AD. Method: Cognitively unimpaired (CU) older adults of European descent who participated in the Anti‐Amyloid Treatment in Asymptomatic Alzheimer's (A4) study screening PET were included in this study. Cortical amyloid‐β burden (Aβ) was quantified as cortical composite SUVR from the florbetapir PET. Screening cognition was measured with Preclinical Alzheimer Cognitive Composite (PACC). We defined cell type‐specific genes as genes expressed higher in a given cell type (FDR<0.05) compared to other cell types in a published human neocortex sNucSeq study, for eight major cell types identified from the same study. Published AD genome‐wide association study results were processed with PRS‐CS to infer posterior effect size of each genetic variant, and we derived cell type‐specific ADPRS by weighted summation and standardization of the genetic risk of AD localized to cell type‐specific genes. We excluded the APOE region from ADPRS, and adjusted for APOE ε4, ε2, age, sex, and the first three genotype principal components in all analyses. Result: In CU older adults from the A4 screen data (n=2961; 71.3±4.8 years old), microglia‐specific ADPRS had the strongest association with higher Aβ (beta=0.018, p=2.0×10‐8), while neuron‐specific ADPRSs showed weaker associations (Figure 1A). By contrast, excitatory neuron‐specific ADPRS had the strongest association with lower PACC (additionally adjusted for years of education; beta=‐0.16, p=1.0×10‐4; Figure 1B), and this association remained significant even after adjusting for Aβ (beta=‐0.14, p=6.1×10‐4). The excitatory neuron‐specific ADPRS was negatively associated with years of education (beta=‐0.12, p=0.018), suggesting a shared heritability between neuron‐specific AD risk and lower cognitive reserve. Conclusion: These results further implicate microglia in fibrillar Aβ accumulation and support the neuronal role in cognitive reserve. Cell type‐specific ADPRSs derived using our novel method demonstrate specific relationships with AD pathology and cognition, and may improve power to predict progression during the preclinical stages of AD. [ABSTRACT FROM AUTHOR]

• Severe optic neuritis is seen in disorders including neuromyelitis optica spectrum disorder • Acute treatment for patients with severe optic neuritis of unclear etiology is not clear • Patients with severe optic neuritis of unknown cause may benefit from treatment escalation to PLEX Severe optic neuritis (ON) is an acute inflammatory attack of the optic nerve(s) leading to severe visual loss that may occur in isolation or as part of a relapsing neuroinflammatory disease, such neuromyelitis optica spectrum disorder (NMOSD), myelin oligodendrocyte glycoprotein antibody associated disease (MOGAD), or more rarely multiple sclerosis (MS). In cases of first-ever severe ON of uncertain etiology best treatment strategies remain unclear. We reviewed records of all patients with a documented diagnosis of ON between 2004 and 2019 at Mass General Brigham (MGB) and Johns Hopkins University (JHU) hospitals. Out of 381 patients identified, 90 (23.6%) satisfied the study criteria for severe ON with visual acuity (VA) equal to or worse than 20/200 (logMAR=1) at nadir in the affected eye and had sufficient follow-up data. Treatment strategies with corticosteroids only or treatment escalation with therapeutic plasma exchange (PLEX) after steroids were compared and evaluated for differences in visual outcomes at follow-up. Of the 90 patients with severe optic neuritis, 71(78.9%) received corticosteroids only, and 19 (17.0%) underwent PLEX following corticosteroids. Of the 71 patients who received steroids without escalation to PLEX, 30 patients (42.2%) achieved complete recovery (VA 20/20 on the affected eye), whereas 35 (49.3%) had a partial recovery and 6 (8.4%) had no recovery. Among the 19 corticosteroid non-responders patients who underwent escalation treatment, 13 (68.4%) made complete recovery, 6 (31.6%) had partial visual recoveries (p=0.0434). The median delta logMAR of patients who underwent escalation of care was -1.2 compared with 2.0 for the ones who did not (p=0.0208). A change of delta logmar 2.0 is equivalent of going from hand motion to light perception and the positive delta value refers to intra-attack worsening. Other than not responding to steroids, patients who underwent PLEX tended to have more severe ON with significantly worse nadir visual acuity compared with those who received corticosteroids alone (logMAR 3.12 (min 2.0 – max 5.0) vs. 2.17 (min 1.3 – max 3.0); p=0.004). In our cohort of first-ever severe optic neuritis of unknown etiology, patients that did not respond adequately to corticosteroids benefited from treatment escalation to PLEX, followed in most cases by Rituximab, regardless of final etiology. Randomized controlled trials are needed to confirm the best treatment strategies. [ABSTRACT FROM AUTHOR]

Abstract: Background: Substantial interindividual variability exists in the disease trajectories of Alzheimer's disease (AD) patients. Some decline rapidly whereas others decline slowly, and there are no known explanations for this variability. We describe the first genome-wide association study to examine rate of cognitive decline in a sample of AD patients with longitudinal measures of cognition. Methods: The discovery sample was 303 AD cases recruited in the Alzheimer’s Disease Neuroimaging Initiative and the replication sample was 323 AD cases from the Religious Orders Study and Rush Memory and Aging Project. In the discovery sample, Alzheimer's Disease Assessment Scale–cognitive subscale responses were tested for association with genome-wide single-nucleotide polymorphism (SNP) data using linear regression. We tested the 65 most significant SNPs from the discovery sample for association in the replication sample. Results: We identified SNPs in the spondin 1 gene (SPON1), the minor alleles of which were significantly associated with a slower rate of decline (rs11023139, P = 7.0 × 10−11) in the discovery sample. A SPON1 SNP 5.5 kb upstream was associated with decline in the replication sample (rs11606345, P = .002). Conclusion: SPON1 has not been previously associated with AD risk, but is plausibly related because the gene product binds to the amyloid precursor protein and inhibits its cleavage by β-secretase. These data suggest that SPON1 may be associated with the differential rate of cognitive decline in AD. [Copyright &y& Elsevier]

Objectives: Early recurrence of cerebral ischemia in acutely symptomatic carotid artery stenosis can precede revascularization. The optimal antithrombotic regimen for this high-risk population is not well established. Although antiplatelet agents are commonly used, there is limited evidence for the use of anticoagulants. We sought to understand the safety and efficacy of short-term preoperative anticoagulants in secondary prevention of recurrent cerebral ischemic events from acutely symptomatic carotid stenosis in patients awaiting carotid endarterectomy (CEA).Materials and Methods: A retrospective query of a prospective single institution registry of carotid revascularization was performed. Patients who presented with acute ischemic stroke or transient ischemic attack (TIA) attributable to an ipsilateral internal carotid artery stenosis (ICA) were included. Antiplatelet (AP) only and anticoagulation (AC) treatment arms were compared. The primary outcome was a composite of preoperative recurrent ischemic stroke or TIA. The primary safety outcome was symptomatic intracranial hemorrhage.Results: Out of 443 CEA patients, 342 were in the AC group and 101 in the AP group. Baseline characteristics between groups (AC vs AP) were similar apart from age (71±10.5 vs 73±9.5, p=0.04), premorbid modified Rankin scale (mRS) score (1.0±1.2 vs 1.4±1.3, p=0.03) and stroke as presenting symptom (65.8 vs 53.5%, p=0.02). Patients in the AC group had a lower incidence of recurrent stroke/TIA (3.8 vs 10.9%, p=0.006). One patient had symptomatic intracranial hemorrhage in the AC group, and none in the AP group. In multivariate analysis controlling for age, premorbid mRS, stroke severity, degree of stenosis, presence of intraluminal thrombus (ILT) and time to surgery, AC was protective (OR 0.30, p=0.007). This effect persisted in the cohort exclusively without ILT (OR 0.23, p=0.002).Conclusions: Short term preoperative anticoagulation in patients with acutely symptomatic carotid stenosis appears safe and effective compared to antiplatelet agents alone in the prevention of recurrent cerebral ischemic events while awaiting CEA. [ABSTRACT FROM AUTHOR]

Background: The development of robust blood‐based biomarkers for pathological and clinical characterization of Alzheimer's disease (AD) is necessary, particularly as therapeutic approaches shift towards early intervention. Novel, ultra‐sensitive OlinkTM technology allows for high‐throughput quantification of protein signatures in biofluids. In this study, we examined the utility of this technology to identify plasma biomarkers associated with longitudinal cognitive performance in individuals presenting with mild cognitive impairment (MCI). Methods: 60 participants from the Massachusetts ADRC Longitudinal Cohort with a clinical diagnosis of MCI, baseline global CDR of 0.5, and at least five annual follow‐up evaluations were classified into two groups based on their global CDR trajectory: MCI‐decline (an increase in global CDR from 0.5 to 1) and MCI‐stable (no change in global CDR). Five OlinkTM Proximity Extension Assay (PEA) panels were assessed for technical reliability and used to quantify 460 plasma proteins at baseline visit. We built statistical models to identify proteins whose plasma levels were predictive of future cognitive decline, and used machine‐learning to evaluate the utility of these proteins for predicting conversion from MCI to dementia, relative to clinical and demographic predictors. Result: OlinkTM panels exhibited excellent technical precision and plate‐to‐plate replication. Of the 460 proteins measured, 60 did not pass quality control thresholds. A final model adjusting for age and sex identified 14 proteins with a significant fold‐change in MCI‐decline compared to MCI‐stable (p<0.05), including NfL, CX3CL1, M‐CSF, VEGF‐A, IL‐8, NOS3, TNFRSF12A, and PHOSPHO1. An additional 10 proteins approached significance (p<0.1), primarily representative of inflammatory and vascular processes. Addition of these proteins to a supervised classification model informed by baseline cognitive measured substantially improved the overall accuracy from 63% to 83.3% (AUC: 0.88, sensitivity: 0.76, specificity: 0.87). Conclusion: Our findings suggest that plasma biomarkers of neuroinflammation and vascular injury have value as predictors of MCI‐to‐dementia progression. These circulating biomarkers may reflect CNS processes, blood‐brain barrier dysfunction, and/or systemic inflammation that drive AD associated pathophysiologies, or represent comorbid vascular pathologies. Developing a plasma biomarker panel could aid in prognostic deliberations by identifying MCI individuals at higher risk of progressing to dementia in clinical practice. [ABSTRACT FROM AUTHOR]

Objective: Rheumatoid arthritis (RA) is associated with an increased prevalence of coronary artery disease (CAD). We investigated the presenting symptoms of CAD, coronary anatomy (single versus multi-vessel CAD), and treatment among a group of subjects undergoing percutaneous coronary intervention (PCI) with angioplasty and/or stenting. Methods: We evaluated a retrospective cohort of 43 RA subjects and 43 matched non-RA subjects undergoing PCI at 2 academic referral centers. RA subjects were matched to non-RA subjects on age, gender, history of coronary artery bypass grafting, date of PCI, and interventional cardiologist. We compared cardiac risk factors, presentation, treatment, and outcomes. Results: The mean age of the study cohort was 71 ± 10 years, and the distribution of traditional cardiac risk factors was similar in the subjects with RA compared with the matched non-RA subjects (all P values > 0.05). Seventy-four percent of subjects with RA compared with 67% of those without RA presented with an acute coronary syndrome before PCI (P = 0.48). All subjects in this cohort undergoing PCI had at least 1 stenosis in a major epicardial vessel and similar percentages of subjects with RA (44%) and without RA (40%) had multi-vessel CAD (P = 0.66). The administration of cardiac medications both at PCI and at hospital discharge was not different among subjects with RA compared with matched non-RA subjects. Conclusions: Among this cohort with significant CAD undergoing PCI, clinical characteristics, presentation, severity of CAD, treatment modalities, and outcomes were similar in subjects with RA and well-matched non-RA subjects. [Copyright &y& Elsevier]

• We characterize a new radiologically isolated syndrome (RIS) cohort in the US. • Approximately a third of RIS patients started an MS disease modifying therapy (DMT). • The DMT-treated group had a significantly greater number of recognized risk factors. • DMTs were most commonly initiated due to new T2-hyperintense lesions. • The average time to clinically evident disease was approximately 3.4 years. Radiologically Isolated Syndrome (RIS) likely represents the earliest detectable form of multiple sclerosis (MS). There are recognized risk factors for conversion of RIS to clinically definite central nervous system (CNS) demyelinating disease. We aim to characterize a new clinical cohort with RIS and to analyze previously established risk factors for conversion to clinically definite disease. A medical records search was performed for patients who were diagnosed with RIS by their treating neurologist at our institution in Boston, USA, from January 2005 to April 2020. Demographic data, clinical outcomes, and treatment courses were analyzed. The time to first clinical event representing a demyelinating disease attack or last follow up without clinically definite disease was calculated for each person. Hazard ratios (HRs) for known risk factors for the conversion of RIS to clinically definite disease were calculated using Cox proportional hazards models. Of 89 patients, the median age at RIS diagnosis was 41.0 years (76% female, 8% with a family history of MS and 16% of any autoimmune disorder, 66% never smokers, 40% BMI >30 kg/m2, 45% with spinal cord MRI lesions). Clinically definite disease was observed in 16 patients (18%) during follow-up (median time to first event 3.4 years; median follow-up duration of full cohort 3.8 years). Median EDSS for those who developed clinically definite disease was 1.25 (range: 0–4) at most recent follow up. Of 84 patients with longitudinal brain imaging, 42 (50%) had new demyelinating lesions. Gadolinium-enhancing lesions were seen in 36 patients (43%) at either baseline (n =24) or follow-up (n =12). Most patients had at least one T1-hypointense lesion (n =70, 83%). Five patients underwent ultra-high field MRI (7 Tesla); all were positive for central vein sign, two demonstrated leptomeningeal enhancement, and one was found to have cortical lesions. Out of 30 patients with susceptibility-weighted imaging acquired during routine clinical care, 8 had at least one paramagnetic rim positive lesion. Previously reported risk factors for conversion to MS were not significant: age ≤37 years HR 1.3 (95% confidence interval (CI), 0.47–3.5), male sex 1.5 (95% CI, 0.41–5.2), and spinal cord lesions 1.3 (0.47–3.4). Nearly one-third of RIS patients (n =26) took a disease modifying therapy (DMT) for MS (median total treatment duration on any DMT=2.7 years). The sub-cohort treated with a DMT had a statistically significantly greater number of recognized risk factors for conversion to clinically definite disease compared with the untreated group (p =0.028). Most patients took a DMT for MRI changes demonstrating new demyelinating disease activity (n =16). Dimethyl fumarate (n=9) and glatiramer acetate (n =7) were the most frequently prescribed DMTs. A second-line DMT was started in 10 patients. We characterize a new cohort of RIS patients, demonstrating time to clinically evident demyelinating disease from RIS diagnosis of approximately 3.4 years. Our data suggest that early use of a DMT in RIS may mitigate the impact of recognized risk factors on the occurrence of clinically evident disease and reduce the likelihood of conversion to clinically definite CNS demyelinating disease in high-risk individuals. [ABSTRACT FROM AUTHOR]