Faculty Bibliography

BACKGROUND/UNASSIGNED:Mal de débarquement syndrome (MdDS) is a chronic vestibular disorder of non-spinning vertigo, with various somatic, cognitive, and affective symptoms. The manifestation of MdDS is often only subjective, and different symptoms are variably emphasized when patients appraise the severity of their illness. The etiology of MdDS remains unclear but may lie in improperly sustained neuroplasticity in the velocity storage mechanism of the central vestibular system. Two broad approaches targeting velocity storage-one focusing on correcting velocity storage's maladapted behavior and the other on attenuating its contribution to higher-order processing-have yielded varying degrees of treatment success. METHODS/UNASSIGNED:We conducted a secondary analysis of data from our recent study contrasting the outcomes of the above two approaches. We examined the variations in individual emphases of separate symptoms by correlating the subjective ratings of overall MdDS severity with those of specific symptoms across time points for each subject. We also explored the possibility that variations in symptom presentation influence the responsiveness to the two approaches of treatment. RESULTS/UNASSIGNED:Many symptoms correlated with the overall severity rating, but even those that showed strong correlation among many subjects, such as dizziness, fatigue, and brain fog, were endorsed variably across subjects. A moderate unfavorable dependence on visual sensitivity was found for the responsiveness to the velocity storage attenuation treatment, which distinguished the two treatment approaches. CONCLUSION/UNASSIGNED:Results provide a glimpse into the complexity of MdDS manifestations. Individual variations in what contributes to their perceived overall symptom severity may aid the choice of treatment approach.

BACKGROUND:The GM2 gangliosidoses (GM2) are ultra-rare neurodegenerative disorders caused by deficient hexosaminidase A and/or B activity, leading to lysosomal GM2 ganglioside accumulation. Disease onset ranges from infancy to adulthood, with earlier onset associated with more rapid progression. Neurofilament light chain (NfL), a sensitive marker of axonal injury, has been extensively investigated as a biomarker for neurodegenerative disorders, including GM2. METHODS:To evaluate its clinical utility as a biomarker for GM2, NfL was measured in patients with GM2 enrolled in a Phase 2b, multinational, rater-blinded study of levacetylleucine [NCT03759665], and in its open-label Extension Phase (EP). RESULTS:Nineteen participants had viable samples for NfL analysis at baseline, after six weeks of treatment, and after a six-week washout; 10 had samples in the long-term EP. After the initial 6-week treatment phase, NfL concentration declined a mean - 8.9% (SD 13%; p < 0.008), followed by a rebound of + 9.2% (SD 16.1%; p = 0.022) during the post-treatment 6-week washout. Changes in NfL correlated with the statistically significant and clinically meaningful changes captured on the primary Clinical Impression of Change in Severity (CI-CS), and secondary Scale for the Assessment and Rating of Ataxia (SARA) and Modified Disability Rating Scale (mDRS). In the EP, patients showed a mean NfL reduction of - 16.9% after 1 year (SD 15.0; p = 0.010) and - 33.5% after 2 years (SD 12.8; p < 0.001) of levacetylleucine treatment. CONCLUSIONS:These findings support NfL as a promising surrogate outcome candidate for GM2 and link biochemical improvement with functional benefit, which is reasonably likely to predict both disease activity and treatment response/clinical benefit.

IMPORTANCE/UNASSIGNED:In vivo biomarkers for detecting neuropathologies from repetitive head impacts (RHI), including chronic traumatic encephalopathy (CTE), are needed. OBJECTIVE/UNASSIGNED:To evaluate the utility of plasma phosphorylated tau 217 (p-tau217), assess its performance as a beta-amyloid (Aβ) biomarker in participants with RHI exposure at risk for CTE, and explore concordance with CTE neuropathology in a postmortem subsample. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This longitudinal, multicenter, case-control study used data from the Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of CTE (DIAGNOSE CTE) Research Project, collected from September 2016 to October 2023. Participants were former American football players (case participants) and asymptomatic men unexposed to RHI (control participants). A subsample had available neuropathologic data. EXPOSURES/UNASSIGNED:RHI, traumatic encephalopathy syndrome (TES) diagnoses, and levels of CTE certainty. MAIN OUTCOMES AND MEASURES/UNASSIGNED:Plasma p-tau217 (classified as positive [≥0.63 pg/mL], intermediate [0.40-0.62 pg/mL], and negative [<0.40 pg/mL]), Aβ-positron emission tomography (PET; 18F-florbetapir; with Aβ-positive defined as a standardized uptake value ratio [SUVR] ≥1.10), and tau-PET (18F-flortaucipir). TES diagnoses were assigned by multidisciplinary consensus conference. Analyses of postmortem brains controlled for age, race, and APOE ε4 status. RESULTS/UNASSIGNED:Among 231 participants (mean [SD] age, 57.75 [8.25] years), 177 were former football players (117 professional and 60 college) and 54 were unexposed participants. Former football players had higher baseline mean (SD) p-tau217 concentrations than unexposed participants (0.35 [0.26] pg/mL vs 0.27 [0.14] pg/mL; P = .008), although this was driven by a higher proportion of Aβ-PET-positive participants among former players. Plasma p-tau217 increased over time across the sample (B = 0.207 [95% CI, 0.117-0.298]; P < .001), with no significant time × exposure group interactions. Among football players, p-tau217 showed no time × group interactions with TES diagnosis, TES-CTE certainty, or RHI metrics. Higher p-tau217 concentration correlated with higher global Aβ-PET SUVR (B = 0.058 [95% CI, 0.053-3.501; P = .01), with a few discordant cases (5 participants were p-tau217-negative and Aβ-PET-positive; 7 participants were p-tau217-positive and Aβ-PET-negative). P-tau217 had similar areas under the curve for projecting Aβ-PET positivity as cerebrospinal fluid (CSF) p-tau181/Aβ42 and CSF Aβ40/42 measures (p-tau217: AUC, 0.88 [95% CI, 0.80-0.96]; CSF p-tau181/Aβ42: AUC, 0.89 [95% CI, 0.79-1.00]; CSF Aβ40/42: AUC, 0.85 [95% CI, 0.72-0.98]). Among 9 brain donors, 6 had CTE (stages II-IV; none with Alzheimer disease). Seven had negative or intermediate p-tau217, concordant with Aβ-PET. Two p-tau217 outliers with stage III CTE had normal concentrations upon additional testing. CONCLUSIONS AND RELEVANCE/UNASSIGNED:The findings of this study suggest that plasma p-tau217 concentration is unlikely to be useful for the detection of CTE, but it does show utility for ruling out Aβ pathology in participants at risk for CTE.

IMPORTANCE/UNASSIGNED:Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) lacks proven relapse-preventive therapies. While clinical trials are ongoing, safety data may be limited and approved drugs are costly. Studies of interleukin 6 receptor blocker (IL-6RB) in MOGAD are limited by small numbers and no comparative studies, contributing to low use. OBJECTIVE/UNASSIGNED:To evaluate the impact of IL-6RB therapy on relapse rates in MOGAD and compare relapse frequency with intravenous immunoglobulin (IVIG). DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This international, multicenter, retrospective cohort study (January 1, 2015, through December 31, 2025) included a historical IVIG-treated cohort of varying doses. The study took place across sites in North and South America (US, Canada, Mexico, Argentina, Brazil, Chile, Colombia, and Peru). Patients with MOGAD (n = 116, no excluded patients) who received at least 1 dose of an IL-6RB were included. These data were analyzed in January 2026. EXPOSURES/UNASSIGNED:Tocilizumab or satralizumab. MAIN OUTCOMES AND MEASURES/UNASSIGNED:Annualized relapse rate (ARR) during IL-6RB therapy, time to next relapse after treatment initiation, and adverse events. Outcomes were compared with the IVIG cohort using inverse probability of treatment weighting (IPTW) adjusted for age, sex, prior ARR, and concomitant therapies. RESULTS/UNASSIGNED:A total of 116 patients with MOGAD (89% relapsing) receiving IL-6RB (tocilizumab, 104 [90%] and satralizumab, 12 [10%]) were included; overall, 60.3% were female, 39.7% were male, and 18% were younger than 18 years. The median (IQR) IL-6RB treatment follow-up was 1.4 (0.7-2.5) years and 23 relapses occurred during 241.8 person-years of IL-6RB therapy. The ARR decreased from 0.64 (95% CI, 0.58-0.70) for relapsing MOGAD before IL-6RB to 0.09 (95% CI, 0.06-0.14) during IL-6RB treatment (incidence rate ratio, 0.08; 95% CI, 0.04-0.16). Adverse events occurred in 58 patients (50%), most commonly mild infections, although 10 (9%) had severe infections. In the IVIG cohort (n = 59), 30 relapses occurred over 133.8 person-years (ARR, 0.22; 95% CI, 0.15-0.32). After IPTW, IL-6RB was associated with a lower hazard ratio (HR) than the group who underwent IVIG therapy less than 1 g/kg every 4 weeks (HR, 4.5; 95% CI, 2.0-9.8), with no significant difference vs the group who underwent IVIG 1 g/kg or more every 4 weeks (HR, 2.0; 95% CI, 0.8-4.5). CONCLUSIONS AND RELEVANCE/UNASSIGNED:In this multicenter observational cohort, IL-6RB use in MOGAD was associated with low relapse rates and a favorable safety profile, though severe infections occurred occasionally. Relapse rates were lower than the group who underwent IVIG less than 1 g/kg every 4 weeks but not significantly different from the group who underwent IVIG 1 g/kg or more every 4 weeks. This supports IL-6RB as a potential relapse-prevention therapy in MOGAD; the wide availability and relative affordability of tocilizumab may enable broad global use.

OBJECTIVE:To describe the evidence- and practice-based processes that led to the International Olympic Committee Sport Mental Health Assessment Tool 2 (IOC SMHAT2). METHODS:Seven stages were conducted including: (1) reviewing the scientific literature related to the use (eg, uptake by physicians) of the IOC SMHAT-1; (2) gathering the view (eg, experience with the tool, advice for improvements) of IOC SMHAT-1 users; (3) exploring the misclassification and measurement properties of the IOC SMHAT-1; (4) performing misclassification analysis of available IOC SMHAT-1 data; (5) designing the initial IOC SMHAT2; (6) evaluating the content validity and feasibility of the initial IOC SMHAT2; and (7) finalising the IOC SMHAT2. RESULTS:The IOC SMHAT2 was developed for sports medicine physicians and other licensed/registered health professionals with the objective of identifying elite athletes (defined as professional, Olympic, Paralympic or collegiate level; 16 years of age and older) potentially experiencing mental health symptoms and disorders. The IOC SMHAT2 is comprised of a three-step approach: (1) universal screening as step 1, including five disorder-specific screening questionnaires and two single questions; (2) conditional screening as step 2, including two disorder-specific screening questionnaires; and (3) an aid to clinical assessment and treatment as step 3 that should be conducted by sports medicine physicians or licensed/registered mental health professionals. CONCLUSION/CONCLUSIONS:Based on scientific and anecdotal reflections on its first version, we developed the IOC SMHAT2 as a second updated version of the tool to identify elite athletes potentially experiencing mental health symptoms and disorders.

The gut microbiome can influence brain health by modulating neuroinflammation through various mechanisms, including immune regulation, the production of metabolites that affect neural function, gut and blood-brain barrier integrity, upstream effects via the vagus nerve, upstream migration of gut-resident lymphocytes to the brain, bile acid signalling, and endocrine activity. Changes in gut microbiota have been observed in demyelinating conditions, autoimmune encephalitis, and epilepsy. Gut microbiota composition changes can affect neuroinflammation, disease progression, and treatment outcomes. Advances in microbiome research have improved the potential for clinical translation of findings; but limitations persist, driven by the largely correlational nature of clinical studies and the complexity of microbiome sequencing and interpretation. At present, only the ketogenic diet is routinely recommended by clinicians, whereas other microbiome-based interventions remain investigational. Multiple strategies for manipulating the gut microbiome, including dietary changes, prebiotics, probiotics, postbiotics, and faecal microbiota transplantation, might be used as disease-modifying therapies in the future.

BACKGROUND:The Movement Disorder Society (MDS) research criteria for possible prodromal multiple system atrophy (PP-MSA) have not been prospectively validated. OBJECTIVE:To evaluate the diagnostic performance of the PP-MSA criteria in a longitudinal cohort of patients with pure autonomic failure (PAF) and to assess whether additional clinical features improve their predictive value. METHODS:Seventy-six patients with PAF enrolled across eight centers in the Natural History Study of the Synucleinopathies were followed for ≥6 years or until phenoconversion. Participants were classified according to MDS PP-MSA criteria and followed for development of MSA, Parkinson's disease, or dementia with Lewy bodies. Diagnostic performance was assessed longitudinally. Analyses were repeated using a stricter olfactory threshold (University of Pennsylvania Smell Identification Test [UPSIT]≤28) as an exclusion criterion. RESULTS:Thirty-eight participants met PP-MSA criteria, of whom 12 phenoconverted to MSA within 6 years. Sensitivity was 100% at year 1 and 92% at year 6, whereas specificity ranged from 56% to 67%. Positive predictive value (PPV) ranged from 21% to 34%. Applying a stricter olfactory threshold improved specificity (90%-97%) and PPV (53%-83%), with a modest reduction in sensitivity (to 83%). Participants who phenoconverted to MSA were younger, had more severe urinary dysfunction, and greater orthostatic heart rate responses. CONCLUSIONS:The PP-MSA criteria demonstrate high sensitivity but limited specificity in patients with PAF. A stricter olfactory threshold improves diagnostic performance and may enhance cohort enrichment for clinical trials. © 2026 International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

BACKGROUND:People with multiple sclerosis (PwMS) frequently experience invisible symptoms, including cognitive impairment, fatigue, depression, anxiety, and psychosocial factors such as stigma, which can substantially affect social role participation (SRP). These factors are often under-recognized in clinical care despite their functional impact. OBJECTIVE:To examine the unique contributions of invisible MS-related symptoms to SRP after accounting for demographic characteristics and objective cognitive performance. METHODS:A cross-sectional sample of 434 PwMS was recruited from a large outpatient neurology clinic specializing in MS care. The sample was predominantly female (75%), largely white (85%), and middle-aged (M = 51.0, SD = 11.7), with mild-to-moderate disability. Participants completed a computerized cognitive battery and validated patient-reported outcome measures assessing disease impact, mood, fatigue, stigma, and SRP. Hierarchical regression models evaluated the variance explained by demographics, cognitive performance, and patient-reported symptoms. RESULTS:Demographic variables were not significant predictors of SRP. Cognitive performance accounted for 13.3% of the variance. Adding patient-reported outcomes increased explained variance to 70.6%. Depression, disease impact, fatigue, and executive functioning remained significant predictors, whereas stigma did not. CONCLUSIONS:Patient-reported symptom burden showed strong associations with SRP and explained more variance than demographic factors and most cognitive measures, while executive functioning also contributed independently.

BackgroundPeople with subjective cognitive decline (SCD) are at increased risk of Alzheimer's disease. Prior research has suggested that amygdala volume may be more sensitive than hippocampal volume in detecting differences between SCD and age-matched controls, as well as in predicting SCD conversion to mild cognitive impairment. However, the microstructure underlying this volumetric change remains unclear.ObjectiveThis study evaluated amygdala microstructural differences in SCD versus control participants as well as associations between amygdala microstructure and volume, age, memory performance, anxiety, and depression using diffusion imaging.MethodsDiffusion tensor imaging, diffusion kurtosis imaging, and neurite orientation dispersion and density imaging were fit to diffusion MRI images. Group differences and correlations between diffusion metrics, age, memory, anxiety, and depression were assessed in 123 SCD versus 194 age-matched controls over age 55.ResultsIn the left amygdala, SCD participants had significantly lower fractional anisotropy (FA), lower kurtosis fractional anisotropy (KFA), and higher free water fraction (FWF). KFA was lower in the right amygdala in SCD. There were no significant group differences in the amygdala volume. Bilateral KFA negatively correlated with FWF, a marker of neuroinflammation and neurodegeneration. Left FA negatively correlated with orientation dispersion index, a marker of neuritic branching. Right KFA correlated with age only in SCD, while left FA correlated with anxiety only in controls.ConclusionsKFA is sensitive to group differences between SCD and controls in bilateral amygdala. KFA may reflect neuroinflammation and increased sensitivity to aging in the amygdala in SCD.