Journal of Neurology, Neurosurgery & Psychiatry

Importance: As new treatments increase quality and length of life in people with multiple sclerosis (MS), effective prevention and management of common comorbidities, including Diabetes Mellitus (DM), is increasingly important. Objective: To compare incidence of DM and its associations with hospitalisation and mortality in adults with MS and matched controls. Design: Using English primary care data from the Clinical Practice Research Datalink (CPRD), linked to Hospital Episode Statistics and national mortality records, we matched adults with MS diagnosed between 2000 and 2023, with up to ten controls without MS by age, sex, and practice. We excluded individuals with preexisting DM, defined using diagnostic and management codes. Outcomes included all-cause hospitalisation (number and duration) and mortality. We used Poisson, negative binomial, linear, and Cox proportional hazards models, adjusting for demographic and socioeconomic factors, adding interaction terms to examine if ethnicity, deprivation, and urbanity were associated with outcomes. Results: We included 9,010 individuals with MS and 78,121 matched controls. Over a mean follow-up of 13.2 years, people with MS had over twice the incidence of DM compared with controls (adjusted incidence rate ratio [aIRR]=2.26, 95% CI: 1.96 to 2.61, p<0.001). Among people with MS, incident DM was associated with higher hospitalisation rates (aIRR=1.82, 95%CI: 1.47 to 2.28, p<0.001), longer hospitalisation duration (median 18 vs 4 days, adjusted beta;=0.53, 95%CI: 0.41 to 0.65, p<0.001), and increased all-cause mortality when incident DM was modelled as a time-varying exposure (adjusted hazard ratio=1.46, 95%CI: 1.17 to 1.82, p<0.001), compared to those who did not develop DM. Similar patterns were observed among controls (hospitalisation rates: aIRR = 2.96, 95% CI 2.63 to 3.23, p<0.001; hospitalisation duration: adjusted {beta} = 0.93, 95% CI: 0.86 to 0.99, p<0.001; mortality [time-varying]: HR = 1.50, 95% CI: 1.27 to 1.77, p<0.001). The relationship between DM and increased hospitalisation was stronger in rural areas among those with MS and stronger in White groups among controls. Conclusions: People with MS are more likely to be diagnosed with DM, resulting in greater all-cause hospitalisation and all-cause mortality. This highlights the importance of equitable screening, prevention, and management of DM in people living with MS, with particular attention to geographical health inequalities.

Introduction Functional neurological disorder (FND) is a common cause of neurological disability and is associated with substantial healthcare utilisation and cost. Most available treatments target specific symptom subtypes, and prospective evidence regarding the effect of treatment on health-system costs remains limited. We evaluated the real-world clinical and economic outcomes of a transdiagnostic outpatient intervention, attention-based rehabilitation (ABR). Methods We conducted a pragmatic waitlist-controlled study in 54 consecutively referred patients with neurologist-diagnosed FND attending a specialist outpatient service. Clinical outcomes--including quality of life (Short Form-36), social and occupational participation (Work and Social Adjustment Scale), symptom severity, and mental health (Hospital Anxiety and Depression Scale)--were assessed at waitlist entry, treatment commencement, treatment completion, and 6 and 12 months post-treatment. Healthcare utilisation and costs were obtained prospectively from health-service financial records for the 6 months preceding treatment, the treatment period, and two consecutive 6-month post-treatment periods. Longitudinal clinical outcomes and healthcare costs were analysed using Bayesian mixed-effects and mixture models, respectively. Results All clinical measures remained stable or worsened during the waitlist control period. Across treatment, six of eight SF-36 domains, WSAS, employment status, and both HADS subdomains improved, with maintenance through 12 months. Patient-reported symptom improvement persisted post-treatment. Expected monthly health system costs approximately halved post-treatment, with net cost savings by approximately 50 days. Conclusion A fixed-duration, symptom-agnostic outpatient ABR programme was associated with durable improvements in functioning and quality of life, alongside substantial reductions in healthcare utilisation and cost, supporting scalable symptom-agnostic treatment models for FND.

Background. Calcitonin gene-related peptide (CGRP)-targeted therapies, including injectable monoclonal antibodies (mAbs: erenumab, fremanezumab, galcanezumab, eptinezumab) and oral gepants (atogepant, rimegepant), represent a paradigm shift in episodic migraine prevention. No direct head-to-head trials across the full drug class exist. We conducted a PRISMA-NMA-compliant Bayesian network meta-analysis (NMA) to compare the relative efficacy and tolerability of all approved CGRP-targeted preventive therapies. Methods. PubMed, Embase, and Cochrane CENTRAL (inception to January 2026) were searched for doubleblind RCTs in episodic migraine. A Bayesian random-effects NMA used Markov Chain Monte Carlo simulation. Primary outcome: change in monthly migraine days (MMD). Secondary outcomes: 50% or greater responder rate, TEAEs, and DAEs. SUCRA probabilities quantified treatment rankings. Transitivity was formally assessed. Publication bias was evaluated using comparison-adjusted funnel plots and Egger test. GRADE certainty was rated for all key comparisons. Results. Thirty-two RCTs (24,418 participants; mean age 39.2 years; 84% female; mean baseline 8.2 MMD) were included (Table 1). All active treatments significantly reduced MMD versus placebo. Eptinezumab 300 mg ranked highest for MMD reduction (MD 2.40 MMD, 95% CrI 3.10 to 1.70; SUCRA 91.2%), followed by galcanezumab 240 mg (SUCRA 85.4%) and erenumab 140 mg (SUCRA 79.8%). For the 50% responder rate, galcanezumab 240 mg ranked highest (OR 3.12, 95% CrI 2.22 to 4.38; SUCRA 92.1%). Oral gepants demonstrated significant but more modest efficacy: atogepant 60 mg (SUCRA 38.4%) and rimegepant (SUCRA 28.9%). The absolute mAb-versus-gepant efficacy difference of approximately 1.1 MMD exceeded the accepted minimal clinically important difference. Gepants demonstrated placebo-comparable tolerability (TEAE RR 1.02, 95% CrI 0.93 to 1.12; SUCRA 93 to 96%). Heterogeneity was low to moderate (I-squared 14 to 31%); no significant network inconsistency (node-split p greater than 0.29); and no significant publication bias (Egger test p = 0.24). GRADE certainty was high for class-versus-placebo comparisons and moderate for indirect mAb-versus-gepant comparisons. Conclusion. CGRP mAbs provide superior efficacy over oral gepants for episodic migraine prevention. Oral gepants offer placebo-comparable tolerability. An individualized, patient-centered approach guided by symptom burden, comorbidities, administration preference, and the efficacy-tolerability tradeoff of each drug class is recommended.

Background: Deep brain stimulation (DBS) of the ventral intermediate nucleus and posterior subthalamic area (VIM/PSA) in Essential Tremor (ET) and the subthalamic nucleus (STN) in Parkinson's disease (PD) are established treatment for tremor. To achieve maximum tremor control, increasing stimulation frequency beyond 130 Hz is part of clinical practice, but lacks scientific evidence. Objective: To compare tremor suppression under total electrical energy delivered (TEED)-equivalent stimulation at 130 Hz versus 185 Hz in STN-DBS for PD and VIM/PSA-DBS for ET. Methods: In this prospective, double-blind study, acute DBS effects were assessed in 18 people with ET (n = 29 hemispheres), and 25 people with PD (n = 30 hemispheres). Tremor-suppressive effects, evaluated by accelerometry, were compared with TEED-equivalent stimulation at 130 Hz and 185 Hz using linear mixed-effects models, explorative pairwise comparisons, and equivalency testing. Results: Linear mixed-effects models revealed no significant effect of stimulation frequency on tremor improvement in both cohorts. Pairwise comparisons showed no consistent differences in total tremor improvement with TEED-equivalent 185 Hz vs 130 Hz DBS. Post-hoc equivalence testing confirmed equivalence of stimulation frequencies under TEED-equivalent conditions within a +/- 20% margin of relative tremor improvement. Conclusion: This study provides Level II evidence that a higher stimulation frequency of 185 Hz does not offer additional benefit in deep brain stimulation for tremor and supports 130 Hz as the standard stimulation frequency for tremor suppression in ET and PD.

Abstract Objectives: Amyotrophic lateral sclerosis (ALS) is a clinically heterogeneous neurodegenerative disease requiring reliable biomarkers to improve patient stratification and trial design. While serum neurofilament light chain (sNfL) reflects neuroaxonal stress and disease aggressiveness, troponin T (TnT) may capture complementary aspects of neuromuscular involvement. We assessed the associations of TnT and sNfL with D50-derived measures of disease aggressiveness (D50) and disease accumulation (rD50) in ALS. Material and Methods: In this retrospective observation, TnT and sNfL levels from ALS patients in two independent German cohorts were analyzed using the D50 disease progression model; discovery cohort (Essen, n =433) and validation cohort (Bonn, n =185). Results: In both cohorts TnT demonstrated a robust correlation with rD50-defined phases across all aggressiveness subgroups (p<0.001). There was no consistent pattern regarding sNfL and the rD50 phases. sNfL concentrations demonstrated a significant and inverse correlation with D50 applied for all disease aggressiveness subgroups (p<0.001). Correlations of TnT levels with D50 disease aggressiveness groups were generally less strong and inconsistent between the two cohorts. In the discovery cohort only low aggressiveness subgroups correlated significantly (p<0.001), intermediate aggressiveness subgroups showed only a weak correlation (p<0.05) with TnT levels. High disease aggressiveness subgroups showed no significant correlation with TnT. Conclusion: In application of the D50 disease progression model, TnT was strongly associated with disease accumulation (rD50) across all disease phases, independent of disease aggressiveness (D50), whereas sNfL robustly reflected disease aggressiveness but not overall disease burden. These complementary biomarker profiles highlight the value of an integrated approach for refined disease stratification in ALS. Combining TnT and sNfL may enhance clinical decision-making, improve monitoring of disease progression and treatment response, and support optimized clinical trial design.

Background. Lifetime exposure to trauma is associated with chronic pain. Separate studies of chronic pain and trauma report overlapping alterations in white matter microstructure, yet their distinct and cumulative effects remain unclear. Methods. White matter microstructure (fractional anisotropy [FA] and mean diffusivity [MD]) from the UK Biobank (N = 21,995) were analysed using linear mixed-effects models. First, group effects (chronic pain versus control) on white matter integrity within this cohort were established. To investigate distinct and cumulative impacts of trauma exposure at different developmental stages, main and interactive effects of group and trauma severity on FA and MD were examined in separate groups exposed to childhood maltreatment only, adulthood trauma only, and both. Sex-stratified analyses were conducted. Results. Chronic pain was associated with widespread alterations and was spatially refined to brainstem tracts and cingulum when accounting for maltreatment/trauma severity. Accounting for chronic pain, cumulative trauma severity was associated with alterations in brainstem, frontal and parietal tracts, whereas adulthood trauma showed comparable but attenuated patterns. Childhood maltreatment severity was associated with localised FA and MD reductions in brainstem tracts, sagittal stratum and superior longitudinal fasciculus. These effects were more pronounced in females than males. A chronic pain-by-maltreatment/trauma severity interaction was observed for FA in the superior cerebellar peduncle in females exposed to childhood maltreatment only. Conclusions. Distinct and interactive effects of chronic pain and maltreatment/trauma severity on white matter microstructure were evident. The findings suggest that trauma-informed care should be tailored by timing of exposure and sex in this population.

Background. Poor sleep quality is common in people with multiple sclerosis (pwMS) and reduces quality of life. Objectives. To examine associations between modifiable factors and sleep quality in pwMS. Methods. In a prospective clinic cohort (2017-2023), we evaluated whether baseline measures of disability, depression, fatigue, and pain were associated with poor sleep quality (Pittsburgh Sleep Quality Index, PSQI) cross-sectionally using covariate-adjusted linear regression, structural equation modeling (SEM), and LASSO logistic regression, and longitudinally using mixed-effects models. Results. In this cohort (n=750; mean age 48.9 years; 80.3% women, 88.7% relapsing type), higher body mass index ({beta} [95% CI]: 0.06 [0.01, 0.12], p=.001) and area deprivation index (6.78 [2.17, 11.39], p<.001) were associated with worse baseline PSQI scores. In adjusted analyses (n=730), disability, depression, fatigue, and pain were each associated with worse sleep. In SEM, pain had a moderate direct effect on sleep ({beta} [95% CI]: 0.56 [0.48, 0.64], p<.001). LASSO models that included pain outperformed the benchmark (AUROC 0.741 vs 0.517). Longitudinally (n=382), time and higher baseline pain predicted worse sleep ({beta} [95% CI]: time in months 0.04 [0.02, 0.06], p<.001; pain 0.36 [0.31, 0.41], p<.001). Conclusion. Pain is a key, potentially modifiable driver of poor sleep quality in pwMS.

Background: Neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP), established biomarkers of neuroaxonal injury and astroglial pathology, are frequently only assessed in blood, which limits conclusions regarding their origin. Bi-compartmental analyses of CSF and serum may help differentiate central or peripheral origin of biomarker elevation. Moreover, studies on NfL and GFAP in distinct neuroinfectious disease (NID) phenotypes are limited. Methods: This retrospective monocentric study analyzed CSF and serum from patients with (meningo-)encephalitis/myelitis (TI+; n=48), meningitis (TI-; n=80), (cranial) nerve palsies/polyradiculitis (PND; n=61), and 113 non-neuroinflammatory/non-neurodegenerative controls. A bi-compartmental model using scatter plots and simple linear regression was applied to assess the origin of blood biomarker levels and discriminate between central and peripheral pathology. Results: CSF and serum NfL and GFAP z-scores were significantly higher in TI+ compared with TI- (CSF-GFAP p<0.001/sGFAP p=0.0083; CSF-NfL p=0.003/sNfL p=0.0004). TI+ and PND differed only in GFAP levels, which were higher in TI+ (CSF-GFAP p=0.0049/sGFAP p=0.003). Bi-compartmental analysis revealed simultaneous elevation of CSF and serum NfL in TI+, indicating predominantly central origin, whereas PND demonstrated a shift toward higher sNfL levels suggesting peripheral origin. Higher clinical severity (modified Rankin Scale 3-5) was associated with elevated serum and CSF GFAP and NfL (sGFAP p=0.012/sNfL p=0.002; CSF-GFAP p<0.0001/CSF-NfL p=0.0001), which also predicted unfavorable outcome at discharge (sGFAP p=0.006/sNfL p=0.004; CSF-GFAP p=0.003/CSF-NfL p=0.012). Conclusions: NfL and GFAP were associated with brain/myelon involvement in NID, predominantly reflecting central pathology. Despite strong CSF-serum correlations, bi-compartmental approaches provide additional insight into biomarker origin and disease compartment.

Importance: The real-world prevalence and the clinical determinants associated with cognitive impairment in diverse patients with Parkinson disease (PD) have been understudied. Objective: To determine the prevalence of cognitive impairment in a diverse PD cohort and explore associations with vascular, motor, and nonmotor factors. Design, setting and participants: Case-only analysis of diverse patients with PD recruited to the East London Parkinson disease project (July 2022 to July 2025) at the Royal London Hospital, a tertiary referral center. Of 237 patients with cognitive status defined by expert, multi-disciplinary, clinical consensus, 223 remained after excluding atypical or secondary parkinsonism, other dementias, and study withdrawal. Exposures: Observational study (no experimental intervention); exposures included vascular risk factors, motor and nonmotor clinical features. Main Outcome(s) and Measure(s): The main outcome was cognitive impairment (PDCI), defined as mild cognitive impairment (PDMCI) or dementia (PDD) by expert clinical consensus based on clinical, imaging, and cognitive screening. Results: Among 223 participants with a median disease duration of 4.0 (1.0-9.0) years, 112 (50.2%) had PDCI, including 62 (27.8%) with PDD and 50 (22.4%) with PDMCI. South Asian ethnicity was associated with PDCI in univariate analysis (OR, 2.30; 95% CI, 1.32-4.00, P = .003) and the association strengthened after adjusting for age, gender, years of education, disease duration and depression scores (OR, 3.60; 95% CI, 1.68-7.69, P < .001). PDCI was associated with increased odds of smoking (OR, 3.62; 95% CI, 1.56-8.41, P = .003) in the adjusted model. Increased odds were also associated with motor severity (Movement Disorders Society Unified Parkinson Disease Rating Scale Part III; OR per point increase 1.07; 95% CI, 1.04-1.10; P < .001), and daytime somnolence score (Epworth Sleepiness Scale; OR per point increase, 1.08; 95% CI, 1.01-1.16; P = .03). Conclusions and Relevance: In this multi-ethnic study of PD using gold-standard expert multidisciplinary consensus, cognitive impairment was common and more prevalent among South Asian individuals. Smoking, greater motor severity, and higher daytime somnolence were associated with increased odds of cognitive impairment.

INTRODUCTION: Amyloid-related imaging abnormalities with microhaemorrhage (ARIA-H) are an important safety consideration with anti-amyloid therapies, yet evidence exploring short-term risk prediction remains limited. METHODS: We analysed longitudinal MRI data from the A4 study, constructing a discrete person-interval dataset for modelling the short-term risk of ARIA-H. Models incorporated baseline covariates, alongside dynamic variables of recent microhaemorrhage accumulation and current microhaemorrhage burden. Incident ARIA-H was defined as 2 or more new microhaemorrhages or 1 or more new superficial siderosis between consecutive MRI scans. RESULTS: Among 1,069 participants (3,647 intervals), 171 ARIA-H events occurred. Both current burden (time-to-event: OR 1.37, 95% CI 1.09-1.73; all-event: OR 1.24, 95% CI: 1.04-1.49) and recent microhaemorrhage accumulation (time-to-event: OR 1.83, 95% CI 1.01-3.30; all-event: OR 1.43, 95% CI: 1.00-2.04) were independently associated with an increased risk of ARIA-H. DISCUSSION: Temporal imaging variables may provide independent prognostic information beyond baseline risk, supporting a dynamic model of haemorrhagic risk in Alzheimer's disease.

In both preclinical and clinical studies, transfusions of plasma from young individuals have been reported to ameliorate aspects of neurodegeneration. This study was designed as a preliminary test of the hypothesis that plasma transfusions from young donors might benefit Parkinson's patients. 19 patients were allocated to receive either 2-liters of plasma from young donors, in two doses spaced two days apart, or two doses of placebo. For the next 24 weeks, this double-blind study evaluated changes on a modified MDS-UPDRS scale, along with blood tests and other observations. Adverse events possibly related to transfusion were mild rise in blood pressure and urticaria. A t-test on the changes in the sum of UPDRS subscales 1-3 showed that the plasma patients did better than the placebo patients (p = 0.03*). For patients given yFFP (young Fresh Frozen Plasma), the estimated decrease in the sum of scales 1-3 was 7.1 (95% conf. interval 4.3 to 9.9). Our results give a preliminary indication that young plasma transfusions reduce Parkinson's symptoms and have a place in treatment of these patients. (NCT 04202757).

The impact of social parameters on brain health among people with traumatic brain injury (TBI) has been extensively documented. However, translation of this evidence into policy and clinical practice remains limited. This may reflect a lack of coordinated and equity-driven approaches to brain health that integrate diverse stakeholder perspectives, limiting progress toward equity-oriented research and service delivery models. We conducted a convergent parallel mixed-methods study guided by the REporting guideline for PRIority SEtting of health research (REPRISE). We utilized the PROGRESS-Plus framework (Place of residence, Race/ethnicity, Occupation, Gender/sex, Religion, Education, Socioeconomic status, Social capital, and context-specific parameters) to ensure systematic consideration of social parameters in the study. For Objective 1, we synthesized existing evidence on social parameters and brain health outcomes. For Objective 2, we surveyed people with lived experience of TBI, family members/friends, clinicians, researchers, and community leaders across the globe to assess their prioritization of social parameters relevant to brain health. For Objective 3, we integrated evidence synthesis and stakeholder input through a structured Round Robin consensus activity to prioritize actionable areas for feasibility and impact. The activity culminated in the development of a knowledge mobilization agenda designed to inform equity-centred policy, research, and clinical practice. In Objective 1, we identified 59 publications with evidence on the effect of PROGRESS-Plus parameters on brain health outcomes following TBI. Meta-research highlighted that education, age, and country-level indicators are prognostic for brain health after TBI. In Objective 2, the highest-ranked priorities of 113 stakeholders across four continents (North America, Europe, Africa, and Oceania) were education, access to benefits, and income. These priorities were at the centre of discussion in Objective 3, which comprised idea sharing, refinement and thematic clustering, and a final prioritization poll. The resulting final 15 priorities were organized into two tracks: Track A, actions feasible in the short term, and Track B, longer-term implementation priorities. Building on this priority-setting process, co-created with stakeholders around the globe, the findings provide a roadmap for integration of social parameters in TBI research, knowledge exchange, policy, and practice.

Background: Low-dose levetiracetam is under investigation as a potential treatment for slowing Alzheimer's Disease progression. This study tests whether levetiracetam enhances executive function in mid-age adults, and whether drug effects differ by Apolipoprotein e4 (APOE4+) genetic risk status. Methods: Fifty-eight adults (aged 45-65 years; 27 APOE33; 31 APOE4+) participated in a double-blind, placebo-controlled study of low-dose levetiracetam (125mg bidaily for two-weeks). At the end of each treatment phase, participants completed a switch-inhibition task. Results: Mid-age APOE4+ carriers were significantly slower and showed a greater cost of increasing executive demand than APOE33 individuals. Response times were quicker under levetiracetam, with increased benefits reported in APOE33 individuals, at younger ages, and in individuals with reduced levels of plasma-based biomarkers. Levetiracetam selectively benefitted accuracy in APOE33 individuals. Conclusion: Low-dose levetiracetam enhances executive function in midlife, particularly in individuals at lower risk of Alzheimer's Disease based on age, APOE4 genotype, and proxies of neuropathology.

BackgroundCognitive dysfunction is a prevalent and debilitating symptom of post-COVID-19 condition with limited evidence-based interventions. Here, we assessed the efficacy of cognitive training (CT) alone and combined with transcranial direct current stimulation (tDCS) for cognitive enhancement in post-COVID-19 patients. MethodsNeuromod-COV was a phase IIb, prospective, randomized, open-label, blinded-endpoint trial conducted at University Medicine Greifswald, Germany. The tDCS intervention was evaluated through a double-blind, sham-controlled design. Adults aged 18-60 with confirmed SARS-CoV-2 infection [&ge;] 6 weeks prior and post-infection cognitive complaints were eligible. Participants were randomly assigned (1:1:1) to CT with active tDCS (CT+AtDCS), CT with sham tDCS (CT+StDCS), or progressive muscle relaxation (PMR, non-cognitive control intervention) with sham tDCS. Intervention consisted of nine 20-minute sessions over three weeks of CT (letter updating task) or PMR with 2 mA tDCS (active/sham) applied over the left dorsolateral prefrontal cortex. The primary outcome was untrained working memory (WM; measured by N-back task accuracy) comparing CT with PMR at post-intervention. Secondary outcomes included trained and untrained WM, visuospatial memory, and self-report measures at post-intervention and 1-month follow-up comparing CT vs. PMR and CT+AtDCS vs. CT+StDCS. The trial was registered at ClinicalTrials.gov (NCT04944147). ResultsBetween October 1, 2021, and August 7, 2024, 60 participants were randomized (76.7% female) to CT+AtDCS (n = 20), CT+StDCS (n = 20), or PMR (n = 20). CT did not improve untrained WM at post-intervention compared with PMR (primary outcome: {beta} = 1.59, 95% CI - 1.30 to 4.48, p = 0.278; 1-back: {beta} = 2.52, 95% CI -1.27 to 6.31, p = 0.191; 2-back: {beta} = 0.66, 95% CI -3.12 to 4.44, p = 0.732). However, CT+AtDCS enhanced untrained WM at post-intervention and follow-up, and visuospatial memory at post-intervention compared with CT+StDCS (secondary outcomes). No intervention improved self-report outcomes. No serious adverse events occurred and incidence rate ratios were similar between groups. ConclusionCT alone did not improve untrained WM performance. However, CT with tDCS enhanced untrained WM and visuospatial memory, suggesting potential benefits of combined neuromodulation approaches for cognitive enhancement in post-COVID-19 patients.

Background: Comorbidities are common in multiple sclerosis (MS) and may influence disability outcomes, but their dynamic impact on bidirectional disability transitions and long-term disability remains incompletely understood. Better understanding of this longitudinal relationship could inform personalized disability management strategies for people with MS. Methods: We leveraged two large electronic health record (EHR)-linked MS registries and applied multi-state Markov models (MSMs) to examine the extent to which individual comorbidities and overall comorbidity burden were associated with short-term disability transitions, long-term disability transition probabilities, and expected time spent in each disability state. We additionally compared MSM-based predictions of confirmed disability worsening (CDW) with Cox proportional hazards (CoxPH) model-based predictions using the integrated Brier score with bootstrap validation. Results: Among 3,723 patients with MS (74.6% female; 86.2% non-Hispanic White; mean age=41.9 years; mean disease duration=5.4 years) contributing 41,860 disability assessments over a mean follow-up of 7.3 years, higher cardiometabolic and psychiatric comorbidity burden was associated with increased transition intensity toward worse disability states and decreased transition intensity toward improvement, with a stepwise gradient across burden levels. Compared with patients without comorbidities, those with [&ge;]4 comorbidities had a 28% higher risk of worsening (HR=1.28 [1.06, 1.55]) and a 20% lower risk of improvement (HR=0.80 [0.67, 0.95]). Each individual comorbidity was significantly associated with worse disability transitions. Long-term estimates indicated a higher 5-year probability of severe disability and fewer years spent in the no-disability state among patients with greater comorbidity burden. CoxPH models showed directionally consistent associations but lower predictive accuracy for CDW compared with MSMs. Conclusion: Cardiometabolic and psychiatric comorbidities are associated with worse disability trajectories in MS, reducing improvement and accelerating progression. By providing a nuanced framework to quantify short-term disability transitions and long-term disability patterns, MSMs may have real-world clinical utility in disability prediction.

Objectives: To investigate the association between pulse pressure and dementia incidence, independent of other blood pressure measurements and established risk factors, and to assess whether this association differs across dementia subtypes. Design: Prospective population-based study. Setting: UK Biobank. Participants: Of the 502,211 participants in the UK Biobank, 470,986 completed at least one blood pressure measurement and were included in the analysis. These participants were recruited between March 2006 and July 2010 and were followed for up to four assessments through to February 2024. Main outcome measures: Incidence of dementia, identified through linked health records using ICD-9 and ICD-10 diagnosis codes, self-reported diagnoses or records of dementia-specific medication use. The association between pulse pressure and risk of dementia was investigated using Cox proportional hazard models. Models were adjusted for age, sex, education, hearing problems, lipid levels, depression, traumatic brain injury, physical activity, diabetes, smoking, hypertension, body mass index, alcohol consumption and mean arterial pressure. Dementia subtype-specific associations were examined using competing risk models, with cause-specific Cox analyses included as supplementary sensitivity analyses. Results: During a median follow-up of 13 years, 9,028 persons developed dementia (Alzheimer's disease: 3,011; Vascular dementia: 1,270; Dementia with Lewy bodies: 234; Frontotemporal dementia: 191; Other/Mixed dementia: 4,322). Each 10mm Hg increase in pulse pressure was associated with a 5.4% higher risk of dementia (95% confidence interval on hazard ratio: 1.036 to 1.071), even after adjustment for age, mean arterial pressure and other established dementia risk factors. The effects were disproportionately stronger for Alzheimer's disease and vascular dementia, with no clear evidence for increased risk for dementia with Lewy bodies or frontotemporal dementia. Results were robust across sensitivity analyses including alternative blood pressure metrics, complete-case models, and alternative dementia classifications. Conclusions: Pulse pressure is independently associated with incidence of dementia beyond conventional blood pressure measures.

Importance: Accurate prediction of chronic traumatic encephalopathy (CTE) remains challenging in life. Objective: To assess the reliability and validity of the NINDS traumatic encephalopathy syndrome (TES) criteria to predict CTE pathology in life. Design: Clinicopathological Diagnostic/Prognostic Study Setting: Six brain banks with varied recruitment criteria Participants: Brain donors were selected across 6 brain banks (15+ donors each), 5 age groups spanning ages 20 to 80+ (25+ donors each) and 9 repetitive head impact (RHI)/traumatic brain injury (TBI) groups (15+ donors each): (1) college or professional American football; (2) less than college football; (3) college or professional contact sports, non-football; (4) less than college contact sports, non-football; (5) military combat, no contact sports; (6) military combat and contact sports; (7) concussion with loss of consciousness, no RHI; (8) moderate to severe TBI, no RHI; (9) no RHI/TBI. Exposures: Blinded to neuropathological information, clinicians reviewed prospective study and medical records and conducted informant interviews, and an expert panel adjudicated TES diagnoses, including provisional levels of certainty for CTE pathology (suggestive/possible/probable). TES diagnoses were a priori dichotomized: TES with possible/probable CTE (CTEpos/prob) vs. no TES/TES with suggestive CTE (CTEsug). Main Outcomes and Measures: Blinded to clinical information, neuropathologists applied NINDS/NIBIB CTE neuropathological criteria and staging (I-IV). CTE diagnoses were a priori dichotomized: stages II-IV vs. no CTE/stage I. Results: Among 193 brain donors [men:153 (79.3%), mean age:66.4 (SD:22.0)], 57 (29.5%) donors met clinical criteria for CTEpos/prob and 42 (21.8%) donors met neuropathological criteria for CTE stages II-IV. There was high agreement between panelists for CTEpos/prob vs. no TES/CTEsug (ICC:0.95, 95%CI:0.88-0.97). CTEpos/prob sensitivity, specificity, positive likelihood ratio (LR) and negative LR for CTE stages II-IV were: 0.77 (95%CI:0.64-0.89), 0.84 (95%CI:0.78-0.90), 4.8 (95%CI:3.02-7.61), 0.28 (95%CI:0.15-0.50); age[&ge;]50:0.90 (95%CI:0.80-1), 0.90 (95%CI:0.85-0.96), 9.2 (95%CI:4.9-17.27), 0.11 (95%CI:0.04-0.33). All younger false positives (age<50; n=13) had a mental health, substance use and/or pain disorder. All older false positives (age[&ge;]50; n=11) had non-CTE neurodegenerative and vascular pathologies. Among 10 false negatives, 8 had stage II CTE. Conclusions and Relevance: The NINDS TES criteria demonstrated good reliability, sensitivity and specificity, and provided moderate to large evidence to both rule out and rule in CTE pathology, particularly above age 50.

Background: Progressive multiple sclerosis (MS) is characterized by ongoing neurodegeneration and limited therapeutic options. Circulating metabolites provide insight into disease biology, yet biomarkers that predict disability progression and reflect treatment response are lacking. We aimed to identify metabolomic signatures associated with longitudinal MRI measures of brain atrophy and to evaluate whether ibudilast treatment was associated with metabolite trajectories over time. Methods: We repeatedly profiled 1,726 plasma metabolites using untargeted UPLC-MS/MS in 244 participants from the 96-week SPRINT-MS randomized trial of oral ibudilast, up to 100 mg daily, versus placebo. Weighted gene co-expression network analysis was used to derive groups of related metabolites. Associations between baseline metabolite groups and longitudinal MRI outcomes were evaluated using linear mixed-effects models adjusted for demographic, clinical, and treatment covariates. The primary outcome was the rate of whole-brain atrophy measured by brain parenchymal fraction (BPF), defined as the proportion of intracranial volume occupied by brain tissue. Secondary outcomes included white matter fraction (WMF), gray matter fraction (GMF), and cortical thickness (CTH). Metabolite groups nominally associated with MRI outcomes, defined as p < 0.05, were followed by individual metabolite analyses to identify potential drivers. Significant metabolites were tested for replication in a comparable real-world observational HEAL-MS cohort with longitudinal MRI data. Lastly, we tested whether ibudilast treatment was associated with metabolite trajectories and performed metabolite set enrichment analysis. Findings: Higher baseline levels of glycerophospholipids were associated with slower decline in both BPF and WMF, and sphingomyelins were similarly associated with slower BPF decline. For example, higher 1-palmityl-2-stearoyl-GPC (O-16:0/18:0) levels were associated with slower BPF decline in SPRINT-MS (beta = 0.016 [95% CI: 0.008, 0.024]; p = 4.35 x 10^-5) and replicated in HEAL-MS (beta = 0.108 [95% CI: 0.006, 0.211]; p = 3.90 x 10^-2). Metabolites associated with GMF preservation were enriched in androgenic steroids and steroid sulfates, with consistent positive associations observed in the replication cohort, whereas metabolites inversely associated with CTH were predominantly xenobiotic-related. Ibudilast treatment was associated with increased sphingomyelin species, such as palmitoyl sphingomyelin (d18:1/16:0; beta = 0.185 [95% CI: 0.085, 0.286]; FDR = 1.79 x 10^-2), and decreased levels of amino acid-related metabolites, such as anthranilate (beta = -0.270 [95% CI: -0.403, -0.137]; FDR = 3.87 x 10^-2). Pathway-based analyses corroborated these findings, highlighting glycerophospholipid and sphingolipid metabolism as key pathways implicated in brain atrophy in MS. Interpretation: Distinct lipid subsets were associated with slower brain atrophy in people with MS, and ibudilast treatment was associated with metabolite alterations in potentially neuroprotective directions. Metabolomics may provide prognostic and pharmacodynamic biomarkers for progressive MS.

Introduction: Incomplete recovery from relapses contributes to long-term disability accumulation in relapsing remitting multiple sclerosis (RRMS), yet the relationship between immune regulation and relapse recovery remains poorly defined. Objective: To longitudinally characterize regulatory/effector immune cell dynamics in untreated RRMS patients and assess their association with immune balance and relapse recovery. Methods: Monocytic myeloid-derived suppressor cells (M MDSCs), regulatory T cells (Treg), and effector CD4 T cell subsets were measured in blood from 69 untreated RRMS patients sampled during relapse or remission and reevaluated after 12 months. Associations with clinical recovery after relapse were examined. Results: During relapse, patients exhibited higher M MDSC and Treg frequencies than in remission, while effector T cell subsets remained unchanged. Over one year, M-MDSCs increased consistently regardless of baseline clinical status, whereas Treg frequencies remained stable. Effector to M MDSC ratios were markedly elevated during relapse and declined over time, while effector-to-Treg ratios showed minimal variation. M MDSC levels during relapse were associated with sustained regulatory features at 12 month follow up. Importantly, higher baseline M MDSC levels, but not Treg frequencies, were associated with complete relapse recovery at one year. Conclusion: These findings suggest that circulating M-MDSCs, but not Treg, reflect interindividual differences in immune regulation and clinical recovery after relapse in early RRMS.

Background Sleep disturbances affect up to 60-80% of people with Parkinsons disease (PD) and are associated with worse clinical outcomes and reduced quality of life. Dyskinesia is a common motor complication of dopaminergic therapy, but its relationship with sleep quality remains incompletely defined. Methods Forty-seven people with PD (median age 68 years; 44.7% female; median disease duration 5 years; 38.3% from non-White ethnic background) were assessed for sleep quality on Pittsburgh Sleep Quality Index (PSQI). Dyskinesia was assessed using Movement Disorder Society-Unified Parkinsons Disease Rating Scale (MDS-UPDRS) Part IV items 4.1 and 4.2, and 7-day wearable monitoring with the Parkinsons KinetiGraph (PKG) to derive median dyskinesia score (DK_50) and fluctuation dyskinesia score (FDS). All analyses were conducted using multivariate regression. Associations with sleep quality were adjusted for age, sex, and disease severity (MDS-UPDRS Part III) in Model A; additionally for levodopa equivalent daily dose (LEDD) in Model B; and further for disease duration in Model C. Results In Model A, all four dyskinesia measures were significantly associated with sleep quality. After adjusting for LEDD in Model B, only DK_50 remained a significant predictor of worse sleep (B=0.18, 95CI: 0.003-0.357, P=0.047). With additional adjustment for disease duration in Model C, the association for DK_50 was attenuated (B=0.18, 95%CI: -0.001 to 0.356, P=0.051). Conclusions Wearable-derived continuous dyskinesia burden was independently associated with worse sleep quality, whereas clinician-rated dyskinesia was not, highlighting the added clinical value of objective motor monitoring in PD. Disease duration may partly confound this relationship. Larger prospective studies are warranted.