Journal of Neurology

BackgroundProgressive supranuclear palsy (PSP) is a rare and devastating tauopathy with limited global data. Given Indias large population, genetic diversity, and clinical heterogeneity, large multicenter datasets are crucial to enrich global understanding of PSP. ObjectiveTo characterize the demographic, clinical, and phenotypic profiles of a large multicenter Indian PSP cohort. MethodsSubjects fulfilling MDS-PSP criteria were prospectively recruited across movement disorders centers (2021-2025). Standardized demographic and clinical data were collected. ResultsA total of 1,035 subjects were enrolled (M:F = 709:326), with a median age of 65 years and a mean onset age of 62.2{+/-}7.9 years. Regional distribution reflected pan-Indian recruitment (South 35%, North 26%, West 21%, East 18%). PSP-Richardsons syndrome was most common (41%), followed by PSP-Parkinsonism (18%) and PSP-CBS (11%); rarer phenotypes included PSP-PI (7%), PSP-F (7%), PSP-PGF (5%), PSP-OM (2%), PSP-SL (1%), and PSP-C (1%). Falls occurred earliest in PSP-PGF (13.7 months) and PSP-SL (16.3 months), while PSP-P showed delayed disability (falls at 31 months). Cognitive onset was prominent in PSP-F (21%) and PSP-SL (57%). Levodopa was prescribed to 893 patients; 186 (21%) reported >25% subjective benefit, and 358 (40%) reported [≤]25% benefit. Amantadine was used in 351 (34%) patients, with improvement in 177. ConclusionThis largest systematically profiled PSP cohort highlights both shared and distinctive features: high frequency of non-RS variants, aggressive course in PSP-RS/SL, better survival in PSP-P, and limited pharmacological benefit. These findings establish a foundation for longitudinal and genetic studies in diverse populations.

Neurodegenerative diseases often feature a prolonged presymptomatic phase during which pathological processes evolve before overt clinical manifestation. In Amyotrophic lateral sclerosis (ALS), defining this prodromal period is critical for identifying early disease features and the optimal window for intervention, yet it remains poorly characterised. In this cross-sectional study, we compared 475 ALS patients with 285 controls recruiting across 20 ALS expert centres in Germany and Switzerland. Participants completed a structured digital questionnaire capturing prodromal complaints, healthcare utilisation, comorbidities, lifestyle factors, and weight changes during the 10 years preceding ALS symptom onset. ALS patients reported substantially higher burden of prodromal complaints than controls (OR=7.50, 95% CI 4.27-13.17; P < 0.001; Padj < 0.001), particularly neuro-motor, sensory, and pain-related symptoms. Prior to symptom onset, ALS patients more frequently consulted neurologists (OR=1.26, CI 1.10-1.44; P < 0.001; Padj = 0.007). Speech therapy consultations were significantly more common among female patients (OR = 2.35, CI 1.05-5.28; P = 0.038) and those with bulbar-onset ALS (OR = 8.67, CI 3.80-19.77; P < 0.001). Prodromal musculoskeletal dysfunction was more frequently reported by ALS patients and exhibited sex- and site-specific patterns. Herniated discs were reported more often by male ALS patients (OR=2.21, CI 1.04-4.68; P = 0.038) and by those with spinal-onset disease (OR=2.32, CI 1.38-3.93; P = 0.002). ALS patients more often completed lower secondary education (OR=1.93, CI 1.24-3.01; P = 0.004; Padj = 0.020) and were more likely to have worked in physically demanding occupations (OR=2.21, CI 1.42-3.43; P < 0.001; Padj = 0.003). Lifestyle factors differed significantly, with higher prior consumption of caffeine (OR=7.21, CI 3.27-15.89; P < 0.001; Padj < 0.001), alcohol (OR=2.25, CI 1.47-3.43; P < 0.001; Padj = 0.002), and cigarettes (OR=1.64, CI 1.20-2.24; P = 0.002) among ALS patients (Padj = 0.011). Weight trajectories differed by sex (P = 0.009), with male ALS patients showing significant loss already during the pre-onset phase (P < 0.001). These findings demonstrate that ALS is preceded by a distinct prodromal phase characterised by mild motor impairment, altered healthcare engagement, and sex- and site-specific patterns in comorbidities, lifestyle, and metabolic change. Characterising these early features of ALS may facilitate earlier diagnosis and enable timely enrolment in clinical trials.

BackgroundChitinases, including chitotriosidase (CHIT1) and chitinase-3-like protein 1 (CHI3L1), are markers of neuroinflammation, a key process in amyotrophic lateral sclerosis (ALS). Tear fluid (TF) can be collected non-invasively and may represent a promising alternative to CSF or blood to study chitinases. MethodsTF was collected from 50 ALS patients and 50 control subjects using Schirmer strips. CHIT1 and CHI3L1 levels in TF, serum, and CSF were quantified using ELISA. Serum NfL was measured using SIMOA. The frequency of a 24 bp-duplication polymorphism in the CHIT1 gene influencing CHIT1 expression was assessed by PCR. ResultsNo group differences in the distribution of the CHIT1 polymorphism were detected. Carriers of the polymorphism in both ALS and controls showed lower CHIT1 levels in serum and TF. CHI3L1 levels in TF were higher in ALS patients compared to controls (p = 0.007), consistent with changes in CSF but not serum. In ALS, males showed higher TF CHIT1-values compared to females (p = 0.009). Combining TF chitinase values with serum NfL values improved discrimination between ALS and controls. ConclusionsChitinases are detectable in TF, and CHI3L1 levels recapitulate changes observed in CSF, highlighting its potential for non-invasive longitudinal assessment. Furthermore, chitinase values in TF, together with serum NfL, may act complementary by capturing distinct aspects of the disease, neuroinflammation and axonal damage. These results suggest TF chitinases and serum NfL could complementarily contribute to the diagnosis and monitoring of the disease, and call for further evaluation of TF as a biomarker source in ALS.

Background: Clinical evidence on the contemporary management and functional outcomes of patients with Wernicke encephalopathy remains limited. This study aimed to clarify the nationwide patterns of thiamine administration and functional outcomes at discharge. Methods: Using the Japanese nationwide inpatient Diagnosis Procedure Combination database, we identified patients hospitalized with Wernicke encephalopathy between July 2010 and March 2024. Initial intravenous thiamine doses were categorized as low ([&le;]300 mg/day), medium (301-900 mg/day), or high (>900 mg/day). Outcomes included in-hospital mortality and functional status (Barthel Index) at discharge. Results: We identified 7856 patients with Wernicke encephalopathy. Over the 13-year study period, the proportion of patients receiving initial high-dose thiamine increased markedly from 5.4% to 49.0%, while the frequency of low-dose therapy decreased from 83.0% to 37.9%. Despite prompt intervention [median time to initial administration: 0 days (interquartile range, 0 to 0 days)], 56.1% of patients were discharged with impaired activities of daily living (Barthel Index <90), and the in-hospital mortality rate was 3.8%. Conclusions: High-dose thiamine treatment is increasingly implemented for Wernicke encephalopathy in Japan. Although in-hospital mortality was relatively low, the high prevalence of functional impairment at discharge, despite early treatment initiation, indicates substantial burden of Wernicke encephalopathy. Given the limited clinical evidence, further research investigating the optimal thiamine dose and develop effective primary prevention strategies for Wernicke encephalopathy is needed.

Introduction: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with limited treatment options. Masitinib, a tyrosine kinase inhibitor targeting microglial and mast cell activity in ALS pathogenesis, offers potential neuroprotection. This study presents a post-hoc analysis of long-term survivors treated with masitinib at 4.5 mg/kg/day in study AB10015, comparing observed survival to predicted and historical benchmarks. Methods: Study AB10015 was a randomized, double-blind, placebo-controlled trial assessing masitinib with riluzole in ALS patients. Overall survival (OS) was measured from symptom onset to death, encompassing the double-blind period and post-study follow-up, including an optional open-label program. The ENCALS model predicted survival of long-term survivors ([&ge;]5 years). A delay in the need for mechanical assistance, such as permanent ventilation, gastrostomy, tracheostomy, or wheelchair dependence, was used as a surrogate measure for quality of life (QoL). Results: Among 130 patients receiving masitinib 4.5 mg/kg/day, the 5-year survival rate from onset was 42.3%, increasing to 50.0% in patients with an ALSFRS-R progression rate from disease onset of <1.1 points/month (AB10015 primary efficacy population), and 52.9% in a subgroup of patients without complete loss of functionality at baseline. Half of the long-term survivors had satisfactory QoL, defined as no mechanical assistance. The median OS for long-term survivors (n=55) was 121 months versus the ENCALS-predicted 42 months, yielding a 79-month residual median survival gain. Long-term survivors were prevalent across ALS baseline prognostic factors, including slow or moderate disease progression rate ({Delta}FS), severe or moderate functional severity, bulbar or spinal site of onset, respiratory function, and age. Long-term survival was less likely in patients with complete loss of function at baseline or fast progressing disease ({Delta}FS [&ge;]1.1 points/month) at baseline. Conclusions: Masitinib treatment in ALS patients showed substantial survival benefit. Long-term survivors were largely independent of ALS prognostic factors, suggesting a subpopulation driven by microglial/mast cell activity. A recently identified biomarker detecting masitinib effect on pro-inflammatory microglia may help identify responsive patients.

ObjectivesFunctional neurological symptoms which do not meet clinical definitions of functional neurological disorder (FND) are common in clinical practice. Understanding the distinction between these benign functional symptoms and FND is crucial in defining FND as an entity for study, and as a clinical syndrome. We aimed to measure the frequency of functional symptoms in people who do not have FND. MethodsA survey was administered to 95 clinicians who attended an international conference on FND. Participants were asked to report the occurrence and characteristics of experiences with features of functional sensory or motor symptoms, or dissociation. ResultsOf the 95 people who responded to the survey, 57.4% reported having experienced any functional symptoms, and 47.9% reported having experienced functional motor or sensory symptoms. The symptoms reported were generally short-lived and caused only mild distress and disruption. Most respondents who reported having experienced a functional symptom reported having had multiple events through their lives. InterpretationThe results suggest that the lifetime occurrence of functional neurological symptoms is at least two orders of magnitude higher than the prevalence of FND. The high prevalence of functional symptoms in people who have never had FND challenges the common assumption that the occurrence of functional neurological symptoms is synonymous with FND. We propose that FND is better conceived of as a failure of the mechanisms by which functional neurological symptoms resolve, rather than the occurrence of functional symptoms per se. This reconceptualization implies new research directions for the underlying aetiology of FND.

BackgroundParkinsons disease (PD) is a progressive neurodegenerative disorder with complex pathophysiology. The potential of integrating biomarkers of neuronal injury, neuroinflammation, and modulators of Wnt signaling for PD diagnosis remains largely unexplored. ObjectiveThis study aimed to evaluate the diagnostic and clinical predictive value of a ten-biomarker serum panel encompassing markers of neuronal injury (NSE, UCHL1), neuroinflammation (GFAP, HMGB1), synaptic plasticity (BDNF), proteinopathy (-Synuclein, {beta}-Amyloid-42), and Wnt signaling (R-spondin-1, DKK1, Sclerostin), with a particular focus on chronic fatigue in PD. MethodsIn this case-control study, 90 PD patients and 45 healthy controls were enrolled. Serum biomarkers were quantified using ELISA. Clinical severity was assessed using the Movement Disorder Society-Unified Parkinsons Disease Rating Scale (MDS-UPDRS) and Fibro-Fatigue (FF) scales. Binary logistic regression and multiple linear regression analyses were used to evaluate the diagnostic and predictive value of biomarkers for PD diagnosis, psychiatric and motoric scores, and an FF score reflecting chronic fatigue syndrome (CFS) severity. ResultsA model incorporating NSE, DKK1, and {beta}-Amyloid-42 effectively discriminated PD patients from controls, yielding an area under the curve (AUC) of 0.932 and an overall accuracy of 83.0%. NSE and DKK1 emerged as the main predictors of overall disease severity, motor symptoms, and CFS severity. Regression analyses indicated that 41.3% of the variance in the FF score was explained by increased NSE, DKK1, {beta}-amyloid, and UCHL1, while 42.9% of the variance in psychiatric symptoms was explained by increased NSE, DKK1, and {beta}-amyloid. Increased GFAP levels were significantly associated with motor dysfunction. ConclusionThe combined presence of neuronal injury, Wnt signaling dysregulation, and amyloid pathology may represent a key pathophysiological component underlying PD, CFS-like fatigue, and psychiatric symptoms in PD. Targeting neuronal injury and Wnt signaling pathways may offer novel therapeutic strategies for managing fatigue and psychiatric manifestations in PD.

BackgroundDisorders affecting the spinal cord (myelopathies) can cause severe disability. Despite diagnostic advances, approximately 12-18% of myelopathy cases continue to elude an etiological diagnosis, hampering effective treatment. MethodsThis retrospective, multicenter, tertiary care cohort study conducted from 2014 to 2025 evaluated archived biofluids from patients with IM, known autoimmune myelitis, or other neurological diseases (ONDs). Proteome-wide phage display was used to discover novel autoantibodies. Targeted immunoassays were used to screen for a candidate autoantibody. Downstream metabolites were measured in the cerebrospinal fluid (CSF). ResultsAutoantibodies targeting the transcobalamin receptor (CD320) responsible for cellular transport of vitamin B12 were identified in 18 out of 32 IM patients (56%) in a discovery cohort. Bioactive B12 concentration was decreased in the CSF of anti-CD320 positive patients compared to OND controls (P = 0.0273), indicative of autoimmune B12 central deficiency (ABCD). Compared to anti-CD320 negative IM cases, anti-CD320 positive IM cases demonstrated a higher frequency of subacute time course (56% vs 7%, P = 0.008), normal CSF profile (83% vs 50%, P = 0.044), and dorsolateral spinal cord abnormalities on magnetic resonance imaging (MRI) (61% vs 7%, P = 0.003). In two independent validation cohorts comprising 94 and 25 patients with IM, anti-CD320 was detected in 43 (46%) and 12 (48%) patients, respectively. Comorbid anti-CD320 was detected in a smaller proportion of patients with other known autoimmune etiologies of myelopathy. Five anti-CD320 positive IM patients received B12 supplementation with or without concurrent immunosuppression, and four out of five clinically improved. ConclusionsABCD is associated with a substantial proportion of IM. Screening for anti-CD320 followed by metabolic confirmation of a CNS-restricted B12 deficiency may be considered in the diagnostic evaluation of myelopathy.

BackgroundContinuous subcutaneous foslevodopa/foscarbidopa infusion (LDp/CDp-CSI) is an effective treatment for patients with Parkinsons disease (PD), but infusion-site nodules are a major cause of treatment discontinuation. Systemic inflammation can influence local skin tolerance; however, predictive biomarkers remain unidentified. ObjectiveTo evaluate the predictive value of the neutrophil-to-lymphocyte ratio (NLR) for clinically significant infusion-site nodules (PD-CSN) during LDp/CDp-CSI and to establish a clinical management framework to mitigate their development. MethodsWe prospectively followed 38 patients with PD initiating LDp/CDp-CSI for [&ge;]3 months. Baseline immunological data were collected before infusion. A subset of 30 patients was followed for an average of 11 months to identify factors associated with skin nodules at longer follow-up. Nodules were classified by blinded raters. Between-group comparisons, ANCOVA, ROC curve, and Kaplan-Meier analyses were performed. ResultsAt 3 months, 42% of patients were PD-CSN and showed higher baseline neutrophil counts (P=0.030) and NLR (P=0.007), with NLR remaining independently associated with nodule status (F=7.06, P=0.012). ROC analysis demonstrated acceptable discrimination (AUC=0.73, P=0.016). At last follow-up, lower baseline lymphocyte counts (P=0.002) and higher NLR (P=0.001) were observed in PD-CSN. High baseline NLR predicted earlier nodule onset (P=0.001). Despite frequent nodules, multidisciplinary team surveillance, including remote and in-person follow-up, limited treatment discontinuation to 5.3%. ConclusionsBaseline systemic inflammation, reflected by NLR, predicts both the onset and persistence of infusion-site nodules during LDp/CDp-CSI. NLR may serve as a clinically accessible biomarker for early risk stratification. Multidisciplinary surveillance facilitates timely nodule management and enhances treatment adherence.

ObjectiveTo compare early cerebrospinal fluid (CSF) cytokine profiles in intracerebral hemorrhage (ICH) versus subarachnoid hemorrhage (SAH), with a focus on angiography-negative SAH (anSAH). MethodsWe conducted a retrospective observational cohort study of adults with spontaneous hemorrhagic stroke (ICH or SAH). For cytokine analyses, we included patients with external ventricular drains (EVDs) and analyzed the first CSF sample obtained within 72 hours of symptom onset. Cytokines were measured using a multiplex bead-based assay and included interleukin-6 (IL-6), interleukin-8 (IL-8), vascular endothelial growth factor A (VEGF-A), C-C motif chemokine ligand-2 (CCL2), and granulocyte colony-stimulating factor (G-CSF). Cytokine concentrations were log-transformed due to non-normal distribution. Functional outcomes were assessed using the modified Rankin Scale (mRS) at discharge and 3 months. ResultsCSF cytokine analyses included 120 patients with available CSF samples (43 ICH and 77 SAH), while functional outcome analyses included a broader cohort of 490 patients with ICH or SAH to characterize discharge and 3-month outcomes across hemorrhage subtypes. Compared with SAH, ICH demonstrated higher early CSF log[IL-8] and log[VEGF-A] and had worse functional outcomes at discharge and 3 months. Within SAH, anSAH had higher log[IL-8] and log[VEGF-A] than aSAH, and its cytokine profile more closely aligned with that of primary ICH in hemorrhages without vascular malformations. DiscussionEarly CSF cytokine patterns suggest anSAH shares a more ICH-like inflammatory signature than aneurysmal SAH, supporting anSAH as a potentially biologically distinct SAH phenotype.

As therapeutic options emerge for hereditary spastic paraplegias (HSP), clinical trials require outcome measures that reflect disease aspects most important to patients. Patient priorities in HSP remain poorly defined. This study aimed to develop a regulatory-compliant framework of patient-prioritised health domains to evaluate treatment response in clinical trials. Patient-reported data on health impacts were collected via two multinational, multilingual online surveys conducted sequentially, including 616 and 504 patients across the clinical and genetic spectrum of HSP. Using a staged approach, we examined prevalence, relevance, and severity, focusing on health impacts that were (i) common (ii) sensitive to disease progression, (iii) highly relevant to patients, and (iv) showed strong severity-relevance correlation. Patient representatives contributed centrally to study design and prioritisation. Our patient-focused analysis yielded five highly prevalent and relevant core health domains: mobility, lower body function, autonomic dysregulation, pain, and psychosocial aspects. Ambulation and lower body function ranked highest across all disease stages. Among non-motor impacts, reduced ability to work, bladder incontinence, and fatigue were most relevant. In mild disease stages, reduced walking distance, reduced walking speed, and the urgency to empty the bladder were the most frequent and most relevant health impact. This work provides the most comprehensive patient-reported and disease stage specific profiling of HSP health impacts to date. It lays the necessary groundwork for developing patient-focused outcome tools capable of capturing treatment effects in future trials.

IntroductionNeurodegenerative dementia syndromes are severely debilitating, progressive and increasing in incidence with an ageing population. A treatable differential diagnosis to neurodegenerative dementia is autoimmune encephalitis (AE), but AE patients are often misdiagnosed, delaying treatment. Previous work in the Netherlands has shown that 0.8% of patients with suspected neurodegenerative dementia suffer from AE. In Sweden, there is considerable variability in the prevalence of AE, possibly indicating under-diagnosis. We hypothesized that some Swedish individuals seeking care for memory impairment might suffer from an undetected AE and that these would show aberrances in available markers of neuroinflammation. MethodsWe retrospectively screened frozen sera from 1041 individuals seen between 2019 and 2023 at the Karolinska University hospital memory clinics in Stockholm for autoantibodies to contactin-associated protein-like 2 (CASPR2), leucine-rich glioma-inactivated 1 (LGI1), gamma-aminobutyric acid receptor B (GABABR), the n-methyl-d-aspartate receptor (NMDA-R) and Immunoglobulin superfamily containing LAMP, OBCAM, and Neurotrimin family member 5 (IgLON5) using live cell-based assays (CBAs) and scored them by microscopy. Serum and CSF from suspected positive patient samples were re-tested and titrated by live CBA, commercial fixed CBAs and tissue based assays. Results8 of the 1021 individuals, or 0.8% of the cohort, tested positive in at least three different tests for antibodies to CASPR2 (n=3), GABABR (n=2), LGI1 (n=1) and NMDAR (n=2). Seven of these patients had not been previously diagnosed with AE. Apart from two CASPR2-antibody positive patients showing neuropathic pain and seizures and neuromyotonia, respectively, the patients lacked clinical signs of encephalitis aside from memory impairment and affect lability. The antibody-positive patients did not differ significantly from autoantibody-negative patients in any available clinical parameter. None showed signs of inflammation on brain magnetic resonance tomography, and 2/7 lacked any sign of neuroinflammation in the CSF with available tests, which is commonly seen in later-onset AE. ConclusionOur work identifies undiagnosed AE patients with subtle symptomatology among Swedish memory clinic visitors, that cannot be sensitively separated from antibody-negative patients with current diagnostic tests. Our results suggest the need for the introduction of more sensitive markers of neuroinflammation to the memory clinic to identify and treat individuals with AE among sufferers of memory impairment.

Spinal muscular atrophy (SMA) is a severe neuromuscular disorder caused by reduced expression of the survival motor neuron (SMN) protein. In addition to affecting motor neuron survival, SMN deficiency impacts multisystem physiology and neurotransmission. Dopaminergic dysfunction has been reported in mouse models of SMA, leading to postural and locomotor impairments that improve upon treatment with L-DOPA and benserazide. However, whether altered dopamine metabolism contributes to clinical symptoms in SMA patients remains unclear. To investigate this issue, we conducted a real-world observational study involving pediatric patients with SMA1, SMA2, and SMA3. We performed a longitudinal measurement of the main dopamine-related catabolites - 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) - in cerebrospinal fluid (CSF) samples collected at baseline and after five intrathecal doses of Nusinersen, an SMN-enhancing therapy. No significant differences were observed in CSF DOPAC and HVA levels across SMA types or following treatment, and no association emerged with SMN2 copy number. In contrast, lower baseline DOPAC levels were detected in SMA1 patients requiring gastrostomy and tracheostomy, and were associated with reduced improvement on the CHOP-INTEND scale. These findings suggest that reduced central dopaminergic turnover reflects disease progression in SMA1 and is associated with more severe clinical impairment and limited functional recovery.

Background and objectivesSTXBP1-related disorder (STXBP1-RD), caused by pathogenic variants in the STXBP1 gene, is a rare neurodevelopmental condition, characterized by early-onset seizures, developmental delay, intellectual disability (ID), and prominent motor dysfunction. Despite the high prevalence of motor symptoms, systematic gait characterization remains limited. We therefore aimed to quantitively assess gait in individuals with STXBP1-RD. MethodsIn this cross-sectional study, we included ambulatory patients aged 6 years or older with genetically confirmed STXBP1-RD. Instrumented 3D Gait Analysis (i3DGA) was performed to objectively quantify gait. Functional mobility was assessed with the Functional mobility scale (FMS) and Mobility Questionnaire 28 (MobQues28). Caregiver health-related quality of life was evaluated using the PedsQL-Family Impact Module (PedsQL-FIM). We explored associations between gait, functional mobility, STXBP1-variant type and clinical features (ID, age at seizure onset, seizure frequency, age at onset of independent walking). Correspondence between i3DGA and the Edinburgh Visual Gait Score (EVGS), an observational gait assessment, was investigated. ResultsEighteen participants were included. Compared to typically developing peers, individuals with STXBP1-RD had significantly reduced walking speed, step and stride length. Gait patterns were highly variable, with the most frequent pattern being an externally rotated foot progression angle (FPA), present in 11/18 participants. At home, 93.75% of the participants (16/18) walked independently, yet community mobility was more variable: 11/16 (68.75%) walked independently, 2/16 (12.50%) with aid and 3/16 (18.75%) used a wheelchair, indicating increasing limitations with distance and environmental complexity. Earlier acquisition of independent walking strongly predicted later unassisted ambulation at community level (p<0.001). Median MobQues28 score was 57.14% and median PedsQL-FIM score was 60.42%, indicating a moderate level of mobility limitations and reduced health-related quality of life of caregivers. EVGS was highly positive correlated with i3DGA (p= 0.001). DiscussionQuantitative gait analysis in individuals with STXBP1-RD demonstrates heterogenous kinematic deviations, with an externally rotated FPA emerging as the most common pattern. Age at independent walking was a clinically relevant predictor of later functional mobility. EVGS showed strong correspondence with i3DGA and may offer a more practical, semi-quantitative assessment for broader use. These findings inform clinical decision-making and guide the selection of scalable outcome measures for natural history studies and interventional trials.

ObjectiveTo evaluate whether the presence of orthostatic hypotension (OH) impacts the association between white matter hyperintensity (WMH) volume and motor symptom burden in persons with Parkinsons disease (PWP). MethodsMotor symptom burden in PWP was quantified using the Movement Disorders Society Unified Parkinsons Disease Rating Scale (MDS-UPDRS) Part III. Total WMH volume was segmented based on high-resolution T1-weighted (T1W) and T2 Fluid Attenuated Inversion Recovery (FLAIR) images. Determination of whether individual participants qualified as having OH was based on orthostatic vital signs. All data were obtained from the Parkinsons Progression Markers initiative (PPMI) dataset. ResultsA total of 218 PWP (mean age, 64.84 {+/-} 9.51) and 50 control participants (mean age, 65.52 {+/-} 11.04) were included in the analyses. WMH volume did not differ significantly between the two groups. 15.1% of the participants in the PD group and only 4% of the control group qualified as having OH. Analysis of covariance determined that in PWP, the association between WMH volume and motor symptom burden was significantly different in participants with OH in comparison to those without OH (steeper in the former group). Follow-up analyses suggested that the effects were strongest for bradykinesia symptoms. Adjusting for disease and symptom duration did not alter results. ConclusionsThe presence of OH in PWP impacts the links between white matter lesion volume and motor symptom burden. These findings may provide a potential mechanism underlying the poorer disease prognosis among PWP with OH.

Amyotrophic Lateral Sclerosis (Lou Gehrigs disease) is a progressive neurodegenerative disease affecting hundreds of thousands of people worldwide. It is characterized by the degeneration of the neurons in the brain and spinal cord of the patients, leading to a loss of control of muscles. Over time, without nerves to stimulate them muscles tend to atrophy. ALS may occur sporadically or run in families; many mutations have been identified for the latter. Treatment of ALS is mostly limited to three approved therapeutic agents: riluzole, edaravone, and tauroursidiol/ sodium phenylbutyrate. Among these, riluzole remains the most effective despite its early discovery. There are no conclusive meta-analysis comparing riluzole monotherapy to all possible co-therapies present. In this work we have attempted to address such a concern and observed that no adjunct therapy significantly improved the performance of riluzole. However, mitochondrial/ oxidative stress modulator and neuroimmune/ neuroexcitability modulator co-therapy exhibited positive trends. Surprisingly, trials were mainly confined to the USA and European countries, indicating unequal demographic representation in ASL research. We have concluded that large double blinded inter-continental RCTs to be carried out for better understanding of the scenario.

Background: Acute treatments for patients with spinal cord strokes (SCS), including lumbar drain, blood pressure augmentation, corticosteroids, antiplatelets, and anticoagulants, are largely extrapolated from literature on cerebral infarcts or based on suspected SCS physiology. This study adds to the knowledge of symptomatology and management of SCS. Methods: This retrospective cohort study included patients from one medical system from 2000-2025. Multivariate ordinal logistic regressions were performed to evaluate associations of SCS treatments with the primary outcome of ambulatory status (independently ambulatory, ambulatory with assistance, non-ambulatory) at first follow-up, as well as secondary outcomes of modified Rankin Scale (mRS) and modified Japanese Orthopedic Association (mJOA) scores. SCS severity by American Spinal Injury Association impairment scale (AIS) with grade A as the comparator, age, sex, and whether SCS was spontaneous/periprocedural were covariates. Odds ratios (OR) greater than 1 were associated with better ambulatory status, lower mRS, and higher mJOA. Results: 130 SCS patients were included. Median age at SCS onset was 62 years, 42% were female, and 39% were periprocedural. Median first follow-up was 57 days. AIS grade was A for 28%, B for 25%, C for 28%, and D for 26%. SCS severity had significant associations with outcomes. For ambulatory status, AIS B OR 2.78, 95% CI 1.03-7.69, p-value 0.045; AIS C OR 16.7, 95% CI 5.56-50.0, p-value <0.01; AIS D OR 125, 95% CI 33.3-500, p-value <0.01. Corticosteroids were associated with improved ambulatory status and mJOA at follow-up (OR 2.38, 95% CI 1.15-5, p-value 0.023 and OR 2.27, 95% CI 1.09-4.76, p-value 0.030, respectively). No treatment had a significant association with mRS. Conclusion: Initial SCS severity had the strongest association with outcomes. Corticosteroids were associated with a better ambulatory status and mJOA. This study can help guide clinician management of patients with SCS.

Multiple system atrophy (MSA) is a sporadic progressive neurodegenerative disorder characterised by central nervous system alpha-synuclein inclusions. MSA pathologically most commonly shows a spectrum of two patterns, olivopontocerebellar atrophy and striatonigral degeneration, with significant overlap. Although germline variants are unlikely to play a major role, an association with the KCTD7 gene was recently reported. Somatic mutations are abundant in the brain, and may play a role in neurodegeneration. In MSA, somatic SNCA (alpha-synuclein) copy number gains occur, but single nucleotide mutations have not been investigated. In Alzheimers disease, somatic mutations in tumour suppressor genes were reported in microglia. We hypothesised that brain somatic mutations in SNCA, KCTD7, or the tumour suppressor genes mutated in Alzheimers, may contribute to MSA. To test this, we developed a targeted duplex sequencing pipeline using unique molecular identifiers, encompassing SNCA, KCTD7, and 10 tumour suppressor genes. Seven of these are involved in clonal haematopoiesis, an age-related process which predisposes to haematological malignancy, and can be subdivided into myeloid and lymphoid, based on the cell type affected, with the former much more frequent. We analysed DNA from the cerebellum, cingulate cortex, and putamen of 20 MSA cases (10 olivopontocerebellar atrophy, 10 striatonigral degeneration) and 9 controls. We observed an enrichment of clonal haematopoiesis gene mutations in MSA brains (median 1 vs 0, p=0.054). These included mutations in DNMT3A and TET2, the most frequently affected myeloid clonal haematopoiesis genes, and a recurrent mutation in three cases in KMT2D, a lymphoid clonal haematopoiesis gene. Clonal haematopoiesis mutations were often found in multiple brain regions, and multiregional mutations occurred in 12/20 MSA cases versus 1/9 controls (p=0.020), with 11 cases harbouring clonal haematopoiesis mutations in all three brain regions, compared to 0/9 controls (p=0.005). In striatonigral degeneration, clonal haematopoiesis mutations showed elevated variant allele fractions in the most pathologically affected region, the putamen, versus the cerebellum (p=0.013). MSA clonal haematopoiesis mutations included eight unique non-synonymous variants, which had higher allelic fractions than synonymous changes (p=0.076), and five of these were predicted to confer a proliferative advantage and were found in multiple brain regions. We detected no coding SNCA mutations, and the small number of KCTD7 variants, including one coding deletion, precludes any conclusions. These findings reveal enrichment of clonal haematopoiesis mutations in MSA brain, potentially due to infiltration from the periphery, suggesting a disease-associated proliferative process extending beyond peripheral haematopoiesis.

BackgroundFunctional motor disorder (FMD) is a common and disabling condition with incompletely understood pathophysiology. Eye-tracking offers a method to objectively examine cognitive and motor control processes and their underlying neural pathways. We aimed to quantify saccade, blink and pupil responses in FMD and healthy controls performing an interleaved pro-/anti-saccade task, and to investigate the relationships between oculomotor measures and motor and non-motor symptom severity. MethodsWe conducted video-based eye-tracking in 104 patients with clinically definite FMD and 115 age- and sex-matched healthy controls performing the saccade task. Patients completed questionnaires on depressive, pain-related, dissociative, non-motor somatic symptoms. Clinician-rated motor severity and centrally acting medication was recorded in FMD patients. ResultsCompared to controls, FMD patients showed increased anti-saccade error rates (p < 0.001), anticipatory saccades (p [&le;] 0.003), altered blink distribution (p < 0.001), and reduced pupil dilation velocity (p < 0.001). However, reduced pupil dilation velocity was not significant in subsample of unmedicated patients. Higher anti-saccade error rates were significantly associated with depressive symptoms, pain severity, dissociative symptoms, non-motor somatic symptom burden, and motor severity (all p < 0.05). ConclusionsWe hypothesize that the altered saccade and blink responses result from altered processing in the frontal cortex and basal ganglia which provide critical input to brainstem oculomotor control areas in FMD. These results support neurobiological models proposing altered predictive and attentional processing underlying FMD. Association between oculomotor measures and symptom severity suggests that specific cognitive abnormalities may play a role in the pathophysiology of these symptoms in FMD. WHAT IS ALREADY KNOWN ON THIS TOPICFMD is increasingly interpreted through predictive coding models suggesting abnormalities in predictions about motor and sensory states driven by abnormally focused attention. Yet the underlying neurobiology remains poorly defined. Empirical studies directly probing basic predictive processes in FMD are scarce, and implicit cognitive-motor interactions, particularly those involving motor learning and adaptation, have been insufficiently explored. WHAT THIS STUDY ADDSOnly two previous studies have used eye-tracking in FMD, focusing mainly on diagnostic saccadic markers. Using time-series analyses of saccadic, blink, and pupillary data, we show abnormalities in inhibitory control, predictive processing, and implicit learning. Due to strong homology between human and primate neurophysiology and neuroimaging findings in oculomotor control, the findings can be linked to dysfunction within cortico-basal ganglia circuits. HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICYOculomotor abnormalities correlated with motor and non-motor symptom severity, indicating mechanistic relevance. The findings provide empirical support for predictive coding accounts and point to involvement of subcortical structures including projections from the frontal cortex to the basal ganglia. This highlights the value of studying cortico-basal ganglia circuits with implications for treatment and of developing oculomotor measures as potential biomarkers in FMD.

BackgroundThe Montreal Cognitive Assessment (MoCA) is a recommended brief screening tool to detect cognitive impairment in people with Parkinsons disease (PD). ObjectiveTo compare English and Bengali MoCA performance in Bangladeshi individuals with PD in East London. MethodsThis cross-sectional study involved participants completing both English and Bengali MoCA. Analyses included ANCOVA, paired and unpaired t-tests, and Bland-Altman methods in full and age-matched samples. ResultsFifty PD participants and 22 healthy controls (HC) were included in the full analysis. Both groups scored higher on Bengali than English MoCA (mean difference [~]4 points, p<0.001). Age-matched analyses (n= 29 PD and 22 HC) detected PD-control differences with the Bengali but not English version (p=0.02). Bengali scores aligned more closely with multidisciplinary assessments, though mean scores remained below normative cut-offs. ConclusionBengali MoCA improves detection of cognitive differences over English but still overestimates impairment, supporting the need for culturally adapted tools and population-specific cut-offs.