Journal of Neurology

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.

CLN3 disease is an inherited neurodegenerative disease, typically with childhood onset, and characterized by vision loss, seizures, cognitive decline, and difficulties. The CLN3 Staging System (CLN3SS) characterizes disease progression. Our aim was to assess differences in cognitive test scores in relation to CLN3SS among individuals with CLN3 disease. We evaluated the relationship between cognitive test performance and the CLN3SS in individuals with genetically confirmed CLN3 disease. Participants completed tasks of verbal reasoning, vocabulary knowledge, attention, fund of information, and ability to recite the alphabet. One-way ANOVA testing assessed differences in mean cognitive test score among CLN3SS score groups, and Chi-square testing was used to compare the proportion in each CLN3SS group that could recite the alphabet. Data were evaluated from a sample of 85 individuals with a total 245 CLN3SS assessments conducted within 6 months of their cognitive testing, A significant decrease in test scores was found between CLN3SS Stages 1 (vision loss present) and 2 (vision loss and seizures present) for each of the cognitive tests. The proportion of participants able to recite the alphabet also decreased from Stage 1 to Stage 2 (X2=12.1, p<.01). Cognitive ability declines with advanced disease severity in CLN3 disease, though motor disability in Stage 3 likely contributes to difficulty participating in cognitive assessment at this later disease stage. Understanding the relationship between cognition and CLN3 disease stage may help guide decision making, i.e., determining who could or should undergo cognitive assessment for clinical care or for group stratification in disease modifying clinical trials.

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.

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 and ObjectivesFunctional neurological disorder (FND) is one of the most common causes of neurological symptoms and disability, but much remains unknown about its pathophysiology. In both clinical conversations and research publications, clinicians and researchers imply a variety of models for onset of the condition with respect to both the process culminating in its onset, and the distribution of susceptibility to the condition across the population. Here we used population-level data as evidence to arbitrate between these generative models of the condition. MethodsWe identified six hazard distributions corresponding to different pathophysiological processes, and four distributions of population susceptibility, as the assumptions underlying the range of plausible generative models resulting in the observed distribution of age of onset of FND. We combined these model families into 24 parametric proportional hazards models, and fitted each to the observed distribution of reported age at onset in two large FND datasets, one for functional movement disorders (FMD) and one for functional seizures (FS). Out-of-sample predictive accuracy for these models was compared using Bayesian model comparison. ResultsStrong trends were seen across model families with different distributions of population susceptibility to FND. For both datasets, the best-fitting model family overall was the mixture-cure family, which represents susceptibility as binary, with a susceptible and an unsusceptible proportion of the population. For the FMD dataset, some models in the log-normal frailty family had comparable fits to the mixture-cure models, and for the FS dataset, a number of the gamma frailty family had comparable fits. The variance parameters for each of these frailty distributions were so large as to imply binary risk, approximating mixture-cure models. Models with exponential hazard distributions--which correspond to a generative process where a single trigger in a susceptible person brings about the condition--were universally poor fits for the observed data. Other hazard distributions were insufficiently distinguished by their out-of-sample predictive accuracy to make further inference as to the underlying process resulting in onset of FND in susceptible individuals. InterpretationOur results suggest that susceptibility to FND is approximately binary, with the susceptible proportion of the population extremely likely to develop FND in their lifetime. The results also argue strongly against a generative model where a single trigger is sufficient to cause the onset of FND in a susceptible person.

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.

BackgroundAs 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. MethodsPatient-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. FindingsOur 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. InterpretationThis 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.

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.

IntroductionAmyotrophic 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. MethodsStudy 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). ResultsAmong 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. ConclusionsMasitinib 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 masitinibs effect on pro-inflammatory microglia may help identify responsive patients.

ImportanceWhile prior work in other neurodegenerative disorders link white matter hyperintensities (WMHs) to disease severity and progression, they remain unexplored in ALS. ObjectiveTo investigate the relationship between presence and progression of WMHs, disease severity, survival, and medication efficacy in ALS. DesignThis retrospective study uses data from the Canadian ALS Neuroimaging Consortium (CALSNIC), containing prospectively acquired multicentre longitudinal (three time points over one year) MRI and clinical assessments between 2014 and 2022. SettingMulticentre study across 9 North American sites. ParticipantsParticipants with a diagnosis of possible, probable, laboratory-supported probable or definite ALS and healthy controls were included. Participants with prior brain trauma were excluded; controls with cognitive impairment or stroke were also excluded. Main Outcome(s) and Measure(s)The main outcomes were differences in baseline and progression of WMHs in ALS patients compared to controls. Secondary outcomes included associations between WMH progression and ALS progression, and subgroup differences (short versus long survival, treatment vs non-treatment groups). ResultsFollowing exclusion criteria, 204 ALS (mean [SD] age, 59.7 [10.4] years; 71 females [34.8%]) and 165 control (mean [SD] age, 55.8 [9.64] years; 70 females [42.8%]) participants were included. ALS patients showed 35.7% greater WMH burden at baseline (p<0.005) and experienced 0.9 cubic centimeters (CCs) more WMH progression over one year (p<0.0001) compared to age and sex matched controls. ALS patients experienced 2 and 4 point drops in ALSFRS-R (p<0.0005) and ECAS-ALS (p<0.005) scores respectively for every 1 CC of WMH progression they experienced. The short survival group (N = 51) experienced faster WMH progression (0.690 CC per year, p<0.05) than the long survival group (N = 75). Patients taking edaravone (N = 181) and riluzole (N = 112) experienced slower WMH progression (0.764 and 0.924 CC per year, respectively, p<0.0005) than those who did not take these medications (N = 23 and N = 90, respectively). Conclusions and RelevanceWMH burden and progression were associated with ALS disease severity, progression, and survival. Edaravone and riluzole treatments were associated with slower WMH progression. Key PointsO_ST_ABSQuestionC_ST_ABSIs the burden of white matter hyperintensities (WMH), and their progression, linked to ALS diagnosis, clinical progression, survival, and medication treatment? FindingThis retrospective study revealed significantly greater WMH burden and progression in ALS compared to healthy controls, as well as links between WMH progression and clinical progression and differences across survival and treatment groups. MeaningWMHs may be utilized as a biomarker for ALS, and should be integrated into prognostic modeling and clinical trial design.

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.

Introduction: Blood neurofilament light chain (NfL) is an accessible biomarker of neuroaxonal injury across a broad range of neurological disorders, but its clinical implementation requires robust cross-platform analytical and clinical comparability. The objective of this study was to evaluate the analytical and clinical comparability of plasma NfL measurements using Simoa and Lumipulse across different neurological conditions, by assessing cross-platform agreement and the ability of both assays to distinguish neurological diseases from healthy controls. Paired CSF analyses were performed in a subset of participants to biologically anchor plasma findings to the central compartment. Methods: 383 individuals were included, comprising healthy controls and patients with neurodegenerative conditions, multiple sclerosis and stroke. Plasma NfL was measured in all participants using both Simoa and Lumipulse, with paired CSF analyses in a subset of 92 individuals The Lumipulse testing intermediate precision and between-day repeatability was assessed as by the CLSI EP15. Cross-platform agreement for plasma NfL was evaluated using correlation analyses, Passing-Bablok regression and Bland-Altman analysis. Associations between plasma/CSF NfL concentrations were assessed using Spearman's rank correlation analysis for each platform, separately. Age-adjusted cross-diagnostic differences were evaluated using permutation ANCOVA and multiple linear regression models for each platform, separately. Results: Plasma NfL measured by Simoa and Lumipulse showed strong cross-platform concordance in the whole cohort ({rho}=0.90), with similarly strong concordance observed for CSF NfL in the subset with paired samples ({rho}=0.90). Method-comparison analyses in plasma demonstrated consistent agreement between platforms, with identifiable constant and proportional bias, alongside systematically higher absolute plasma NfL values measured by Lumipulse. Within-platform analyses showed significant correlations between plasma and CSF NfL concentrations ({rho}=0.72 for Simoa; {rho}=0.78 for Lumipulse). Noteworthy, Lumipulse NfL CSF and Blood kits exhibited high precision and analytical accuracy. Across both assays, plasma NfL increased with age and was significantly elevated in patients with neurological disorders compared with healthy controls. Discussion: Simoa and Lumipulse capture a consistent biological signal in plasma across patients with neurological disorders, although their absolute NfL values differ, supporting the use of platform-specific reference ranges in clinical practice.

AIM: STXBP1-related disorder (STXBP1-RD) is a severe developmental and epileptic encephalopathy characterized by early-onset seizures and persistent cognitive and motor impairments. With disease-modifying trials emerging, a disorder-specific severity scale is needed. To address this, we adapted a validated clinician-reported measure from CDKL5 Deficiency Disorder to develop the STXBP1 Clinical Severity Assessment (S-CSA) and evaluated its psychometric properties. METHOD: The S-CSA was adapted from the CDKL5 Clinical Severity Assessment through expert consensus sessions with STXBP1 clinicians. Revisions addressed gaps in motor and vision domains, adding tremor and vision items. The measure was administered to 123 individuals with STXBP1-RD. Psychometric evaluation included confirmatory factor analysis, internal consistency, composite reliability, average variance extracted, and distinctiveness, compared with recommended thresholds. RESULTS: Analyses supported a three-domain structure (motor, communication, vision) with factor loadings >0.5 and strong internal consistency (Cronbachs alpha >0.7; composite reliability >0.88). Model fit and variance metrics met recommended standards, and domains demonstrated distinctiveness. No ceiling or floor effects were observed. Minimal skew was seen in motor (0.34) and communication (0.16) domains; positive skew in vision (2.2) was seen, identifying patients with and without cortical visual impairment. INTERPRETATION: The S-CSA demonstrates strong validity and reliability in STXBP1-RD and may show utility in clinical trials for STXBP1-RD and potentially other severe DEEs. Key Words: STXBP1-Related Disorder, Developmental and Epileptic Encephalopathies, Clinical Outcome Assessments

Ankle clonus is a sustained, involuntary, rhythmic muscle contraction frequently observed in humans with spinal cord injury (SCI). Although its pathophysiology remains incompletely understood, converging evidence suggests a role for brainstem systems in its generation. Following SCI, brainstem neuromodulatory inputs partially compensate for the loss of descending motor pathways by regulating motoneuron excitability during involuntary contractions, suggesting their involvement in the generation of clonus. To test this hypothesis, motoneuron excitability in response to Ia synaptic input was quantified using the soleus H reflex and maximal motor response (H/M ratio), and brainstem involvement was probed using the long lasting component of the cutaneous reflex (LLR) in the tibialis anterior and soleus muscles, as well as the StartReact response-an involuntary release of a movement triggered by a startling stimulus thought to engage the reticulospinal tract. We studied individuals with chronic SCI, both with and without ankle clonus, using standardized clinical tests across two days. Participants with clonus showed elevated H/M ratios, indicating increased motoneuron excitability, whereas those without clonus exhibited lower values than controls. Additionally, individuals with clonus exhibited longer LLR duration and greater LLR magnitude in both muscles, along with shorter reaction times to startle stimuli, consistent with enhanced monoaminergic and reticulospinal contributions. Notably, LLR duration was positively correlated with both StartReact response and H/M ratio. Together, these findings support a role for descending brainstem systems-particularly monoaminergic and reticulospinal pathways-in the maintenance of clonus in chronic SCI.

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.

We investigated whether people with Parkinson's disease who are dual GBA1+LRRK2 carriers have a milder, LRRK2-like phenotype as previously reported. This was accomplished by comparing clinical features and alpha-synuclein seed amplification assay (SAA) positivity rates between dual GBA1+LRRK2-PD(n=13), GBA1-PD(n=169) and LRRK2-PD(n=175) carriers in a cross-sectional retrospective study of Parkinson's Progression Markers Initiative (PPMI) data. Our results show that GBA1+LRRK2-PD rate(83%) is closer to GBA1-PD rate(87%) rather than LRRK2-PD rate (62%mp-value>0.05). GBA1+LRRK2-PD have both non-motor and motor phenotypic similarity of GBA1-PD(p-value>0.05). This small PPMI cohort indicates that dual GBA1+LRRK2-PD carriers' SAA positivity and phenotype are aligned with GBA1-PD.

BackgroundAlthough neurogenic orthostatic hypotension (nOH) is a common and debilitating feature of multiple system atrophy (MSA), little is known about the burden of symptoms in the real world. ObjectivesTo design and conduct a cross-sectional community-based research survey targeting patients with MSA, with and without nOH. MethodsWe recruited patients with MSA to complete an anonymous online survey covering three core themes: 1) timely diagnosis, 2) nOH pharmacotherapy and refractory symptoms, and 3) confidence in physician knowledge. Responses were grouped by pre-specified diagnostic certainty levels. Relationships between symptoms, function, and pharmacotherapy were assessed using univariate and multivariate methods. ResultsWe analyzed 259 respondents with a self-reported diagnosis of MSA (age: M=64.38, SD=8.09 years; 44% female). In total, 42% also had a diagnosis nOH; 40% had symptoms highly suspicious of nOH, but no diagnosis; and 21% reported having never had their blood pressure measured in the standing position at a clinical visit. Treatment with a pressor agent was independently associated with the presence of other symptoms of autonomic failure. Each additional nOH symptom reported increased the odds of requiring pharmacotherapy by 18%. Yet, despite anti-hypotensive medication use, 97% of patients reported limitations in their ability to bathe, cook, or arise from a chair/bed with 76% needing caregiver support for refractory nOH symptoms. ConclusionsThis cross-sectional representative sample shows nOH is underrecognized and undertreated in MSA patients, leading to substantial functional limitations. It is our hope that these findings are leveraged for planning future trials and advocating for better treatments.

BackgroundFlorzolotau (18F) positron emission tomography (florzolotau PET) enables high-contrast in vivo detection of four-repeat tau pathology in progressive supranuclear palsy (PSP), but whether longitudinal tau imaging reflects disease progression remains unclear. ObjectivesTo explore longitudinal tau accumulation using florzolotau PET and evaluate its association with clinical progression in PSP. MethodsA total of 26 patients with PSP (18 Richardsons syndrome [PSP-RS], 8 non-RS) and 10 age- and sex-matched healthy controls (HCs) underwent florzolotau PET, MRI, and clinical assessments at baseline and after 1 year. Regional standardized uptake value ratios (SUVR) were extracted across 57 regions of interest. Partial least squares (PLS) multivariate analyses revealed regions with elevated baseline SUVR and longitudinal increase ({Delta}SUVR) in PSP relative to HCs, alongside regions where {Delta}SUVR was associated with changes in PSP Rating Scale scores. ResultsAt baseline, tau deposition was most prominent in the globus pallidus (GP) and midbrain in patients with PSP. Longitudinal tau increases were observed in the GP, frontoparietal cortex, and cerebellum, whereas minimal progression was observed in the midbrain. GP tau accumulation exhibited the strongest association with clinical progression in the PLS model among PSP-RS and a univariate correlation (Spearmans {rho} = 0.674, p = 0.002). ConclusionsThis study provides in vivo evidence of the spatiotemporal progression of tau pathology in PSP. In the GP, tau accumulation emerges early and continues to rise with clinical deterioration. These findings support the utility of florzolotau PET for monitoring disease progression and as a biological outcome measure in tau-targeted therapeutic trials.

BackgroundHyperglycemia after intracerebral hemorrhage (ICH) may be associated with worse outcomes. In this study, we evaluated the association of early post-ICH glucose trajectories and clinical outcomes. MethodsWe performed a secondary analysis of the ATACH-2 trial dataset. Hyperglycemia was defined as a blood glucose of [&ge;]140 mg/dl. Glucose levels at 0h, 24h, 48h, and 72h were analyzed using a linear mixed effects model, with fixed effects for time and random intercept/slopes. Patient-specific estimates were used to predict glucose values at 0h and 72h, informed by all four timepoints, to classify patients into the following glycemic trajectory groups: (1) early hyperglycemia, (2) late hyperglycemia, (3) persistent hyperglycemia, and (4) persistent normoglycemia. Outcomes were compared using univariate analysis and log-rank test survival analysis. Good outcomes were defined as a modified Rankin Score of 0 to 2. The association between glycemic trajectories and functional outcomes was tested using logistic regression models adjusted for patient demographics and clinical variables. ResultsOf 1000 patients (median age 62 [IQR 52-71]; 38% female) in the study, 81 (8.1%) had early hyperglycemia, 59 (5.9%) late hyperglycemia, 225 (22.5%) persistent hyperglycemia, and 635 (63.5%) persistent normoglycemia. On univariate analysis, 45.8% of patients with persistent normoglycemia had favorable 90-day functional outcomes compared to 30.9% in early, 30.5% in late, and 32.0% in persistent hyperglycemia patients (p<0.001). The late hyperglycemia patients had the highest rate of hematoma expansion (35.3%, p=0.029) and the lowest Kaplan Meier-estimated survival (86%, p=0.015). In adjusted multivariable regression models, early hyperglycemia was significantly associated with a poor functional outcome (OR 2.27, 95% CI 1.10-4.68, p=0.026). ConclusionEarly hyperglycemia was associated with worse functional outcomes, while late and persistent hyperglycemia were associated with worse survival rates. These findings suggest that glycemic trajectories may affect or predict prognosis. This highlights the importance of continuous glucose monitoring and glycemic control strategies after ICH.