Journal of Neurology, Neurosurgery & Psychiatry

ImportanceElevated circulating low-density lipoprotein (LDL) cholesterol is associated with an increased risk of amyotrophic lateral sclerosis (ALS) onset. Previous studies have explored the relationship between statin use and ALS onset. However, findings have been inconsistent, potentially due to methodological limitations, such as confounding by indication, and failure to account for baseline differences in LDL cholesterol levels. ObjectiveTo compare the risk of ALS onset between new users of statins and ezetimibe among patients with hypercholesterolemia. DesignActive-comparator, new-user cohort study using inverse probability of treatment-weighted Cox proportional hazards models. The study period spanned April 2012 to February 2024. SettingTwo administrative claims databases in Japan. ParticipantsPatients with hypercholesterolemia who newly initiated statins or ezetimibe, and patients with dyslipidemia who newly initiated fibrates. All participants were required to have at least 365 days of baseline observation and no prior diagnosis of ALS. Exposure(s)Statin use compared with ezetimibe use. Fibrate use was assessed for benchmarking. Main Outcome(s) and Measure(s)The outcome was incident ALS, defined as a first definitive diagnosis of ALS. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated to compare ALS risk between statins and ezetimibe. ResultsThe study included 607,292 statin users (median [IQR] age, 61 [51-71] years; 51.4% male), 26,963 ezetimibe users (median [IQR] age, 59 [49-71] years; 50.1% male), and 114,871 fibrate users (median [IQR] age, 61 [51-71] years; 51.4% male). The incidence rate per 100,000 person-years of ALS was 6.8, 15.9, and 4.3, respectively. Statin use was associated with a lower hazard of ALS onset than ezetimibe use (adjusted HR [95% CI]: 0.42 [0.19-0.92]). The mean (SD) LDL cholesterol immediately prior to treatment initiation was 171.0 (28.6) mg/dL in the statin group and 162.8 (30.8) mg/dL in the ezetimibe group. After treatment, mean LDL cholesterol levels decreased to and stayed below 140 mg/dL in both groups. Conclusions and RelevanceThis study suggests that statins may lower the risk of ALS onset among patients with hypercholesterolemia. The mechanism underlying this association is not yet clear and may involve pathways beyond circulating LDL cholesterol reduction. Key pointsO_ST_ABSQuestionC_ST_ABSDoes statin use lower the risk of amyotrophic lateral sclerosis (ALS) onset among patients with hypercholesterolemia? FindingsIn this active-comparator, new-user cohort study of 607,292 statin users and 26,963 ezetimibe users with hypercholesterolemia, statin use was associated with a lower hazard of ALS onset compared with ezetimibe use. Prior to treatment initiation, mean LDL cholesterol levels were similar between statin and ezetimibe users. MeaningThese findings suggest that statins may lower the risk of ALS among patients with hypercholesterolemia.

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.

ObjectiveTo replicate and extend recent findings suggesting that higher serum alpha-linolenic acid (ALA) levels are associated with reduced disease activity and progression in multiple sclerosis (MS). MethodsWe reanalysed clinical trial data from 85 people with MS, who had serum ALA, magnetic resonance imaging (MRI), and clinical (EDSS, PASAT) assessments collected for two years, with additional follow-up at 12-years. Linear and mixed models were used to assess the relationship between ALA and clinical and MRI outcomes. Mediation analyses tested whether ALA mediated associations between brain volume or T2 lesion load, and disability. ResultsALA measures were consistent over time ({kappa}= 0.83). Higher ALA predicted lower EDSS ({beta} = -0.41, 95% CI [-0.73, -0.08]) and larger brain volume ({beta} = 0.22, 95% CI [0.09, 0.36]). ALA was a non-significant mediator of brain volume or lesion effects on EDSS and did not predict long-term clinical or cognitive change. DiscussionWe replicate prior associations between higher serum-ALA levels and reduced disability in MS and extend these by showing a beneficial association of serum-ALA with brain volume. However, ALA did not predict long-term progression, limiting its prognostic value.

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.

INTRODUCTIONCore cognitive deficits in iNPH include slowed information processing, psychomotor slowing and executive dysfunction. However, the cognitive benefits of iNPH treatment with shunt surgery are not well understood. This review synthesised evidence on cognitive assessment methods and outcomes following shunt surgery in iNPH. METHODSPubMed, Scopus, PsycINFO and Web of Science were searched for peer-reviewed studies including adults with iNPH who underwent shunt surgery and had within-subject cognitive evaluations pre- and post-operatively. Key data were extracted and study quality was assessed. Random-effects meta-analyses were performed on pooled baseline and post-shunt difference scores for frequently reported cognitive tests with comparable data. RESULTSOf 1,876 records, 195 met the inclusion criteria, comprising 11,445 patients. Cognitive evaluation methods ranged from subjective reports and NPH grading scales to brief screening tools and comprehensive test batteries. Over 193 distinct tests were reported and 54.4% of studies did not formally assess any core iNPH cognitive deficits. Post-shunt improvement rates, follow-up times and criteria for defining improvement varied widely. Eighty-five studies contributed data to meta-analyses of ten outcomes. Pooled estimates indicated post-shunt cognitive improvement, with Trail Making Test-A, Grooved Pegboard-Dominant and Trail Making Test-B showing changes exceeding thresholds for clinically significant improvement. CONCLUSIONSCognitive assessment in iNPH is highly heterogeneous and frequently omits core domains, limiting detection of treatment effects. When domain-relevant cognitive measures are used, shunt surgery is associated with statistically and clinically significant cognitive improvement. These findings highlight the need for standardised iNPH-specific cognitive evaluation tools with validated criteria for detecting clinically meaningful change and have direct implications for clinical assessment, interpretation of shunt response and the selection of cognitive endpoints in future interventional studies. Summary BoxO_ST_ABSWhat is already known on this topicC_ST_ABSCognitive outcomes after shunt surgery for idiopathic normal pressure hydrocephalus (iNPH) have been inconsistently reported, with cognitive improvement reported less reliably than gait outcomes, in the context of highly variable assessment practices across centres. What this study addsThis systematic review of 195 studies (11,445 patients) shows substantial heterogeneity in iNPH cognitive assessment and demonstrates that when tests sensitive to frontal-subcortical dysfunction are used, shunt surgery is associated with statistically and clinically meaningful cognitive improvement. Widely used dementia screening tools, including the MMSE and MoCA, show changes largely within expected practice-effect ranges and do not adequately capture core iNPH cognitive deficits. How this study might affect research, practice or policyThese findings demonstrate the need to standardise cognitive assessment in iNPH using appropriate iNPH-specific tools with validated metrics for determining clinically meaningful improvement. This will enable robust trial endpoints and accurate evaluation of cognitive benefits of shunting in routine clinical practice.

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.

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.

ObjectivesTo validate whether cerebrospinal fluid oxyhaemoglobin (CSF-Hb), measured from external ventricular or lumbar drains, is associated with secondary brain injury (SAH-SBI) after aneurysmal subarachnoid haemorrhage (aSAH), and to assess its value as a real-time monitoring biomarker. DesignPreregistered multicentre prospective observational cohort study. SettingEight neurosurgical tertiary centres in Switzerland, Germany, and Austria, between August 2021 and June 2024. Participants366 patients with aSAH (mean age 58 years; 65% women). Of these, 260 provided cerebrospinal fluid (CSF) samples via external ventricular drain (EVD; 2,467 samples, median 10 days per patient) and 66 via lumbar drain (LD; 379 samples, median 6 days). InterventionsDaily CSF samples were collected via EVD or LD from day 1 to day 14 after haemorrhage; no therapeutic interventions were tested. Main outcome measuresCSF-Hb and its metabolites were analysed post hoc in a blinded manner. The primary outcome was SAH-SBI, defined as a composite of angiographic vasospasm (aVSP), delayed cerebral ischaemia (DCI), and delayed ischaemic neurological deficits (DIND), assessed daily over 14 days. Secondary outcomes included temporal CSF-Hb profiles and associations with aneurysm location, haematoma volume, intraventricular haemorrhage, chronic hydrocephalus, and 3-month functional outcome. ResultsCSF-Hb showed a delayed peak pattern: concentrations were low after aSAH, rose to a maximum on day 10 (EVD-derived CSF-Hb median 11.3 {micro}M, IQR 2.64 to 25.90), and then declined. Larger haematoma volume (p<0.001) and intraventricular haemorrhage (p<0.001) were associated with higher EVD-derived CSF-Hb. SAH-SBI occurred in 209/366 patients (57%). Daily EVD-derived CSF-Hb showed no association with SAH-SBI (p=0.25) and only poor prognostic potential of same-day SAH-SBI (area under the curve 0.59, 95% confidence interval 0.56-0.63), with substantial between-centre heterogeneity. The oxidised haemoglobin metabolite methaemoglobin was positively associated with SAH-SBI (p=0.023; odds ratio 1.18 per log[{micro}M], 95% confidence interval 1.02-1.36). Acute-phase EVD-derived CSF-Hb correlated with chronic hydrocephalus (p=0.012) and poor 3-month functional outcome (p=0.008). Catheter-related infection rates were low (2.2%). ConclusionsIn this preregistered multicentre validation study, EVD-derived CSF-Hb did not perform as a robust real-time monitoring biomarker for SAH-SBI, showing limited same-day discrimination and substantial between-centre heterogeneity. These findings argue against clinical implementation of CSF-Hb point-measurement as a single-parameter biomarker. In contrast, CSF methaemoglobin remained consistently associated with SAH-SBI, supporting the mechanistic relevance of haemolysis-related pathways. Future work using the HeMoVal biobank will apply multi-marker, pathway-level analyses to define haemolysis-related biomarker signatures and provide a platform for robust external validation of future candidates. Study registrationClinicalTrials.gov NCT04998370; date of registration 10 August 2021. Summary BoxesO_ST_ABSWhat is already known on this topicC_ST_ABSO_LIPreclinical animal models link cell-free haemoglobin in cerebrospinal fluid (CSF-Hb) to secondary brain injury after aneurysmal subarachnoid haemorrhage (SAH-SBI). C_LIO_LIA single-centre study reported strong associations between daily external ventricular drain (EVD) derived CSF-Hb levels and SAH-SBI, and suggested a strong predictive potential(area under the curve 0.89). C_LIO_LICSF-Hb monitoring has therefore been proposed as a bedside biomarker, but it has not undergone multicentre validation. C_LI What this study addsO_LIIn a preregistered multicentre cohort of 366 patients from eight neurosurgical centres, once-daily EVD-derived CSF-Hb measurements showed poor same-day discrimination for SAH-SBI (area under the curve 0.59) and substantial between-centre heterogeneity. C_LIO_LIIn contrast, CSF methaemoglobin was consistently associated with SAH-SBI, and higher acute-phase CSF-Hb was related to chronic hydrocephalus and worse 3-month functional outcome. C_LIO_LIThese findings argue against routine adoption of CSF-Hb point-measurements as bedside single-analyte, while supporting haemolysis-related pathways as mechanistic targets. C_LI

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 [&le;]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.

Background / ObjectivesWe investigated whether the interthalamic adhesion (IA), a midline structure connecting the thalami, is altered in MS and associated with thalamic damages and cognition. MethodsWe prospectively included 32 clinically isolated syndrome/early MS, 31 RRMS, 31 PPMS patients, and 103 matched controls. All underwent anatomical 3T MRI and completed a comprehensive cognitive battery. IA presence, subtype, and volume were assessed by two blinded readers. Thalamic nuclei and other brain structures were segmented automatically. We compared IA subtypes/volumes across groups, analyzed their predictors and explored cognitive associations with multivariate regressions. ResultsIA prevalence did not differ between MS and controls (81.9% vs 74.7%). MS patients showed a shift toward a short IA subtype and reduced IA volume (mean [SD], 146.8 [117.9] vs 230.2 [138.2] mm3; p<0.0001), worsening across phenotypes. Reduced IA volume was independently associated with medial and posterior thalamic nuclei volumes, but not with white matter lesion load or global atrophy. Among cognitive domains, smaller IA volume was independently associated only with executive dysfunction (OR = 0.89 [0.77-0.99], p = 0.021). ConclusionIA volume reduction in MS reflects vulnerability of adjacent thalamic nuclei and is associated with executive dysfunction, supporting IA as a marker of thalamic neurodegeneration. Trial RegistrationMICROSEP: NCT03692975; AUBACOG: NCT03768648; PROCOG: NCT03455582.

BackgroundTraumatic spinal cord injury (SCI) is a major cause of long-term neurological disability, with limited pharmacological therapies targeting secondary inflammatory and neurodegenerative injury mechanisms. Minocycline, a tetracycline derivative with anti-inflammatory and neuroprotective properties, has been investigated in both experimental and clinical settings; however, its therapeutic efficacy in acute traumatic SCI remains uncertain. MethodsA systematic review was conducted in accordance with PRISMA 2020 guidelines. Major electronic databases were comprehensively searched to identify preclinical animal studies and human clinical studies evaluating minocycline, alone or in combination therapies, for acute traumatic SCI. Risk of bias was assessed using Joanna Briggs Institute (JBI) critical appraisal tools tailored to study design. Qualitative synthesis included all eligible studies, while quantitative synthesis was restricted to clinical studies reporting extractable effect estimates for neurological improvement. ResultsA total of 11 studies met inclusion criteria for qualitative synthesis, including experimental animal studies and human clinical investigations. Preclinical studies demonstrated consistent biological effects of minocycline on inflammatory markers, oxidative stress, and histopathological outcomes, particularly in combination therapies, although functional recovery with minocycline monotherapy was inconsistent. Clinical studies indicated that minocycline was generally well tolerated; however, most trials did not demonstrate statistically significant improvements in neurological or functional outcomes. Only two clinical studies provided suitable data for meta-analysis, yielding a pooled odds ratio of 1.70 (95% CI 0.95-3.06) for neurological improvement, which did not reach statistical significance. ConclusionCurrent evidence suggests that while minocycline exhibits promising biological activity and an acceptable safety profile in acute traumatic SCI, robust clinical efficacy has not been conclusively demonstrated. Well-designed, adequately powered randomized controlled trials with standardized outcome reporting are required to determine whether these biological effects translate into meaningful functional recovery.

BackgroundThe prodromal phase of multiple sclerosis (MS) is increasingly recognized, but most studies have focused on isolated symptoms or static comorbidity counts, leaving the evolving structure of pre-onset disease burden underexplored. ObjectiveTo characterize dynamic disease trajectories preceding MS onset through longitudinal network modeling. MethodsHealth data from 10,273 MS patients and 47,167 matched controls in Sweden were analyzed. Disease co-occurrence networks were constructed for three pre-onset windows (0-5, 5-10, 10-15 years), with comparisons of centrality, clustering, and path length. Rewiring scores captured structural shifts, while Markov clustering and trajectory mapping identified comorbidity communities. ResultsMS networks were denser, more clustered, and showed shorter path lengths than controls, reflecting higher systemic interconnectivity. Psychiatric and metabolic diagnoses, especially depression, anxiety, diabetes, and abdominal pain, were hubs that gained prominence over time. Distinct clusters, including neuropsychiatric-toxicological and immune-endocrine constellations, were observed only in MS. Rewiring analysis revealed significant topological shifts in key diagnoses, such as inflammatory CNS disorders and substance use, as onset approached. ConclusionsMS is preceded by dynamic reorganization of the comorbidity landscape, marked by increasing connectivity and rewired hubs. This framework highlights systemic disruption before diagnosis and provides a novel, network-based tool for studying prodromes in complex disorders.

An overlap syndrome of myositis and/or myocarditis associated with myasthenia gravis (MG) has emerged as a life-threatening immune-related adverse event (irAE) in cancer patients treated with immune checkpoint inhibitors (ICIs). This syndrome closely resembles a rare form of idiopathic inflammatory myopathy (IIM) seen in a subset of MG patients. In this systematic review, we searched PubMed for reports of concurrent MG and IIM as well as ICI-related overlap syndromes. By integrating clinical, serological, and pathological observations, we delineated a previously unrecognized clinicopathological subtype of myositis that overlaps with MG. This entity is defined by a strong association with striational antibodies (StrAbs) and frequent co- occurrence with thymoma as a paraneoplastic process, and we classify it as StrAb-associated myositis. The idiopathic and ICI-induced forms share similar, though not identical, clinical, serological, and histopathological characteristics. We found that AChR antibody positivity, independent of established clinical risk factors such as respiratory or cardiac involvement, predicted more severe ICI-myotoxicity. Together with supporting evidence, our findings suggest a pathogenic model in which thymoma-driven cytotoxic T-cell responses trigger secondary AChR autoimmunity. These results highlight the potential utility of StrAbs and anti-AChR antibodies as practical biomarkers for diagnosis, risk stratification, and early intervention in patients at risk for severe neuromuscular irAEs.

BackgroundBiomarkers of abnormal alpha-synuclein (asyn) that can be obtained with minimal invasiveness are needed. Promising data on dermal serine-129-phosphorylated alpha-synuclein (dermal-ps129-asyn) have emerged but accuracy for aggregated asyn in cerebrospinal fluid (CSF) has not been examined. ObjectiveDetermine sensitivity and specificity of dermal-ps129-asyn for neuronal asyn measured with cerebrospinal fluid asyn seed amplification assay (CSFasynSAA). MethodsCross-sectional observational study; 50 individuals with positive or negative CSFasynSAA underwent 3 skin biopsies for blinded assessment of phospho-serine-129 asyn in nerve terminals. Sensitivity and specificity versus CSFasynSAA were calculated. ResultsAmong 50 participants, 30/38 CSFasynSAA+ were dermal-ps129-asyn+; 6/12 CSFasynSAA-were dermal-ps129-asyn-, yielding sensitivity of 79% and specificity of 50%. ConclusionDermal-ps129-asyn has low specificity for CSF asyn SAA in this small sample. This precludes its use as a marker of CSF neuronal asyn aggregates. Future studies are needed to determine optimal methods to assess asyn aggregates in central and peripheral compartments.

IntroductionThe 2024 McDonald criteria incorporate the central vein sign (CVS) and paramagnetic rim lesions (PRL) as supportive imaging biomarkers for MS diagnosis. While susceptibility-weighted-imaging (SWI) and T2*-weighted echo-planar-imaging (EPI) are generally used to assess CVS/PRL, their relative performance remains unclear. This study compared high-resolution isotropic-T2*-EPI with non-isotropic SWI for CVS/PRL detection. Materials and MethodsIn this multi-centre study, 21 patients with MS underwent harmonized 3T-MRI including EPI and SWI. CVS and PRL were evaluated according to NAIMS criteria. Whole-brain and controlled lesion analyses on 120 pre-selected lesions were performed independently for each contrast, with EPI serving as reference standard. ResultsIn whole-brain analyses, SWI showed good sensitivity for CVS eligibility and positivity (AC1=0.68-0.78) but significant directional disagreement with EPI (p<0.0001). Discrepancies were primarily attributed to limited lesion-parenchyma contrast and venous visibility on SWI, which improved using low-flip-angle SWI. Controlled lesion analyses supported these observations. For PRL, SWI demonstrated high sensitivity (88%) and precision (97%) compared to EPI, though systematic bias persisted (p<0.001). Controlled lesion analyses showed more balanced, albeit moderate performance. ConclusionSWI diverged systematically from EPI for CVS and PRL detection. When available, EPI should be preferred, while optimised low-flip-angle SWI may serve as an alternative to conventional SWI.

TDP-43 proteinopathy is a neuropathological hallmark of nearly all amyotrophic lateral sclerosis (ALS) and approximately half of frontotemporal dementia (FTD) cases. Nuclear loss of TDP-43 leads to widespread RNA misprocessing, such as the inclusion of cryptic exons that are no longer repressed by TDP-43. Notably, in-frame cryptic exons encode novel cryptic peptides that can be detected in biofluids, including that found in the HDGFL2 transcript. Here, we quantified HDGFL2 cryptic peptide and neurofilament light chain (NfL) in paired cerebrospinal fluid (CSF) and plasma samples from ALS and FTD patients. Cryptic HDGFL2 peptide was detected in the CSF of ALS patients, whereas no significant differences were observed between genetic and behavioral FTD subgroups. In contrast, NfL levels were elevated in both ALS and FTD, although this biomarker does not reflect TDP-43 pathology. Notably, NfL:HDGFL2 cryptic peptide ratio outperformed either marker alone in discriminating ALS and FTD cases from controls, achieving high specificity. Moreover, this ratio correlated with disease progression in ALS, suggesting added prognostic value. Collectively, our findings support the NfL:HDGFL2 cryptic peptide ratio as a promising fluid biomarker that integrates neurodegeneration with TDP-43 dysfunction, potentially improving diagnostic accuracy, disease stratification, and longitudinal monitoring in TDP-43-associated neurodegenerative disorders.

BackgroundCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic hereditary cerebral small vessel disease (CSVD). Existing studies have confirmed that it is caused by mutations in the NOTCH3 gene, but the specific mechanisms underlying its pathogenesis and progression remain elusive. Existing research indicates that inflammation plays a critical role in the development and progression of CSVD. The Systemic Immune-Inflammation Index (SII) has revealed to be a reliable new marker to assess immune status and inflammatory response intensity. This study reveals the relationship of SII with cognitive impairment and magnetic resonance imaging (MRI) markers of CSVD in patients with CADASIL. MethodsThis cross-sectional investigate included patients diagnosed with CADASIL who had confirmed NOTCH3 gene mutations and complete clinical data. Cognitive function in patients with CADASIL was appraised by the Mini-Mental State Examination (MMSE). SII is obtained by calculating the number of platelets, neutrophils and lymphocytes in blood routine examination. Summary SVD score and imaging markers of CSVD, including cerebral microbleeds, lacunae, white enlarged perivascular space and matter hyperintensity were evaluated based on magnetic resonance imaging. The association between cognitive impairment and SII and MRI markers in CADASIL were evaluated using logistic regression models and Spearman correlation. ResultsAt baseline, A total of 96 Patients with CADASIL were enrolled in this cross-sectional study. the median age of patients with CADASIL was 59.00 (interquartile range 52.25-66.75) years, and 58.3% of patients were male. The correlation analysis results indicate that the SII level was negatively correlated with MMSE scores in patients with CADASIL (rs=-0.336, P <0.001). An elevated SII was statistically significantly linked with the risk of cognitive impairment (Q4 vs. Q1: OR 5.230, 95% CI 1.040-26.297; P=0.045) after adjusting for age, sex and education. In contrast, there was no considerable difference between SII and summary SVD score or MRI imaging markers. ConclusionsElevated SII was linked with cognitive impairment in CADASIL patients. Nevertheless, there were no significant differences between SII and summary SVD score or MRI imaging markers.

IntroductionThe ischaemic penumbra is the principal therapeutic target in acute ischaemic stroke (AIS). Although perfusion imaging enables identification of salvageable tissue, its availability is limited and iodinated contrast exposure carries risk. Validated blood-based biomarkers could serve as scalable surrogates for imaging-defined penumbra. ObjectiveWe conducted a systematic review and meta-analysis to assess the association between blood-based biomarkers reported in the literature and the ischaemic penumbra. MethodsWe searched Ovid MEDLINE, Embase (Ovid), PsycINFO (Ovid), and Web of Science until December 3, 2025, for studies involving human subjects with AIS aged over 18 years or animal subjects that reported the presence of infarct and ischaemic penumbra. The primary outcome was the difference in mean biomarker levels in subjects with and without ischaemic penumbrae as defined by the study authors. We used the QUADAS-2 tool to assess risk of bias. We calculated each biomarkers pooled standardized mean difference (SMD) and 95% CI where possible. Protein-protein interaction network (PPI) and pathway analyses were conducted in Cytoscape and the enrichR R package (PROSPERO: CRD42023453175). ResultsWe identified 11 studies (1765 human subjects and 8 nonhuman primates) that assessed 53 candidate blood-based biomarkers. Two studies had a low risk of bias, while nine had a risk of bias. A meta-analysis was conducted for seven biomarkers in humans from four studies. Of these, three biomarkers demonstrated significant association with penumbrae in humans: mid-regional pro-adrenomedullin (MR-proADM; SMD 0.80 [95% CI 0.49 to 1.10]), interleukin-10 (IL-10; SMD 1.94 [0.85 to 3.03]), and neuron-specific enolase (NSE; SMD -0.71 [-1.40 to -0.01]). However, substantial statistical heterogeneity was observed for several pooled biomarkers (I{superscript 2} >90%), limiting confidence in effect size precision. Amongst biomarkers where meta-analysis was not possible, 37 biomarkers showed significant association with presence of a penumbra. Oxygen radical absorbance capacity after perchloric acid treatment (ORACPCA; SMD 0.31 [0.01 to 0.60]) showed significant association with penumbra presence; 34 genes (e.g., STK26 r = 0.58, p = 0.003; MGA r = 0.58, p = 0.004; IL1B r = -0.59, p = 0.003; NUP98 r = -0.71, p < 0.001), circOGDH (r = 0.962, p = 0.002), and NT-proBNP (r = 0.199, p < 0.001) were significantly correlated with penumbra volume. PPI analysis identified IL-1{beta} as the most highly connected node (10 interactions), followed by IL-10 and HDAC1/HCAR2. Cdc42 was reported to be significantly associated with penumbrae in nonhuman primates, but there were insufficient data to calculate SMD. Pathway enrichment revealed positive associations with angiogenesis and IL-12 signalling, and negative associations with leukocyte migration, chemokine signalling, and platelet activation. ConclusionsCurrently reported biomarkers of ischaemic penumbra are not ready for clinical implementation. Although implicated pathways converge on inflammatory regulation, haemostasis, and cerebral perfusion, rigorous prospective validation is required before integration into prehospital or emergency triage workflows.

While 18F-Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) is an established biomarker in amyotrophic lateral sclerosis (ALS), the metabolic correlates of motor neuron disease motor variants remain poorly defined. This is why we investigated patterns of cerebral glucose metabolism across the spectrum of motor neuron disorders (MND), including progressive muscular atrophy (PMA), primary lateral sclerosis (PLS) and amyotrophic lateral sclerosis (ALS). We retrospectively included 18 PMA, 25 PLS and 43 matched non-hereditary ALS patients according to most recent diagnostic criteria. FDG-PET imaging revealed similar widespread hypometabolism in PMA, as in ALS, whereas PLS showed a more focal motor cortical pattern of hypometabolism. Despite clinical differences between MND subtypes, PMA and ALS showed similar FDG-PET metabolic patterns, whereas PLS exhibited a more restricted cortical signature in this retrospective study.

BackgroundThe causes of neuropsychiatric symptoms in Parkinsons disease (PD) remain ill-defined. Disruptions in dopamine-dependent reward learning, a consequence of midbrain dopamine loss, potentially represent a mechanism that could underlie the neuropsychiatric symptoms of apathy, depression, and impulsivity, all of which have been proposed to reflect aberrant goal-directed behaviour. However no large-scale investigation that jointly considers these symptoms in PD has ever been undertaken. We aimed to determine if reward learning is associated with apathy, depression and impulsivity symptom in two samples of PD patients. MethodsTwo samples of PD patients (nsample1=81, nsample2=90), tested in their medicated state, completed two widely used reward learning tasks (probabilistic stimulus selection task, probabilistic reward task) from which we derived five summary measures of performance. Apathy, depression, and impulsivity were evaluated using validated self-report questionnaires. ResultsOverall, there was poor consistency in the relationship between reward learning and neuropsychiatric symptom severity. Greater depressive symptom severity was associated with slower reward learning performance in sample 1, but with both slower and faster reward learning performance in sample 2. Greater impulsivity symptom severity was associated with slower reward learning performance in sample 1 but not in sample 2. There were no associations between apathy and reward learning. ConclusionsWe found inconsistent relationships between symptoms of apathy, depression, and impulsivity and reward learning performance across two samples of PD patients. While this doesnt rule out the possibility that reward learning impairments contribute to these symptoms, it suggests any effect is likely to be small and overshadowed by other non-measured factors.