OBJECTIVE:Idiopathic hypersomnia (IH) presents with excessive daytime sleepiness (EDS) despite apparently preserved nocturnal sleep, challenging traditional models of hypersomnolence based on sleep loss or fragmentation. We aimed to test the hypothesis that EDS in IH reflects excessive stabilization of the sleep state, consistent with dysfunctional thalamocortical control rather than impaired sleep quantity or continuity. METHODS:We analyzed overnight polysomnography from 62 IH and 81 age- and sex-matched healthy controls using sleep bout duration, sleep stage transition dynamics, and automated spindle detection. Principal component analyses derived composite indices of NREM and REM sleep stability. Group differences were assessed using ANCOVAs controlling for age and sex, and associations with EDS severity were examined. RESULTS:Compared with controls, IH patients showed reduced transitions from N3 sleep toward lighter stages and wakefulness. Moreover, REM sleep was characterized by longer durations, fewer transitions to wakefulness, and more frequent transitions to lighter stages. In parallel, spindle amplitude was reduced in IH while spindle density was preserved, and smaller spindle amplitudes were associated with shorter latencies on the Multiple Sleep Latency Test. INTERPRETATION:IH is characterized by excessive N3 stabilization and reduction in transitions toward wakefulness in both NREM and REM sleep. These findings suggest that altered sleep-wake dynamics, rather than impaired sleep continuity, may contribute to persistent daytime sleepiness in IH and support sleep stability as a potential target for future research and therapeutic strategies.
BACKGROUND:Hereditary Spastic Paraplegia (HSP) comprises a group of rare genetic diseases characterized by length-dependent axonal degeneration of the corticospinal tracts and dorsal columns, whose main clinical feature is spastic gait. Pathogenic variants in the SPG4 gene cause Spastic Paraplegia Type 4 (SPG4-HSP), the most common form of HSP. SPG4/SPAST encodes spastin, a protein involved in microtubule regulation and lipid droplet behavior. SPG4-HSP shows extreme heterogeneity in both clinical manifestations and genetics. Although no cure is currently available, several strategies aimed at restoring spastin levels are emerging; however, SPG4-HSP still lacks accessible cellular readouts for clinical studies. This study evaluates a cell-imaging approach that quantifies the distance between nucleus and cell centroid (dcnc) in peripheral blood mononuclear cells (PBMCs) in a genetically and clinically heterogeneous SPG4-HSP cohort. METHODS:PBMCs from 48 molecularly confirmed SPG4-HSP patients and 21 healthy controls (HC) were analyzed by automated cell imaging. Dcnc and additional cytoskeletal and lipid droplet-related parameters were measured. Patient-level discrimination was assessed via cross-validated classification; correlations with molecular and clinical features were explored. RESULTS:At the patient level, dcnc distinguishes SPG4-HSP from HC, independently of mutation type and disease severity, supporting robust cross-validated classification and inverse correlation with spastin protein levels. CONCLUSION:Dcnc is a robust, non-invasive, and mutation-independent cellular candidate biomarker for SPG4-HSP. It also offers preliminary evidence consistent with spastin target engagement supporting evaluation in future clinical trials.
OBJECTIVE:Multiple sclerosis (MS) is a neurodegenerative demyelinating disease of the central nervous system. This study aimed to identify micro-RNA (miRNA)-mRNA regulatory networks underlying region-specific molecular mechanisms in white matter and gray matter lesions in progressive MS. METHODS:Global miRNA and mRNA expression profiling were previously performed on white matter and gray matter lesion tissues from postmortem progressive MS brains. These datasets were integrated using Ingenuity Pathway Analysis (IPA) to identify enriched canonical pathways based on experimentally validated miRNA target genes. Functional effects of selected miRNAs were evaluated in primary oligodendrocyte progenitor cells (OPCs) following miRNA mimic transfection using immunocytochemistry and qPCR. RESULTS:Nine miRNAs were commonly dysregulated in both White Matter lesions (WMLs) and Gray Matter lesions (GMLs). Pathway analysis identified two major downstream pathways-cellular senescence and EIF2 signaling-with opposing predicted activation states (activated in White Matter lesions and inhibited in Gray Matter lesions). Among the shared miRNAs, miR-30a and miR-100 exhibited opposing expression patterns, with downregulation in GMLs and upregulation in WMLs, and both were predicted to regulate each pathway. Corresponding target genes of these miRNAs were significantly dysregulated in MS lesions. In primary Oligodendrocyte Progenitor Cells, overexpression of miR-30a or miR-100 significantly reduced proliferation and impaired differentiation, accompanied by decreased expression of their respective target genes. INTERPRETATION:These findings identify miRNAs commonly dysregulated across white matter and gray matter lesions in progressive multiple sclerosis. Furthermore, this study also identifies distinct miRNA-mRNA networks and miRNA-driven regulatory mechanisms that contribute to region-specific impairment of oligodendrocyte maturation and remyelination.
OBJECTIVE:To determine whether ordinal Subtype and Stage Inference (SuStaIn) applied to routine ALSFRS-R item scores can identify reproducible disability progression patterns in amyotrophic lateral sclerosis (ALS) and provide clinically meaningful staging. METHODS:We analysed baseline ALSFRS-R item responses from 866 PRO-ACT participants. Ordinal SuStaIn inferred subtype-specific sequences of functional deterioration and assigned each participant to a subtype and a SuStaIn-derived functional stage. Longitudinal stability was assessed across 3625 consecutive follow-up visit pairs from 697 participants. Structural reproducibility was evaluated in an independent cohort of 301 consecutive ALS patients. Associations of baseline subtype and stage with survival and subsequent ALSFRS-R decline were examined using Cox and piecewise-linear models. RESULTS:A three-subtype solution identified fine motor-, gross motor- and bulbar-predominant patterns of early disability. Within each subtype, SuStaIn reconstructed ordered multidomain sequences of functional deterioration and assigned each participant a SuStaIn-derived stage. Subtype assignment was stable across 90.4% of consecutive visit pairs, and stage was non-decreasing in 98.8%. Subtype-specific event ordering was reproduced in the validation cohort. Higher baseline stage was associated with increased mortality risk in the fine motor- and gross motor-predominant subtypes, but not clearly in the bulbar-predominant subtype. Baseline stage showed subtype-dependent, non-linear associations with subsequent functional decline, with acceleration up to mid-stage breakpoints in the fine motor- and gross motor-predominant subtypes and less evident stage-dependent acceleration in the bulbar-predominant subtype. INTERPRETATION:Routine ALSFRS-R item-level data can define clinically interpretable ALS progression subtypes and latent SuStaIn-derived functional stages. Joint subtype-stage modelling may refine prognostic stratification and support prognosis-informed trial enrichment.
Amyotrophic lateral sclerosis is an incurable neurodegenerative disease involving motor neuron degeneration and metabolic and immune dysfunction. We combined clinical data, cerebrospinal fluid biomarkers and fluorodeoxyglucose positron emission tomography with magnetic resonance imaging to investigate the role of reactive microglia in disease pathogenesis. Patients showed increased cerebrospinal fluid levels of neurofilament light chain and chitinases, along with hypermetabolism in the medulla oblongata. Chitinase levels correlated with brainstem metabolism and clinical severity. These findings suggest a link between microglial activation, brainstem hypermetabolism and disease progression in amyotrophic lateral sclerosis, supporting a central role for neuroinflammation in disease pathogenesis.
Adult-onset cerebral adrenoleukodystrophy is potentially treatable but often difficult to recognize before advanced cerebral involvement. Herein, we describe three men with early-stage disease who initially presented with subtle visual complaints rather than subcortical dementia. Targeted neuropsychological testing revealed higher-order visual dysfunction and posterior interhemispheric disconnection signs, including visual-field-dependent reading or naming deficits and dichotic listening abnormalities. Diffusion tensor imaging showed preferential involvement of posterior callosal and visual stream-related white-matter pathways. These findings define a posterior disconnection phenotype of adult-onset cerebral adrenoleukodystrophy and provide a clinically useful framework for early recognition and timely therapeutic consideration of this treatable leukodystrophy.
OBJECTIVE:To determine whether discontinuing anti-CD20 therapy in people with relapsing-onset MS aged over 50 is associated with an increased risk of relapse, inflammatory activity, confirmed disability accrual, and serious infection compared with continuing therapy. METHODS:This observational, multicenter, retrospective cohort study included 2283 patients from the French MS registry aged > 50, who had received at least two cycles of anti-CD20 and had experienced no relapses or MRI activity for at least one year prior to inclusion. Patients were classified as discontinuing or continuing therapy and 1:1 matched using a time-dependent propensity score. Outcomes were time to first relapse, inflammatory activity (relapse and/or MRI activity), confirmed disability accrual, and serious infection. RESULTS:Among 1900 patients continuing therapy and 383 discontinuing, 224 in each group were matched (mean age = 57.7 ± 5.9 years; mean EDSS = 5.4 ± 1.7; median follow-up after matching = 34.8 [21.6-50.4] months). There were no significant differences between groups in time to first relapse (HR = 0.6, 95% CI 0.3-1.3, p = 0.2), inflammatory activity (HR = 0.9, 95% CI 0.5-1.4, p = 0.6), confirmed disability accrual (HR = 1.2, 95% CI 0.9-1.7, p = 0.2), and serious infections (HR = 1.0, 95% CI 0.6-1.8, p = 0.9). INTERPRETATION:This retrospective study found no evidence of differences between stopping and continuing anti-CD20 therapy regarding relapse, inflammatory activity, disability accrual, or serious infections in older patients with long-standing non-active MS over a median 2.9-year follow-up.
OBJECTIVE:Susac syndrome (SS) is a rare CD8+ T cell-mediated microangiopathy affecting the brain, retina, and auditory labyrinth. Endothelial injury is thought to be a central mechanism; however, no circulating disease biomarkers are known. We performed targeted proteomic profiling to identify circulating endothelial-associated proteins as biomarkers in SS. METHODS:Serum from four cases with definite or probable SS and eight healthy controls was analyzed using data-independent acquisition mass spectrometry. Analyses were restricted to proteins with established endothelial cell surface or membrane association, and differential abundance was assessed using detection-based (Fisher's exact) and quantitative (probabilistic dropout analysis) modeling. RESULTS:Six endothelial-associated proteins demonstrated differential abundance in SS (p < 0.05 on unadjusted analysis). Low-density lipoprotein receptor-related protein 1 was increased (log2 fold change = +2.19, p = 0.0059), whereas Nectin-2, Melanoma cell adhesion molecule, Fatty acid transport protein 4, P-selectin, and Interleukin-6 signal transducer were decreased (log2 fold change -1.38 to -1.89; all p < 0.05). CONCLUSIONS:Our findings suggest circulating proteins on the endothelial cell surface or membrane as potential biomarkers for SS and support endothelial dysfunction as a central disease mechanism. This pilot study provides a rationale for validation in larger, longitudinal cohorts. TRIAL REGISTRATION:ClinicalTrials.gov, NCT00001248 and NCT02435810.
OBJECTIVE:Peak-width of skeletonized mean diffusivity (PSMD) and diffusion tensor imaging-analysis along the perivascular space (DTI-ALPS), reflecting white matter integrity and glymphatic function, are altered in Alzheimer's disease (AD). We evaluated whether these biomarkers differ between AD participants with and without concomitant cerebral amyloid angiopathy (CAA). METHODS:The study included 50 AD participants with mild cognitive impairment/mild dementia, and intermediate to high AD neuropathologic change at autopsy. AD was categorized as AD with CAA and AD without CAA based on CAA neuropathology. We evaluated global and regional (frontal, parietal, temporal and occipital) PSMD; left, right and mean DTI-ALPS indices and their association with clinical measures [Clinical dementia rating sum-of-boxes (CDR-SB) from CDR Dementia Staging Instrument, mini mental state examination (MMSE), cognitive composites: memory, processing speed, executive function, and language]. RESULTS:AD participants with CAA (n = 17) had higher global [4.02 ± 1.44 (mean ± SD × 10-4 mm2/s) vs. 3.12 ± 0.91, β = -0.80, 95% CI (-1.42, -0.18), p = 0.012] and occipital PSMD [4.02 ± 1.10 vs. 3.00 ± 1.08, β = -0.88, 95% CI (-1.51, -0.26), p = 0.026] than those without CAA. No PSMD metric was associated with any clinical measure. However, imaging-by-group interactions showed global PSMD associated with language [β = -0.89, 95% CI (-1.53, -0.26), p = 0.027] and parietal PSMD with language [β = -1.05, 95% CI (-1.74, -0.36), p = 0.014] and memory [β = -0.83, 95% CI (-1.38, -0.28), p = 0.015]. DTI-ALPS indices did not differ by group. Higher mean and right DTI-ALPS indices were associated with preserved language function [mean: β = 9.33, 95% CI (2.05, 16.62), p = 0.036; right: β = 7.75, 95% CI (1.54, 13.95), p = 0.043] without imaging-by-group interactions. INTERPRETATION:Global and occipital PSMD may help identify AD participants with concomitant CAA.
OBJECTIVE:Reserve refers to the brain's ability to maintain function after an injury and strongly relates to traumatic brain injury (TBI) outcomes. This study examined (1) whether associations between pre-injury reserve proxies and outcomes differed across injury severity categories, and (2) whether the impact of injury severity varied across functional, symptomatic, and cognitive outcomes. METHODS:This observational cohort study used data from CENTER-TBI. Of 4509 enrolled patients, 3377 were between 18 and 75 years and alive 6 months post-injury. Outcomes included functional outcome (GOSE, n = 2790), self-reported symptoms (RPQ, n = 1470), and cognition (composite score, n = 1968). Pre-injury reserve proxies were education, age, and psychiatric history. Injury severity was categorized as uncomplicated mild TBI, complicated mild TBI, moderate, and severe TBI. RESULTS:Of nine tested interactions between reserve proxies and injury severity, only the interaction of age with injury severity on cognition was significant (β = 0.1, p < 0.001), with age being less influential in severe TBI. Higher education and no psychiatric history predicted better outcomes across all severities. Younger age predicted more favorable GOSE and cognitive scores. RPQ symptoms peaked among adults aged 46-60. Increasing injury severity was associated with progressively lower odds of GOSE ≥ 6. RPQ scores plateaued in moderate TBI. Cognitive performance was similar in uncomplicated and complicated mild TBI. INTERPRETATION:Pre-injury reserve proxies predicted outcome largely independent of injury severity, with higher reserves linked to better recovery. Injury severity showed a graded relationship with functional outcome. Symptom burden and cognitive impairment demonstrated non-linear patterns across severity categories. TRIAL REGISTRATION:ClinicalTrials.gov identifier: NCT0221022.
OBJECTIVE:Managing obesity in patients with epilepsy is complicated by the weight-gaining properties of essential antiseizure medications (ASMs) such as valproate and pregabalin. We evaluated the safety and efficacy of initiating glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in this population. METHODS:We conducted a retrospective cohort study using the NIH All of Us Research Program database, identifying adults with comorbid epilepsy, type 2 diabetes, and obesity. New initiators of GLP-1 RAs were compared with matched controls using 1:1 propensity score matching that included baseline weight-gaining ASM use. The primary safety outcome was a composite of seizure-related hospitalization or new ASM addition. Secondary efficacy endpoints (weight and HbA1c change at 12 months) were stratified by concomitant weight-gaining ASM use. RESULTS:The propensity-matched cohort included 610 patients with well-balanced baseline characteristics. GLP-1 RA initiation was not associated with failure to control seizure compared with standard care (hazard ratio 0.92, 95% CI 0.68-1.23; p = 0.57); given the observed events, the study could detect a hazard ratio of 1.53 or greater. GLP-1 RA users achieved a mean adjusted weight loss of -5.73% (p = 0.001) and an HbA1c reduction of -0.71% (p = 0.018). Significant weight reduction was achieved even among patients concomitantly treated with weight-gaining ASMs (adjusted difference -4.15%, p = 0.003). INTERPRETATION:GLP-1 RAs showed no evidence of seizure worsening and remained effective for weight loss even among patients receiving weight-gaining ASMs, supporting their use for metabolic benefit in patients with epilepsy.
BACKGROUND/OBJECTIVE:Arterial spin-labeling (ASL) MRI can measure perfusion signal adjacent to CSF spaces and may provide information regarding CSF-adjacent water transport physiology. We developed an automated pipeline to extract cortical-CSF interface (IF) perfusion for comparison between Alzheimer disease (AD) and cognitively normal controls. METHODS:In this retrospective study, participants with AD and cognitively normal controls with ASL and 3D T1-weighted MRI were included. Parenchymal cerebral blood flow (CBF) was evaluated globally (whole brain, gray matter, white matter) and across 12 brain regions. IF-perfusion values were quantified using an automated pipeline with tissue segmentation, registration, partial-volume-aware masking, and arterial-signal exclusion. Multivariable sensitivity analysis was performed, adjusting for age, sex, scanner vendor, and acquisition site. Predictive modeling was performed using LASSO-regularized logistic regression with nested repeated stratified cross-validation, and feature contributions were summarized using SHAP. RESULTS:A total of 51 patients with AD, age (median: 73 years) and 53 cognitively normal subjects (median age: 69) were included. Global CBF did not differ between groups. However, IF-perfusion values were significantly lower in AD (median 4.4, IQR 3.2-4.8) than in controls (median 5.2, IQR 4.5-6.3; p < 0.001). In multivariable analysis, AD remained independently associated with lower IF-perfusion after adjustment for age, sex, scanner vendor, and acquisition site (β = -1.88, 95% CI: -3.52 to -0.25; p = 0.025). In LASSO-regularized logistic regression model, only IF-perfusion and cuneus-CBF remained as significant contributing features for the prediction of AD probability with the highest contribution from IF. The final model showed mean ROC-AUC 0.81 in the training and AUC of 0.78 in the testing dataset. CONCLUSION:ASL-derived IF-perfusion is reduced in AD and may represent a promising imaging marker of altered CSF-adjacent water transport physiology. Further validation against established biomarkers of CSF dynamics and clearance pathways is warranted.
OBJECTIVE:The aim of this study was to characterize intellectual and motor function, neurological features including epilepsy, treatment response, and adaptive behavior in patients with pyruvate dehydrogenase complex deficiency (PDCD) in Sweden. METHODS:Forty-two individuals with genetically confirmed PDCD (86% PDHA1-related disease) were identified from a nationwide epidemiological study and were included in this cross-sectional study comprising systematic neurological evaluations (n = 41) and caregiver interviews assessing adaptive behavior (n = 35). RESULTS:Intellectual disability was detected in 33/42 (79%) individuals, while 31/35 (89%) demonstrated significant impairments in adaptive functioning. Although 27/39 (69%) were ambulatory, only 8/39 (21%) demonstrated age-appropriate walking ability. Clinical signs of polyneuropathy were observed in 24/41 (59%), bulbar symptoms in 22/41 (54%), spasticity in 19/41 (46%), ataxia in 13/41 (32%), and dystonia in 9/41 (22%). Lifetime epilepsy was present in 16/41 (39%) of individuals. Ketogenic diet treatment, administered to 30 individuals, was effective in both prenatal- and postnatal-onset disease. Seizure frequency decreased in individuals with epilepsy (8/9; 89%) and relapses of dystonia, ataxia, exercise intolerance, and lactic acidosis were prevented in all affected individuals (15/15). Improvements in communication and motor function were also noted. DISCUSSION:Intellectual disability and deficits in adaptive behavior are frequent in PDCD, although cognitive outcomes are more heterogeneous among individuals with postnatal onset. Prenatal onset and epilepsy are associated with severe-profound intellectual disability. Although most are ambulatory, motor deficits are frequent. A ketogenic diet treatment is a safe and effective therapeutic option, contributing to both seizure control and remission of neurological deterioration relapses.
BACKGROUND:We aimed to identify the proportion of individuals with a confirmed diagnosis of childhood absence epilepsy (CAE) or juvenile absence epilepsy (JAE) who show a negative routine EEG (rEEG), and to determine the main factors associated with this finding. METHODS:Individuals with CAE or JAE underwent both an rEEG and a 24-h ambulatory EEG (24-h-aEEG). Participants were classified as 'rEEG positive' if generalised spike-wave discharges (GSWs) and/or typical absences (TAs) were observed, and as 'rEEG negative' if no such features were detected. 24-h-aEEG recordings served as the ground truth to confirm the diagnosis in cases with a negative rEEG. RESULTS:Eighty-two individuals [40/82 (48.8%) females; mean age 12.5 ± 5.6 years] were included, of whom 39/82 (47.6%) were not receiving anti-seizure medications (ASMs) at the time of the EEG. Overall, 31/82 (37.8%) had a negative rEEG, including 10/39 (25.6%) in the cohort of ASM-naïve individuals. Compared with rEEG-positive participants, those in the rEEG-negative group had a later age at epilepsy onset (12.1 ± 4.5 years; p < 0.001) and were older at the time of EEG (16.5 ± 5.3 years; p < 0.0001). Older age at EEG emerged as significantly associated with a negative rEEG (OR = 1.23; 95% CI = 1.03-1.46; p = 0.019), independent of age at onset, epilepsy syndrome (CAE or JAE) and ASM exposure. Sensitivity analyses confirmed the association between older age and rEEG negativity across all cohorts: ASM-naïve individuals (OR = 1.41; 95% CI = 1.12-1.78), CAE (OR = 1.27; 95% CI = 1.02-1.58), and JAE (OR = 1.36; 95% CI 1.09-1.69) groups. Youden's exploratory analysis identified ≥ 14 years as the optimal threshold for predicting a rEEG negative. CONCLUSION:Age significantly reduces the diagnostic yield of rEEG in CAE and JAE, regardless of ASM treatment.
The claustrum sign is a distinctive neuroimaging finding characterized by bilateral T2/FLAIR hyperintensity of the claustrum, one of the most interconnected regions of the human brain. It was first described in new-onset refractory status epilepticus (NORSE) and febrile infection-related epilepsy syndrome (FIRES). A systematic search was conducted according to PRISMA guidelines from 2018 (formal definition of NORSE) to February 2026 (PROSPERO 2026 CRD420261307306). We included peer-reviewed original studies reporting MRI findings and patient-level data, and compared clinical characteristics, treatments, and outcomes of patients with claustrum alteration versus NORSE/FIRES patients without this finding. Of 785 records identified, 65 studies met inclusion criteria; 41 provided individual patient data, yielding 206 NORSE cases (72 with the claustrum sign, 134 without). All but one patient with the claustrum sign met criteria for cryptogenic NORSE. Patients were predominantly young (mean age 24.9 years) and had a febrile prodrome in 93% of cases. Convulsive status epilepticus (SE) occurred in 98%, progressing to super-refractory SE (SRSE) in more than half reported cases. Bilateral claustrum hyperintensity was detected in 68/71 patients during the acute phase, typically emerging 7 days after SE onset. Immunotherapy was administered in 92% of patients. In-hospital mortality was 9%, while 74% of patients developed chronic epilepsy. Compared with patients without claustrum involvement, those with the claustrum sign more often had febrile onset (93% vs. 51%, p < 0.001) and convulsive SE (98% vs. 81.5%, p = 0.008), lower rates of SRSE (51% vs. 96.5%, p < 0.001), and ICU admission (71% vs. 99%, p < 0.001), and a trend toward lower mortality (9% vs. 16%, p = 0.240). Recognition of the claustrum sign may support early diagnosis and targeted treatment. Trial Registration: PROSPERO 2026 [CRD420261307306].
OBJECTIVE:To explore whether routine outpatient video combined with deep learning-based pose estimation and clinically interpretable kinematic features can support multi-label phenotyping of co-occurring hyperkinetic movement disorders (HMDs). METHODS:In this exploratory single-centre proof-of-concept study, videos from 21 patients with HMDs and 4 healthy controls were processed with markerless pose estimation (YOLOv8) and 2-dimensional keypoint trajectories transformed into kinematic descriptors spanning statistical, temporal, spectral, and complexity domains. Ten-second windows were aligned to expert annotations for eight hyperkinetic phenomenologies. Conventional supervised classifiers were trained on these tabular descriptors. Window-level predictions were aggregated to the patient level, and label-specific thresholds were tuned on training participants only. RESULTS:In patient-level multi-label performance reporting, (i) the best single pipeline selected by discrimination (StandardScaler + MLP) achieved a macro-AUPRC of 0.821 ± 0.019 and a macro-receiver operating characteristic area under the curve of 0.830 ± 0.029. (ii) The best single pipeline selected by Hamming accuracy (MinMaxScaler + SVM) reached 0.764 ± 0.041. (iii) Under prespecified nested cross-validation with per-label model selection within training folds (primary analysis), macro-AUPRC was 0.717 ± 0.030, macro-AUROC was 0.767 ± 0.069, Hamming accuracy was 0.764 ± 0.014 and patient-label agreement was 153/200 (76.5%). (iv) Post hoc per-label selection of the best-performing pipeline defined an exploratory upper bound of 172/200 (86.0%). INTERPRETATION:In this exploratory study, a hybrid pipeline combining deep learning pose estimation with feature-engineered supervised classification produced encouraging patient-level multi-label performance for co-occurring HMDs. These findings are proof-of-concept; external, multicentre, prospective validation is required before clinical or trial use.
OBJECTIVE:Intracerebral hemorrhage (ICH) causes high morbidity and mortality, with neurotoxic inflammation driven by infiltrating monocytes. This study is an in-depth longitudinal examination of the immune response during the first week of ICH in the presence and absence of the immunomodulatory drug BAF312 (Siponimod). METHODS:We performed single-cell RNA sequencing on peripheral blood samples taken 1, 3, and 7 days post-ICH in patients treated with BAF312 (5 patients) or placebo (2 patients). The correlation of gene expression with time, drug treatment, measures of ICH severity, and clinical outcome was examined. Results were validated by comparison with previous studies and measurement of plasma cytokine concentration. RESULTS:A broad peripheral inflammatory response involving both lymphoid and myeloid cells peaked at day 3 post ICH. BAF312 markedly reduced peripheral blood T and B lymphocyte numbers by day 3. BAF312 also impacted the myeloid response, suppressing TNF signaling in classical and nonclassical monocytes. Multiple cytokine signaling pathways were decreased, though BAF312 did not impact plasma cytokine or chemokine concentrations. Surprisingly, increased monocyte TNF signaling was associated with better 90-day clinical outcome. INTERPRETATION:These findings demonstrate broad peripheral leukocyte activation after ICH and suggest that during ICH, BAF312 suppresses both lymphoid and myeloid responses. The positive association of monocyte TNF signaling with better outcome points to the positive role of monocytes during the subacute stage of ICH and supports a complex role of monocytes in this disease. Larger studies will determine the extent to which these findings apply beyond the small cohort examined here.
OBJECTIVES:A history of vascular disease has been shown to be associated with an increased risk of Parkinson's disease, but this may be due to reverse causation. In addition, non-steroidal anti-inflammatory drugs are thought to reduce Parkinson's disease risk, but evidence is inconsistent and confounding by prior vascular disease is possible. Our objective was to examine these associations in the UK prospective Million Women Study. METHODS:A total of 819,575 women were followed from median year 2001 for first hospital admission or death from Parkinson's disease. A history of ischaemic heart disease and of cerebrovascular disease was ascertained through hospital admission records and self-report at baseline. Use of the two non-steroidal anti-inflammatory drugs, aspirin and ibuprofen, was ascertained through self-report at baseline. Cox regression was used to estimate adjusted hazard ratios. RESULTS:During an average follow-up of 18 years, 10,364 cases of Parkinson's disease occurred. Women with prior ischaemic heart disease had an increased risk of Parkinson's disease (Hazard ratio 1.45, 95% confidence interval 1.35-1.54), as did women with prior cerebrovascular disease (1.51, 1.32-1.73); both associations were still pronounced 10 or more years after baseline. There was little association of aspirin use with risk of Parkinson's disease (1.06, 1.00-1.13) after adjustment for vascular disease, and no association with ibuprofen use (1.04, 0.97-1.11). INTERPRETATION:Ischaemic heart disease and cerebrovascular disease are both positively associated with subsequent risk of Parkinson's disease and these associations are unlikely to be solely due to reverse causation. In contrast, use of non-steroidal anti-inflammatory drugs is not materially associated with risk.
