Introduction

[F]FDG PET/CT scan is sometimes performed as part of the diagnostic evaluation of non‐compressive myelopathies, but the spinal cord lesion metabolism is not systematically evaluated. We aimed to investigate the diagnostic value of spinal cord lesion metabolism on [F]FDG PET/CT for differentiating inflammatory myelitis from neurosarcoidosis and tumoral lesions.

Methods

We conducted a retrospective cohort study of patients presenting with spinal cord lesions who underwent [F]FDG PET/CT. Patients were classified as primary inflammatory myelitis, neurosarcoidosis, tumoral lesions, or other etiologies. PET/CT examinations were reviewed by a nuclear medicine physician, masked to final diagnosis, who assessed the presence of hypermetabolism (qualitative analysis) and measured lesion SUV, lesion‐to‐liver ratio, and level‐standardized ‐score to account for physiological uptake variability (quantitative analysis).

Results

A total of 106 patients were included: 60 (56.6%) with inflammatory myelitis, 20 (18.9%) with neurosarcoidosis, 10 (9.4%) with tumoral lesions, and 16 (15.1%) with other etiologies. Hypermetabolism was found in 80.0% of tumoral lesions, 50.0% of neurosarcoidosis, and 23.3% of inflammatory myelitis. PET/CT showed good performance in differentiating inflammatory myelitis or neurosarcoidosis from tumoral lesions using qualitative analysis (hypermetabolism: sensitivity 0.77, specificity 0.80, and 0.50, respectively) and quantitative analysis (SUV: AUC 0.89 and 0.84, respectively). The performance of SUV for distinguishing inflammatory myelitis from neurosarcoidosis was low (AUC 0.55), but improved with the lesion‐to‐liver ratio (AUC 0.64) and level‐standardized ‐score (AUC 0.65).

Conclusion

Spinal cord hypermetabolism on [F]FDG PET/CT demonstrated good performance for distinguishing tumoral lesions from inflammatory or neurosarcoidosis, but lower performance for differentiating inflammatory myelitis from neurosarcoidosis.

Abstract

The global burden of age‐associated diseases continues to grow. In particular, the accelerating impact of neurodegenerative diseases on individuals, communities and societies necessitates more effective approaches to diagnosis, prognosis and treatment of such disorders. Hence, the establishment of imaging biomarkers for early detection of disease, progression monitoring, and therapeutic evaluation is of utmost importance. Yet, despite the scientific consensus on the benefits of scientific collaboration and consequently medical innovation including biomarker development, substantial barriers for sharing neuroimaging data remain, demanding a transformation in how scientific data are generated, made accessible, re‐used and valued. These barriers range from technical and infrastructural limitations to legal and motivational challenges that hinder widespread adoption of open science practices. Here, we present a comprehensive overview of the current landscape of brain imaging data sharing in neurodegenerative disease research. We explore the status of preregistration, data harmonization and storage standardization, legal compliance, and researcher incentives. We highlight best practices before, during and after data generation and the pressing need for a coordinated strategy regarding simplified and unified legal frameworks compliant with the General Data Protection Regulation of the European Union. Finally, we advocate for the establishment of an academic credit system designed to reward data stewardship. Only with a combined effort from researchers, stakeholders and funding agencies including a sustained infrastructure investment and community education, the field can fully overcome inertia and move towards much‐desired open science, thereby fully leveraging shared data to improve patient outcomes and scientific discovery.

Background

Blood–brain barrier (BBB) dysfunction is an early feature of Alzheimer's disease (AD), influenced by amyloid pathology, astrocyte activation, and vasoactive mediators such as endothelin‐1 (ET‐1). ET‐1 has been implicated in apoptosis and vascular senescence through induction of p53, a pro‐apoptotic factor, whereas BCL‐X exerts antiapoptotic effects. We investigated the interplay between ET‐1, p53, and BCL‐X in AD and their contribution to BBB permeability.

Methods

We studied 101 individuals (70 AD, 31 controls) who underwent cerebrospinal fluid (CSF) analysis for Aβ42, p‐tau, ET‐1, p53, BCL‐X, and the CSF/serum albumin quotient (QAlb), an index of BBB permeability. Correlations between biomarkers were explored, followed by multiple regression and mediation analysis to assess whether p53 mediated the ET‐1–BBB relationship.

Results

No absolute differences in ET‐1, p53, or BCL‐X were found between AD and controls. However, in AD, ET‐1 correlated positively with p53 and negatively with BCL‐X, whereas no such associations were seen in controls. None of these biomarkers related to the p‐tau/Aβ42 ratio. Regression analysis identified both ET‐1 and p53 as independent predictors of BBB permeability. Mediation analysis further revealed that ET‐1 influenced BBB permeability both directly and indirectly through p53.

Conclusion

Our findings suggest that AD is characterized less by absolute biomarker changes and more by altered interrelationships linking ET‐1, apoptosis, and BBB integrity. ET‐1 may promote BBB dysfunction partly via p53, which is consistent with the mechanisms of vascular senescence. These results highlight apoptosis–vascular interactions as potential drivers of BBB impairment in AD.

Late‐onset Pompe disease (LOPD) is a progressive myopathy. Enzyme replacement therapy is effective, but long‐term outcomes vary. Avalglucosidase alfa, shown to be non‐inferior to alglucosidase alfa in a phase 3 trial, became available in France through compassionate use for patients with insufficient response to alglucosidase alfa.

Methods

Data from the French Pompe registry were analyzed for patients who switched to avalglucosidase alfa with at least 1 year of follow‐up. Respiratory function (forced vital capacity, FVC) and motor function evaluated with gait performance (Six‐Minute Walk Test, 6MWT) were assessed before the switch, and one and 2 years after. Individual changes were compared using paired‐sample tests.

Results

Forty‐seven adult patients were included. A stabilization of motor decline was observed: prior to switching, the 6MWT decreased by −27 m/year, whereas an improvement of +17 m/year was seen during the first year after the switch ( = 0.001), followed by overall stability in the second year (−10 m/year,  = 0.280). Respiratory changes were not statistically significant: a decline of 60 mL/year before the switch versus 10 mL/year after 1 year ( = 0.161), and 20 mL/year during the second year ( = 0.346). Three patients died during follow‐up, with causes unrelated to the disease or treatment.

Discussion

Gait deterioration halted during the first year after transitioning to avalglucosidase, with sustained stabilization thereafter, while respiratory parameters showed minimal change. For patients experiencing significant walking decline under alglucosidase alfa therapy, switching to avalglucosidase alfa resulted in disease stabilization, beginning with mild improvement in the first year and a return to pre‐switch baseline thereafter.

Background

The prodromal phase of Dementia with Lewy bodies (DLB) remains unexplored and poorly defined. This systematic review scrutinised studies on the earliest cognitive DLB deficits, focusing on the most useful neuropsychological tests.

Methods

From an initial pool of 2307 articles, 37 articles met inclusion criteria including either a prodromal DLB population or DLB cohorts comprehensive of individuals in prodromal or Mild Cognitive Impairment (MCI) due to Lewy Bodies pathology. These studies included comparisons with healthy controls, MCI due to Alzheimer's Disease (MCI‐AD), or other aetiologies, and patients with established dementia.

Results

Mild impairments were found in attention, executive functions, visual perception, and working memory in prodromal DLB patients. Prodromal DLB exhibited worse performance in memory and language than healthy controls, while showing better memory but worse performance in visual perception, attention, and executive tasks than MCI‐AD. Comparisons in some articles with MCI of other aetiologies confirmed the distinctiveness for prodromal DLB of this pattern of impairment. The most used tests to detect prodromal DLB included the Frontal Assessment Battery (FAB), Digit Symbol Substitution Test (DSST), Stroop test, AX continuous performance test (AX‐CPT), digit span backward, Rey‐Osterrieth Complex Figure copy, pareidolia test, and Visual Object and Space Perception battery (VOSP).

Conclusions

Prodromal DLB can be detected using test batteries focused on specific cognitive domains and facilitating early diagnosis. It is possible to standardise a targeted test battery centred on specific visuoperceptual and attention domains for early detection of subtle cognitive decline due to Lewy body pathology.

Background

In the early time window, direct mechanical thrombectomy (MT) is not non‐inferior to combined treatment with intravenous thrombolysis (IVT) for patients with large vessel occlusion (LVO) stroke, while its non‐inferiority in the extended time window remains uncertain. This study assessed whether direct MT is non‐inferior to IVT + MT beyond 4.5 h or at wake‐up.

Methods

We emulated a non‐inferiority trial, comparing direct MT vs. IVT + MT, including patients with anterior circulation LVO between 4.5 and 24 h from symptom onset or at wake‐up, without contraindications to IVT and with target perfusion mismatch. We used inverse probability weighting (IPW) adjusted for pre‐specified covariates. The primary outcome was 90‐day mRS 0–2, with non‐inferiority defined by a lower 95% CI boundary of the Risk Difference (RD) ≥ −1.3%.

Results

Among 347 patients, 212 received direct MT and 135 received IVT + MT. After IPW, patients treated with direct MT and IVT + MT had a similar likelihood of achieving a 90‐day mRS of 0–2 (adjRD –2.90 [95% CI –6.64 to 0.84]) with the lower boundary of the RD 95% CI crossing the non‐inferiority margin. Additionally, direct MT was associated with a shift toward a higher score on the 90‐day mRS (adjusted Common OR 1.59 [95% CI 1.05–2.39]), not confirmed after IPW, and with lower odds of successful recanalization (adjOR 0.38 [95% CI 0.18–0.78]). Rates of 90‐day mRS 0–1, sICH, and mortality were similar between groups.

Conclusions

In our target trial emulation, direct MT was not non‐inferior to IVT + MT treatment beyond 4.5 h from symptom onset or at wake‐up, with IVT before MT yielding higher successful recanalization rates.

Introduction

Ataxia‐telangiectasia (AT) is characterized by progressive cerebellar ataxia, oculomotor apraxia, immunodeficiency, and increased cancer susceptibility. No disease‐modifying treatment is available. This systematic review aimed to evaluate the efficacy and safety of pharmacological interventions for ataxia in pediatric AT.

Method

A systematic search was conducted across MEDLINE, Scopus, Web of Science, and through December 2025. Eligible studies included randomized controlled trials (RCTs) and single‐arm interventional studies evaluating pharmacological treatments for cerebellar ataxia in patients aged ≤ 18 years with genetically confirmed AT.

Results

Thirteen studies (3 RCTs, 10 single‐arm trials) involving 314 participants (mean age 10.87 years) were included. Interventions included betamethasone, erythrocyte‐encapsulated dexamethasone (eDSP), nicotinamide riboside (NR), leucine derivatives, and amantadine. Betamethasone demonstrated transient improvements in the Scale for the Assessment and Rating of Ataxia (SARA) and International Cooperative Ataxia Rating Scale (ICARS) scores, with dose‐dependent systemic toxicity. eDSP showed favorable tolerability but was ineffective in phase 3 trials, although subgroup analyses suggested a potential benefit in children aged 6–9 years. NR supplementation improved SARA and AT Neurological Examination Scale Toolkit (AT‐NEST) scores in open‐label studies. Leucine derivatives showed mixed results. Amantadine showed benefits in patients with extrapyramidal symptoms.

Conclusions

The recurrent pattern of promising open‐label findings followed by negative phase 3 results highlights a translational gap attributable to methodological limitations, including small sample sizes, heterogeneous populations, and variable outcome measures. The non‐linear disease progression and age‐dependent treatment response further complicate trial design. Current evidence remains insufficient to guide clinical practice.

Trial Registration

PROSPERO number: CRD420251184721

Background

Sleep disorders can exacerbate headache burden, yet their prevalence and reversibility in medication‐overuse headache (MOH) remain unexplored. We aimed to evaluate sleep disorders and associated factors in MOH patients compared with controls, and to assess outcomes following headache treatment.

Methods

This prospective case–control study was conducted at a specialised headache center. Patients aged ≥ 18 years with MOH ( = 171; mean age 43.3 years; 81.9% female; migraine 64.9%; tension‐type headache 35.1%) and age‐ and sex‐matched headache controls without MOH ( = 173; mean age 41.4 years; 74.6% female; migraine 57.8%; tension‐type headache 42.2%) underwent semi‐structured interviews and standardised assessments including semi‐structured interviews, validated questionnaires, headache and sleep calendars and polysomnography when indicated. Follow‐up assessments were performed after headache treatment in 87 MOH patients (mean 24.2 months) and 70 controls (mean 26.4 months).

Results

Chronic insomnia was more prevalent in MOH than in controls (60.2% vs. 47.4%; OR 1.7, 95% CI 1.1–2.6,  = 0.03), as was restless legs syndrome (37.4% vs. 22.0%; OR 2.1, 95% CI 1.3–3.4,  = 0.003). Factors associated with chronic insomnia in MOH included nocturnal headache (OR 2.0), nighttime analgesic use (OR 2.5), overweight (OR 2.7), and arterial hypertension (OR 2.6). Following treatment, chronic insomnia decreased to 33.3% and restless legs syndrome to 14.9% (both  < 0.001), paralleling reductions in headache frequency and analgesic use.

Conclusions

This is the first study to demonstrate high sleep disorder prevalence in MOH and its reversibility following headache treatment. Early screening for sleep disorders in MOH patients is recommended.

Background

Oropharyngeal dysphagia is a common and disabling consequence of stroke. Transcranial direct current stimulation (tDCS) has shown potential in promoting swallowing recovery, although evidence remains limited.

Objective

To determine whether bilateral anodal tDCS combined with intensive speech‐language therapy (SLT) improves swallowing outcomes compared with sham stimulation in patients with post‐stroke dysphagia. Exploratory analyses examined the influence of treatment phase, sex, lesion site, and baseline severity.

Methods

This multicenter, randomized, double‐blind, sham‐controlled trial enrolled patients with supratentorial or infratentorial ischemic stroke and oropharyngeal dysphagia. Participants received either bilateral anodal tDCS or sham stimulation (1.5 mA, 20 min/day, 5 days/week for 2 weeks) combined with intensive SLT over 6 weeks. Swallowing outcomes were assessed at baseline, 2 weeks, and 6 weeks using the Dysphagia Outcome and Severity Scale (DOSS, primary outcome), Penetration–Aspiration Scale (PAS), Mann Assessment of Swallowing Ability (MASA), and Swallowing Quality of Life questionnaire (SWAL‐QoL).

Results

Forty‐six patients (24 active, 22 sham) completed the protocol. Both groups showed significant improvement across all outcomes ( < 0.001), with no significant difference between active and sham stimulation. The DOSS was the most sensitive measure, showing sustained improvement over time. Exploratory analyses indicated greater MASA gains with active tDCS in infratentorial strokes ( = 0.04). Correlation analyses showed that greater baseline dysphagia severity was associated with larger functional gains.

Conclusions

Intensive SLT was associated with meaningful recovery in post‐stroke dysphagia, regardless of stimulation condition. Exploratory findings suggest that bilateral tDCS may confer additional benefit in selected lesion subgroups.

Background

Medications for migraine prevention targeting the calcitonin gene‐related peptide (CGRP) pathway have substantially reduced symptom burden in many patients that have failed previous treatment strategies. In contrast, data on treatment response to monoclonal antibodies (mAbs) or small molecule receptor antagonists (gepants) in patients suffering from vestibular migraine (VM) is scarce and preliminary.

Methods

We discuss the existing literature on VM‐prevention using mAbs and gepants with a special focus on biases and limitations such as small sample sizes, retrospective study design, lack of blinding, and patient selection.

Results

Studies identified ( = 8) assessed different mAbs and gepants and generally reported improvement of vestibular symptoms and scores used, but were often of small sample size and lacked blinding and control groups. In a single randomized controlled trial, a significant treatment response to galcanezumab was identified, with a medium to large effect size (ranging between 0.56 and 1.02) for dizzy days reported and on scores applied (dizziness handicap inventory [DHI] and Vestibular Migraine Patient Assessment Tool and Handicap Inventory [VM‐PATHI]).

Conclusions

Data on anti‐CGRP treatments for VM remain limited, and efficacy established in headache migraine cannot be straightforwardly extrapolated to VM given differences in underlying pathophysiology. There remains a risk that initial effect estimates may diminish over time, with early outcomes partially inflated by a novelty effect, expectancy, and more nuanced methodological approaches. Targeted treatment options for this common and often debilitating condition are genuinely welcomed, but the current evidence warrants careful interpretation for CGRP‐related therapies.

Objectives

Intracerebral hemorrhage (ICH) is associated with adverse functional outcomes and elevated mortality, driven by hematoma size and expansion. Timely blood pressure (BP) management may help mitigate hematoma growth. We aimed to assess the effects of clevidipine, an intravenously administered calcium‐channel blocker, on hematoma volume and functional outcomes compared with standard antihypertensive therapy in hypertensive ICH patients.

Methods

We performed a prospective cohort study with a historical control group assessing serial hematoma volume measurements and clinical outcomes in acute hypertensive ICH patients treated with intravenous clevidipine (2023–2025) compared with standard antihypertensive therapy using labetalol, clonidine and/or diuretics (2020–2022; prior to clevidipine availability).

Results

Sixty‐four patients (cases:25; controls:39) were included. There was no difference in demographic characteristics and admission National Institutes of Health Stroke Scale (NIHSS) scores between cases and controls. Clevidipine administration resulted in effective BP control (< 140/90 mmHg) within 3.5 ± 3.2 h from treatment onset, with no hematoma expansion (0.0 vs. 7.7% in controls;  = 0.172) and significant ICH volume reduction on 24‐h follow‐up brain‐CT (14.7% vs. 4.5% in controls;  = 0.023). A trend toward greater improvement in NIHSS scores during hospitalization and numerically lower 3‐month mortality rates were observed in clevidipine group. No serious adverse events were reported in the clevidipine‐treated patients. In multivariable linear regression models adjusting for potential confounders, clevidipine‐use was independently associated with greater ICH‐volume reduction ( = −0.16, 95% CI: −0.30, −0.02,  = 0.024).

Conclusions

The present study highlights that clevidipine represents a safe and effective option in terms of acute BP management among patients with hypertensive ICH and may limit hematoma expansion.

Background

Agrin‐congenital myasthenic syndrome (‐CMS) is a rare, heterogeneous genetic disorder of the neuromuscular transmission that can present from infancy to adulthood. The clinical phenotype includes distal weakness mimicking distal myopathies. Additionally, electromyography and muscle biopsy may demonstrate myopathic features, increasing the diagnostic challenge. Mitochondrial dysfunction has not been reported in the muscle of ‐CMS patients.

Methods

We report the clinical, electrophysiological, radiological, myopathological, and genetic findings of a patient with CMS.

Results

A 47‐year‐old male presented at age 18 with sudden onset of eyelid ptosis, weakness, and fatigue, followed by dysphagia, dyspnea on exertion, exercise intolerance, and myalgias. Three sisters had similar symptoms. Neurological examination showed lower limb weakness, predominantly affecting the calf muscles with associated atrophy. Tendon reflexes were normal but absent at the ankles. Creatine kinase levels were normal. Electromyography demonstrated myopathic changes in distal muscles with fibrillation potentials in the gastrocnemius. 2 Hz‐Repetitive nerve stimulation of the fibular nerve revealed a 32% decrement in the extensor digitorum brevis without facilitation. Tibialis anterior biopsy showed non‐specific myopathic changes, neurogenic features, and histological evidence of mitochondrial dysfunction, as suggested by the scattered cytochrome c oxidase‐negative fibers. Whole exome sequencing detected a homozygous pathogenic variant (c.5012G>A, p.Arg1671Gln). No pathogenic or suspected pathogenic variants were detected in muscle mitochondrial DNA or in nuclear genes affecting mitochondrial function.

Conclusions

This patient expands the pathological spectrum of ‐CMS to include mitochondrial dysfunction and highlights the importance of low‐frequency repetitive nerve stimulation in the assessment of patients with distal weakness for differentiating myopathies from CMS.

Background

Headache is one of the most frequent reasons for emergency department (ED) visits, and distinguishing primary from secondary headache remains challenging. Blood biomarkers may improve early risk stratification. This study evaluates serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) as potential biomarkers in patients presenting with non‐traumatic headache to the ED.

Methods

Secondary analysis of a prospective multicenter case–control study at University Hospital Basel and Aarau, Switzerland. Patients presenting with acute non‐traumatic headache were included. Final headache diagnoses were adjudicated by two board‐certified neurologists. Blood samples obtained at ED presentation were analyzed for sNfL and sGFAP, excluding patients with conditions known to affect biomarker levels. Primary headache samples were matched to serious secondary headache samples. Biomarker levels were expressed as age‐, BMI‐, and sex‐adjusted Z‐scores.

Results

A total of 82 patients were analyzed (42 serious secondary, 40 primary headache). Median[IQR] sNfL ‐scores were significantly higher in serious secondary compared with primary headache (0.8 [0.0–1.8] vs. 0.2 [−0.3–0.8];  < 0.01). sGFAP Z‐scores showed an even greater difference (1.2 [−0.1–2.3] vs. −0.2 [−0.7–0.2];  < 0.001). Both biomarkers demonstrated a specificity of 85%, but sGFAP showed higher sensitivity (57% vs. 43%), NPV (65% vs. 59%), and PPV (80% vs. 75%). In multivariable analysis adjusted for clinical risk factors, sGFAP remained independently associated with serious secondary headache (OR 1.9, 95%‐CI 1.2–3.4), whereas sNfL did not.

Discussion

sGFAP may represent a promising biomarker to support differentiation between primary and non‐traumatic serious secondary headache in the ED, warranting validation in larger cohorts.

Objective

To report an atypical phenotype associated with two rare glycine missense variants located in exon 23.

Methods

Clinical, neuropsychological, and brain imaging data of four patients with such variants were reported.

Results

Four unrelated patients presented with late‐onset cognitive alterations starting between 55 and 65 years of age. Brain magnetic resonance imaging (MRI) showed extensive white‐matter hyperintensities on T2 or Flair images in all subjects, associated with multiple dilated perivascular spaces in the basal ganglia with features of in the three oldest individuals. None of the patients had a history of haemorrhagic stroke. Three of these patients had previously experienced mood disturbances. All had a family history of depression and/or suicide. Three of these unrelated patients shared a rare missense variant p.(Gly474Arg) in , whereas the fourth one carried a p.(Gly486Glu) variant; these two variants affect two closely linked glycine residues encoded by exon 23 and located in a major cell‐binding site of the triple helix.

Conclusion

Missense variants affecting closely clustered glycine residues within the glycine–X–Y repeats encoded by exon 23 of are associated with an atypical, late‐onset form of cerebral small vessel disease, characterised by diffuse leukoencephalopathy with a pattern and predominantly cognitive and/or neuropsychiatric manifestations.

Background

Foslevodopa/foscarbidopa continuous subcutaneous infusion (LDp/CDp CSI) has emerged as an effective and well‐tolerated therapy for reducing OFF and increasing non‐troublesome ON in advanced Parkinson's disease (PD). Neuropsychiatric adverse events (AEs) have been reported in both clinical trials and real‐world studies, with some cohorts suggesting higher rates among patients with prior hallucinations or cognitive impairment. The present study aimed to determine the incidence and risk factors of neuropsychiatric AEs in a large prospective cohort.

Methods

We analyzed data from the DATs‐PD GETM Spanish Registry, an observational, prospective, multicenter, open‐label study.

Results

214 patients treated with LDp/CDp CSI were included. Median age was 69 years, and median disease duration was 12 years. At baseline, 35% had cognitive impairment, 25.7% hallucinations/psychosis, and 26.2% impulse control disorders (ICDs). During follow‐up after initiation (median 163 days), 19.2% developed at least one neuropsychiatric AE, mostly mild–moderate, and only 2.3% required device removal. Most events occurred more than 1 month after treatment initiation. In adjusted Cox, none of the evaluated variables were associated with the development of hallucinations/psychosis/confusion. The presence of ICD at baseline was associated with an increased risk of ICD‐related AEs.

Conclusion

Neuropsychiatric AEs, mainly hallucinations/psychosis, occurred in a clinically relevant proportion of patients treated with LDp/CDp CSI. However, they were generally mild‐to‐moderate and rarely led to treatment discontinuation. Except for ICD, baseline cognitive and psychotic features were not associated with higher incidence. These findings support its use in appropriately selected patients while highlighting the importance of individualized careful clinical monitoring.

Background and Objectives

B‐cell repopulation patterns in ocrelizumab treated patients with multiple sclerosis are highly variable between individuals, but the course of B‐cell reoccurrence after subsequent doses within an individual is not yet determined. Our aim was to determine the intraindividual variability of CD19+ B‐cell repopulation after each ocrelizumab dose when using CD19+ B‐cell guided interval dosing.

Methods

This was a prospective cohort study, as part of the ongoing BLOOMS trial, investigating participants randomised for B‐cell guided interval dosing of ocrelizumab with ≥ 2 dosing intervals. Coefficients of variation were calculated for time from last ocrelizumab dose to first CD19+ B‐cell measurement ≥ 0.01 × 10 cells/L.

Results

Seventy‐five participants with a total of 209 B‐cell guided intervals were included. Time from last dose to first appearance of CD19+ B‐cell count ≥ 0.01 × 10 cells/L showed wide variability between individuals (20.6–72.1 weeks), but the median variation was 5.6% (IQR: 3.1–8.4) within an individual. This translated to a variation of 2 weeks per dosing interval on average.

Discussion

Time to CD19+ B‐cell repopulation after each ocrelizumab dose is individually stable. This finding could pave the way for easier and more accessible future personalised interval dosing of B‐cell depleting therapies if this stability is confirmed in long‐term treatment.

Background

Parkinson's disease (PD) is associated with an increased rate of mortality. It is unclear whether this is due to complications and comorbidities associated with the disease or the disease process of PD itself.

Methods

We undertook a cohort study in patients with PD in an electronic primary care record database. Mortality rate ratios and risk differences per 1000 person‐years were calculated for each complication and comorbidity using multivariable Poisson regression analysis.

Results

There were 10,104 patients with incident PD and 55,664 controls. The rate of falls, dementia, hallucinations, postural hypotension, stroke, depression, anxiety, sleep disorders, gastrointestinal and urinary disorders, headaches, epilepsy, and myocardial infarction was higher in individuals with PD compared to controls. Conversely, the rates of chronic obstructive pulmonary disease (COPD), congestive heart failure, and gout were lower. In the PD group, the comorbidities of dementia, falls, stroke, cancer, chronic heart failure, COPD, myocardial infarction, and gastrointestinal disorders were associated with higher mortality rates. However, for all comorbidities, the increase in mortality rate was similar to or lower in the PD group compared to people without PD, except for falls which tended to be associated with higher mortality in the PD group.

Conclusion

This study provides data on the increased rate of mortality associated with different complications and comorbidities in PD. The mortality associated with these alone, however, does not explain the increased mortality in PD. This underscores the need for treatments to slow the underlying disease process.

Background

Irradiation of cellular blood components prevents transfusion‐associated graft‐versus‐host disease (TA‐GVHD). UK and Spanish guidance recommend lifelong irradiation for all patients treated with purine analogues, including cladribine, irrespective of indication or dose.

Objective

To assess whether this approach is justified for people with multiple sclerosis (pwMS) receiving cladribine.

Methods

Narrative synthesis of immunological data, hemovigilance evidence, and national European transfusion guidelines.

Results

Cladribine used in pwMS induces transient lymphopenia with modest, reversible T‐cell effects and preserved vaccine responsiveness. Since introduction of universal pre‐storage leucocyte depletion, hemovigilance data show no reported cases of TA‐GVHD in this setting. European guidance is heterogeneous, ranging from indefinite to time‐limited or unspecified durations.

Conclusion

Current evidence does not clearly support the need for lifelong irradiation after cladribine treatment in pwMS. Time‐limited or individualized approaches merit consideration.

Objectives

To expand the mutational and clinical spectrum by reporting a novel hinge‐region variant associated with an adult progressive phenotype and a marked therapeutic response to valproate.

Methods

We describe a 61‐year‐old woman with lifelong intellectual disability who developed subacute severe motor deterioration in adulthood. Evaluation included brain MRI and whole‐exome sequencing.

Results

Whole‐exome sequencing identified a novel heterozygous variant, c.551C>G (p.Pro184Arg), in the hinge region (domain D) of , a region not previously implicated in human disease. While ‐related disorders are typically described as neurodevelopmental conditions, our patient showed progressive motor decline with loss of independent ambulation. Brain MRI demonstrated marked vermian atrophy, supporting a possible progressive component. Withdrawal of valproate was followed by severe clinical worsening, whereas reintroduction led to marked improvement in tremor and gait, restoring independent ambulation.

Discussion

This case expands the mutational and phenotypic spectrum of ‐related disorders and suggests that hinge‐region variants may contribute to a more severe phenotype. It also supports a role for cortical hyperexcitability in the motor manifestations and highlights a potentially treatable component, with implications for clinical management.

Background

Understanding speech despite background noise is essential for everyday communication, but makes heavy neural processing demands. It is therefore potentially vulnerable to neurodegenerative diseases, particularly those led by communication deficits (primary progressive aphasia). However, how speech‐in‐noise perception is affected in these diseases is poorly understood.

Methods

Here we addressed this in 59 patients representing typical Alzheimer's disease and canonical logopenic, nonfluent/agrammatic and semantic variant syndromes of primary progressive aphasia, compared with 24 cognitively‐well, older controls. We administered a digit triplet test of speech‐in‐noise perception based on the task used in the UK Biobank study, alongside pure tone audiometry and a general neuropsychological assessment. Voxel‐based morphometry of patients' brain MRI scans was used to identify structural neuroanatomical associations of speech‐in‐noise perception.

Results

After adjusting for age, peripheral hearing and general cognitive function, the Alzheimer's, logopenic and nonfluent primary progressive aphasia groups performed significantly worse on speech‐in‐noise perception than controls. The nonfluent primary progressive aphasia and Alzheimer groups additionally had significantly worse peripheral hearing function than controls. Speech‐in‐noise perceptual performance correlated with grey matter atrophy in the right supramarginal gyrus.

Conclusion

Profiles of central (brain) and peripheral hearing impairment stratify major dementias, with implications for diagnosis and development of interventions to improve real‐world communication in people living with dementia.

Background

Using multi‐shell diffusion MRI, we aimed to identify whether corticospinal tract (CST) subfiber damage can be detected in prediagnostic amyotrophic lateral sclerosis (ALS) patients. We also explored whether the combination of serum neurofilament light chain (NfL) levels and CST subfiber abnormalities may provide better diagnostic performance in differentiating prediagnostic ALS patients from disease controls (DCs) and healthy controls (HCs) than single markers.

Methods

In this retrospective study, prediagnostic ALS was used as an operational term for patients who presented at baseline with chronic progressive limb weakness or bulbar symptoms, had no clinically evident typical UMN signs, and were subsequently confirmed to have sporadic ALS according to the Awaji criteria during longitudinal follow‐up. Patients whose final diagnosis was not ALS after follow‐up were classified as disease controls. Probabilistic tractography was performed on baseline MRI data to assess CST subfiber damage in 47 ALS patients, 20 DCs, and 51 HCs.

Results

Compared with Controls, ALS patients had significantly lower neurite density index (NDI) values of CST subfibers, particularly those originating from the primary and supplementary motor cortex. The diagnostic performance of the combined model incorporating serum NfL and CST subfiber NDI values in differentiating prediagnostic ALS patients from HCs and DCs was 0.925 and 0.928, respectively, which was better than that of single markers (0.634–0.886 and 0.699–0.856, respectively).

Conclusions

Our findings suggest that CST subfibers NDI values are promising neuroimaging markers for detecting in vivo UMN degeneration in prediagnostic ALS. Moreover, combining blood and neuroimaging markers may further improve early diagnostic performance.

Background

Biomarkers reflecting the complex pathophysiology of genetic frontotemporal dementia (FTD) will be increasingly important with the advent of therapeutic trials aiming to slow or prevent the disease. In this study, we aimed to identify blood biomarker candidates using a multiplex panel of CNS‐related proteins.

Methods

We cross‐sectionally evaluated 67 carriers (21 presymptomatic and 46 symptomatic) of pathogenic FTD‐causing mutations in the ( = 30 symptomatic) and ( = 16 symptomatic) genes and 42 matched non‐carriers. Clinical severity was estimated using the CDR Dementia Staging Instrument with National Alzheimer Coordinating Centre Frontotemporal Lobar Degeneration component (CDR plus NACC FTLD). A total of 124 CNS‐related proteins were measured in plasma using the NUcleic acid Linked Immuno‐Sandwich Assay (NULISA) CNS panel. Group‐level changes were then investigated using linear and non‐linear regression models.

Results

In and ‐FTD, neurofilament light (NfL) was the most clearly altered protein compared with non‐carriers ( β [95% CI] = 4.0 standard deviations [3.6–4.4], : β = 2.8 [2.2–3.4]), followed by neurofilament heavy (NfH; : β = 0.83 [0.39–1.3], : β = 1.4 [0.8–2.0]). Proteins exclusively altered in ‐FTD included glial fibrillary acidic protein (GFAp; β = 0.50 [0.20–0.81]) and vascular cell adhesion protein 1 (VCAM1; Standardized β = −0.90 [−1.4 to −0.38]), changing with increasing disease severity. Neuronal pentraxin receptor (NPTXR; β = −0.94 [−1.5 to −0.4]) was selectively reduced in FTD. Nominally changed proteins in ‐FTD included several inflammatory mediators.

Conclusions

Using this multiplex panel, established markers recapitulated previously established trends, while less‐studied biomarker candidates were also identified. If validated in independent cohorts, these candidates could broaden the repertoire of blood biomarkers reflecting genetic FTD pathophysiology.

Background and Purpose

Polytherapy in epilepsy is associated with a higher risk of adverse events, poorer adherence, and impaired quality of life. Thus, reducing concomitant antiseizure medications (ASMs) and/or using a newly added ASM such as cenobamate with only 1 other ASM (i.e., bitherapy) may improve tolerability. This analysis evaluated the impact of the number and type of concomitant ASMs on treatment‐emergent adverse events (TEAEs) that occurred in the cenobamate C021 open‐label clinical trial.

Methods

Adjunctive cenobamate was initiated in adults (aged 18–70 years) with uncontrolled focal seizures who were taking 1 to 3 ASMs. The number and type of concomitant ASMs and the frequency, severity, and time to resolution of TEAEs were assessed.

Results

The most frequently reported (≥ 10%) TEAEs in the overall population ( = 1340) were somnolence, dizziness, fatigue, and headache. The percentage of patients with dizziness, somnolence, and fatigue increased with increasing numbers of concomitant ASMs, especially when combined with benzodiazepines, chiefly clobazam, and in patients taking ≥ 2 sodium channel blockers. Median time to resolution of frequently reported TEAEs was shorter in patients taking fewer concomitant ASMs, with the exception of fatigue. The proportion of patients experiencing more severe TEAEs (except for headache) also increased with increasing numbers of concomitant ASMs.

Conclusions

Patients taking fewer concomitant ASMs reported better tolerability as evidenced by fewer and less severe AEs and faster time to resolution. These findings emphasize the importance of optimizing concomitant ASM regimens through dose adjustments, ASM substitution, and treatment simplification to improve tolerability.

Objective

To determine whether repetition‐based saccadic fatigability measured with three‐dimensional video‐oculography (VOG) distinguishes myasthenia gravis (MG) from unilateral ocular motor cranial nerve palsy (CNP) in patients with diplopia.

Methods

In this prospective cross‐sectional diagnostic study conducted from August 2022 to July 2024, consecutive patients with MG or unilateral third, fourth, or sixth CNP, and healthy controls underwent repetitive horizontal and vertical saccade testing (±°15 targets; 75 cycles at 0.25 Hz). Prespecified index metrics were percentage change in saccadic range and time to target acquisition from the second saccade to the mean of the last five saccades. Diagnostic discrimination was assessed using receiver operating characteristic (ROC) curves.

Results

The cohort comprised 231 participants: 93 with MG, 54 with CNP and 84 healthy controls. MG showed greater repetition‐related range decrement and longer time to target acquisition than healthy controls and axis‐matched CNP. In the horizontal comparison (MG vs. sixth CNP), AUCs were 0.800 for percentage range change and 0.787 for percentage time‐to‐target change. In the vertical comparison (MG vs. third/fourth CNP), percentage range change showed the best discrimination (AUC 0.868, 95% CI 0.783 to 0.934); a threshold of −5.95% yielded 79.6% sensitivity and 87.5% specificity. CNP showed early baseline slowing, whereas MG showed progressive hypometria with relatively preserved peak velocity.

Conclusions

Repetition‐based VOG captures a dynamic fatigability signature in MG that differs from the more static deficit of unilateral ocular motor CNP. Quantitative saccadic fatigability may provide a useful objective adjunct to the neuro‐ophthalmic evaluation of diplopia.

Background

Experimental studies show inflammatory cytokines can modulate calcitonin gene‐related peptide (CGRP) signaling, suggesting systemic inflammatory markers might reflect biological processes relevant to anti‐CGRP therapies. We aimed to determine whether serum high‐sensitivity C‐reactive protein (hs‐CRP) and tumor necrosis factor‐alpha (TNF‐α) are associated with erenumab response in adults with migraine and assess longitudinal biomarker changes during and after treatment.

Methods

In this prospective, observational single‐center study, adults with episodic or chronic migraine self‐administered 140 mg erenumab subcutaneously every 4 weeks for 24 weeks. Serum was collected at baseline, Week 24 (end of treatment), and Week 48 (24 weeks post‐treatment). Treatment response was defined as a ≥ 50% reduction in monthly migraine days from baseline to Weeks 13–24. Logistic and linear regression models evaluated associations between baseline biomarkers and response, while longitudinal changes were analyzed using linear mixed‐effects models.

Results

Of 679 enrolled participants, serum was analyzed in 623. Among 541 with sufficient data to determine response, 281 (51.9%) were responders. Neither baseline hs‐CRP (OR 1.04; 95% CI 0.96–1.12;  = 0.30) nor TNF‐α (OR 0.75; 95% CI 0.49–1.16;  = 0.20) predicted treatment response. TNF‐α increased from baseline to Week 24 (mean rise 3.0%; 95% CI 0.5%–5.4%;  = 0.030), but no responder–non‐responder differences were found.

Conclusions

Peripheral inflammatory biomarkers such as hs‐CRP and TNF‐α neither predict response nor change meaningfully during CGRP‐receptor blockade. These results suggest broadly applied inflammatory markers do not capture treatment‐relevant biology and highlight the need for mechanism‐specific biomarkers to advance personalized migraine therapy.