Journal of Neurology, Neurosurgery & Psychiatry

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.

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.

Multiple sclerosis (MS) is a chronic neurodegenerative disease characterised by progressive neurological disability and heterogeneous symptom trajectories. Current clinical monitoring methods, including magnetic resonance imaging (MRI) and episodic neurological assessments, provide limited insight into subtle disease progression and functional changes. Digital health technologies integrating multimodal biosignals and behavioural assessments may enable continuous monitoring and personalised rehabilitation in patients with MS. This study aims to evaluate the clinical utility of the BodyMirror Clinical MS platform, a multimodal SaMD that combines wearable biosensors, neuroscience-based games, and machine learning to remotely monitor disease progression and deliver personalised neurorehabilitation for individuals with multiple sclerosis. This study is a prospective, randomised, double-blind, controlled, multisite clinical trial enrolling 400 participants (300 individuals with multiple sclerosis and 100 healthy controls). MS participants will be randomly assigned (1:1) to either an adaptive neurorehabilitation intervention group or a control group receiving non therapeutic digital activities matched for engagement and exposure. Participants will perform three 30-minute sessions per week over 24 months using the BodyMirror platform. The system integrates multiple biosignals, including electroencephalography (EEG), electromyography (EMG), inertial measurement unit (IMU) motion data, speech analysis, and behavioural performance metrics to generate digital biomarkers of neurological function. The primary endpoint is a change in Expanded Disability Status Scale (EDSS) score from baseline to 24 months. Secondary outcomes include changes in Multiple Sclerosis Functional Composite (MSFC), MRI brain volume, cognitive performance, patient-reported outcomes, adherence to digital rehabilitation, and health economic outcomes.

Clinical progression is strongly linked to grey matter atrophy in multiple sclerosis (MS), detectable early on MRI and progressing non-randomly across the brain. However, the mechanisms driving its spatio-temporal progression and individual variability remain unclear. Using MRIs from 2,187 participants, alongside normative data, we systematically investigated network-based mechanisms underlying MS-related atrophy. Regional atrophy colocalised with functional cortical hubs, supporting the nodal stress hypothesis, and propagated along anatomical and functional connections, consistent with transneuronal degeneration. Lesional disconnection and transcriptomic vulnerability played marginal roles. Patient- and subgroup-level analyses revealed that network-based mechanisms are specifically linked to MS-related neurodegeneration and may operate differently in distinct subtypes or disease phases. Atrophy patterns were anchored to the connectivity profiles of disease epicentres involving the visual, sensorimotor, and temporal cortices, and the hippocampi and thalami. Network-based measures enhanced the prediction of future atrophy progression in individual with MS, providing a mechanistic framework to understand neurodegeneration in MS.

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

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

BackgroundPathogenic KCNQ2 variants are the most common genetic cause of neonatal-onset epilepsies, with phenotypes ranging from self-limited (familial) neonatal epilepsy (SeL(F)NE) to severe developmental and epileptic encephalopathy (KCNQ2-DEE). Sodium channel blockers (SCBs) have shown promise for seizure control in these disorders, but their impact on neurodevelopmental outcomes and possible relationship with timing of initiation remain incompletely understood. MethodsWe leveraged a large, multicentre international cohort comprising 282 individuals with KCNQ2 pathogenic variants to retrospectively assess the effectiveness of antiseizure medications (ASMs), particularly SCBs, on seizure control and neurodevelopment. Individuals were grouped according to the predicted variant-specific functional effects: loss-of-function (LOF) variants known to be associated with SeL(F)NE or DEE respectively, and gain-of-function (GOF) variants. Epilepsy course, ASM effectiveness, and neurodevelopmental milestones were systematically collected and analysed. ResultsSCBs, especially carbamazepine (CBZ) and oxcarbazepine (OXC), emerged as the most effective ASMs in both LOF groups. In LOF KCNQ2-DEE, early SCB initiation within the first month of life was associated with significantly more favourable neurodevelopmental trajectories, including higher rates of achievement of major motor milestones. Early seizure freedom itself was a strong predictor of improved neurodevelopment, with the positive effect of SCBs likely mediated by their ability to control seizures. However, considerable phenotypic variability persisted, with some individuals experiencing severe impairment despite early seizure control and SCB initiation. Variant severity and possible genetic modifiers likely contribute to this heterogeneity, underscoring the need for precision therapies beyond nonspecific ASM approaches. ConclusionOur results strongly support the use of SCBs as first-line therapy in (LOF) KCNQ2-DEE and SeL(F)NE due to their high effectiveness. Moreover, SCBs appear most beneficial when initiated during the neonatal period, with earlier treatment linked to earlier seizure offset and better developmental outcomes. These results highlight the importance of early genetic diagnosis and timely SCB therapy, and support CBZ or OXC as first-line agents. We however emphasise that early treatment is not universally transformative, and further work, including exploration of targeted therapies but also standardised neurodevelopmental assessments, is needed to optimise long-term outcomes in this heterogeneous population.

Background and ObjectivesNotch homolog 3 (NOTCH3) gene variants were fully penetrant to produce the disease phenotype of CADASIL. Aberrant NOTCH3 protein leads to degeneration of vascular SMCs and pericytes, targeting microcirculation dysfunction and blood-brain barrier (BBB) leakage. MethodsWe evaluated neuroimaging data of forty patients with NOTCH3 gene variants including eighteen missense/insertion mutations in epidermal growth factor repeat (EGF), negative regulatory region (NRR), and disordered region (Dis). We performed an AI-driven pipeline integrating AlphaFold3, Foldseek, and molecular dynamics simulations to elucidate clinical and molecular consequences. ResultsDistinct domain mutations exhibited characteristic patterns: EGFs 1, 2, 13-15, 32 and Dis correlated with microbleeds/macro-bleeds, lacunes, perivascular spaces, and acute cerebral microinfarcts; EGFs 2, 3, 13-15, 25 with disrupted disulfide bonds or binding motif of protein O-glucosyltransferase 1 (POGLUT1) were predicted to undergo greater structural and functional deteriorations in Notch signaling pathways. NRR/Fab (antigen-binding fragment) destabilized dominant motions and single apo-Dis exhibited low structural disorder. Agreement between computational and experimental data for wild-type EGFs/POGLUT1 and C49F, R75Q, R141C mutants suggests testable hypotheses that advance understanding of cerebral small-vessel disease. DiscussionTargeting POGLUT1 to modulate EGF-like domains and using the Fab region to stabilize NRR complexes may be a promising therapeutic approach deserving rigorous exploration.

BackgroundPost-stroke cognitive impairment (PSCI) affects nearly 30% of stroke survivors and significantly impairs functional recovery. Brain-derived neurotrophic factor (BDNF)-tropomyosin receptor kinase-{beta} (Trk{beta}) signalling is crucial for synaptic plasticity and cognitive function. While altered expression of truncated TRK{beta}-T1 isoforms has been linked to stroke, the contribution of the TRK{beta}-SHC isoform to PSCI in humans remains poorly understood. ObjectivesThis study aimed to (i) assess isoform-specific expression changes of NTRK2 associated with PSCI, (ii) evaluate the role of an isoform-specific genetic variant in disease susceptibility, and (iii) identify DNA methylation changes regulating NTRK2 expression (if any). MethodsGene expression levels of three major NTRK2 isoforms and MEK2 were analyzed in peripheral blood mononuclear cells from 19 PSCI patients, 21 post-stroke cognitively normal (PSCN) individuals, and 11 healthy controls. Expression data were correlated with raw memory scores and MEK2 expression. DNA methylation profiles of NTRK2 and its transcriptional regulators were assessed using whole-genome bisulfite sequencing. ResultsTRK{beta}-FL expression was significantly reduced in stroke patients compared with controls. In contrast, TRK{beta}-SHC expression was elevated in PSCN individuals relative to PSCI cases and showed a positive correlation with MEK2 expression and memory performance. No significant association was observed between rs65339833 and cognitive subdomains. Gene body hypermethylation, but not promoter methylation, was detected in NTRK2 and its regulatory genes. ConclusionsElevated TRK{beta}-SHC expression may contribute to preserved cognitive function following stroke. DNA methylation status of NTRK2 may regulate alternative splicing and thus represent a novel therapeutic avenue for preventing or mitigating PSCI.

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

Importance: Dementia is common in Parkinson's disease (PD), causing greater disability than other symptoms, but varies in timing. Although visual deficits are linked with PD dementia, how these interact with genetic factors to predict PD dementia has not been characterised. Objective: To investigate whether visual deficits and genetic factors predict PD dementia. Design: Large prospective longitudinal case-control study, mean follow-up 32.7 (SD=12.3) months. Setting: Cases were recruited between 2017-2020 at 35 UK PD clinics. Participants: People with PD without dementia at baseline were included. Main outcomes and measures: Visual function was measured using a web-based platform. The main outcome measure was global cognition, measured as the Montreal Cognitive Assessment (MoCA). Blood samples were collected for genetics. Results: 450 patients with PD were included. Mean age of PD patients was 71.7 (SD=7.8), 68% male. Mean baseline MoCA was 27.7 (SD=1.7). 263 patients with PD were classed as poor-vision based on baseline visual tests: mean age 74.4 (SD=6.8) compared to 69.7 (SD=7.5) with good-vision. Poor-vision PD patients had higher rates of progression to mild cognitive impairment (PD-MCI) (HR=2.34, CI=1.58-3.48, pFDR=0.00062, age- and sex-corrected). The combination of genetic factors together with vision influenced outcomes. In good-vision PD patients, high-risk GBA1 gene variants were linked with greater progression to PD-MCI (HR=4.61, CI=1.73-12.28, pFDR=0.0068). Polygenic Risk Score (PRS) for both PD and Alzheimer's disease (AD) also modified cognitive survival when combined with vision status. High PD-PRS was associated with greater progression to PD-MCI in good-vision patients (HR=2.66, CI=1.21-5.81, pFDR=0.0381); and high AD-PRS with greater progression to PD-MCI in poor-vision PD patients (HR=1.91, CI=1.10-3.32, pFDR=0.04999). Combining high PD- and AD-PRS, compared to low PD- and AD-PRS in good-vision PD showed even higher progression to PD-MCI (HR=6.14, CI=1.36-27.83, pFDR=0.046). Simulations showed that adding visual and genetic stratification reduced sample size from n=705 to n=160 for clinical trials. Conclusions and relevance: Poor vision in PD predicts progression to PD-MCI and dementia. This combines with the effects of genetic factors including GBA risk variants and PD- and AD-PRS. These findings can enable enrichment of clinical trials for patients at higher risk of PD dementia, for more efficient trial design for interventions to slow progression.

BackgroundPersons with epilepsy are at increased risk of depression/anxiety. Older antiseizure medications (ASMs) had drug-drug interactions that complicated pharmacotherapy of depression/anxiety; newer ASMs lack this drawback but can have psychiatric side effects. Anxiety/depression are increasingly recognized and treated pharmacologically. We hypothesized that the likelihood of treatment with selective serotonin uptake inhibitors (SSRI) would have increased in adult-onset epilepsy when prescription habits shifted towards newer ASMs. MethodsWe linked national health registers and included 28569 persons with epilepsy incident in 2006-2020 and 68509 age- and sex matched controls. We assessed the risk of starting SSRI treatment compared to age- and sex-matched controls across three incidence periods: 2006-2010, 2011-2015, and 2016-2020. Cox regression was used to estimate adjusted hazard ratios (HRs), and subgroup analyses explored age, sex, and comorbidities. Specialist psychiatric care was also assessed as a measure of more severe depression. Analysis including persons with SSRI-use before the epilepsy diagnosis were used for sensitivity analyses. FindingsPersons with epilepsy had higher risks of starting SSRIs compared to controls; 1986/9561 (20.8%) received SSRI during follow-up after epilepsy in 2006-2010 and 2020/9165 (22.0%) in 2016-2020; adjusted HRs were 1.92 (95%CI:1.79 - 2.06) in 2006-2010, 1.84 (95%CI:1.72-1.97) in 2011-2015, and 1.81 (95%CI:1.69 - 1.94) in 2016-2020. Among individuals aged 18-30 years at their epilepsy diagnosis, the proportion receiving SSRIs remained the same between the first and last calendar periods (18.2%). Because of increased treatment of controls, the adjusted HRs of SSRI-treatment decreased from 2.33, (95% CI:1.96 - 2.78) to 1.63, (95% CI 1.39 to 1.91). The HR of specialist psychiatric care was not significantly different between the time periods. Most comorbidities were consistently associated with increased likelihood of SSRI treatment, whereas intellectual disability decreased the likelihood in some periods. InterpretationWe found no evidence of overall increased SSRI initiation or psychiatric care after the shift to newer ASMs. Person with epilepsy remain more likely to receive SSRI treatment, but probably not to a level matching the higher prevalence of depression. Increased SSRI treatment of younger age adults has not been matched by increased treatment of young adults with epilepsy. This suggests a potentially widening treatment gap and a need for increased recognition of depression in young adults with epilepsy. FundingSwedish Research Council (2023-02816), Swedish state through the ALF-agreement (ALFGBG-1006343), Knut och Ragnvi Jacobsson foundation, Swedish Society for Medical Research (S18-0040), Swedish Society of medicine (SLS-881501), Epilepsifonden, Rune och Ulla Amlovs stiftelse.

We describe the design of the first non-pharmacological prevention trials of Parkinsons Disease worldwide: the randomised controlled Slow-SPEED trials. The three trials examine the feasibility and preliminary efficacy of a gamified, remotely administered exercise intervention vs. active control program over 18-36 months in the Netherlands (n=110), United Kingdom (n=110) and United States (n=600). Each trial focuses on a complementary prodromal subgroup: isolated/idiopathic REM sleep behavioural disorder, hyposmia, or LRRK2/GBA1 mutation carriers. These trials will provide unique insights for large-scale Parkinsons Disease prevention studies.

BackgroundMRI plays an essential role in diagnosing and monitoring neurological diseases. Conventional protocols rely on multiple sequences to obtain complementary contrasts, increasing scan time, cost, and tolerability. Generating multiple contrasts from a single acquisition may streamline workflow while maintaining clinical utility. PurposeTrain attention-based convolutional neural networks (ACNNs) to generate clinical-quality FLAIR, MPRAGE, R2*, and derived contrasts from a single Gradient Echo Plural Contrast Imaging (GEPCI) acquisition, enabling multi-contrast imaging from one scan. Study TypeRetrospective. Population43 MRI scans from individuals with multiple sclerosis (25/18 F/M, 49{+/-}11 years old). Field Strength/Sequence3T MRI was used to obtain 3D GEPCI, MPRAGE, and FLAIR sequences. AssessmentTechnical quality of the AI-generated contrasts was evaluated against directly acquired MRI images using structural similarity index (SSIM). Quantitative accuracy for R2* maps was evaluated using normalized root-mean-square error (NRMSE). Clinical image quality was assessed by expert physicians. Lesion volumes and counts were obtained using automated segmentation. ResultsAI-generated FLAIR and MPRAGE images achieved mean SSIM values of 0.923{+/-}0.028 and 0.935{+/-}0.022, respectively. The generated R2* maps achieved a mean SSIM of 0.996{+/-}0.006, with quantitative accuracy reflected by an NRMSE of 0.031{+/-}0.020. Physicians rated GEPCI-FLAIR images at 4.2 and GEPCI-MPRAGE images at 4.5 (on a 1-to-5 scale), both exceeding the clinically routine standard of 4.0. Lesion volume and count comparisons from automated segmentation showed strong agreement between AI-generated and ground-truth measurements (R{superscript 2}=0.988 and R{superscript 2}=0.933, respectively). ConclusionAI-GEPCI generated multiple clinically relevant MRI contrasts from a single GEPCI acquisition with high similarity to corresponding acquired images. Radiological reviews and quantitative analyses supported the feasibility of producing high-quality, intrinsically co-registered multi-contrasts for comprehensive brain evaluation.

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

BackgroundHuntingtons disease (HD) causes progressive loss of function, cognition, and motor control, with no approved therapy yet shown to slow disease progression. In the PROOF-HD phase 3 trial, pridopidine did not meet the primary or key secondary outcomes in the overall population, but participants who remained off antidopaminergic medications (ADMs) showed benefits compared to placebo during the double-blind phase. Whether such benefits continue with longer duration treatment and how they compare with expected natural-history trajectories remains unknown. MethodsWe evaluated outcomes through Week 104 from baseline in participants who received continuous pridopidine (45 mg twice daily) and remained off-ADMs throughout the double-blind and open-label extension period (n=90). External comparators from ENROLL-HD and TRACK-HD were constructed using propensity-score weighting methods. Least-squares mean changes from baseline to Week 104 were estimated using mixed-effects models for repeated measures across outcomes. ResultsAt two-years, pridopidine treatment was associated with benefits versus propensity-score weighted natural-history comparators across multiple outcomes. Relative to ENROLL-HD, participants receiving pridopidine showed slowing of progression over 104 weeks, expressed as percent slowing across cUHDRS, TFC, SWR, SDMT, and TMS outcomes (39.5-88.3% slowing). Similar patterns were observed relative to TRACK-HD across the same measures (48.5 - 81.5% slowing), including quantitative motor performance assessed by Q-Motor FT-IOI (77.8% slowing). Exploratory analyses including participants receiving concomitant ADMs showed similar directional patterns as the primary analyses. ConclusionsIn a two-year follow-up, continuous pridopidine treatment in participants remaining off-ADMs was associated with slower clinical progression relative to expected natural-history trajectories. (Clinical Trials Identifier: NCT04556656)

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

Lysosomal dysfunction is central to Parkinsons disease pathogenesis, with GBA1 as the strongest established genetic risk factor. Numerous other genes involved in lysosomal sphingolipid, glycosphingolipid and ceramide metabolism have been proposed as contributors to Parkinsons disease, underscoring the need for comprehensive genetic analyses across these pathways. We analysed rare variants (minor allele frequency < 0.01) across 36 lysosomal genes (excluding GBA1) in 8,267 individuals with Parkinsons disease and 68,208 controls, including a subset of 793 early-onset Parkinsons disease ([&le;]50 years) cases. Targeted sequencing was performed in four cohorts at McGill University (3,456 Parkinsons disease patients and 2,664 controls) and results were combined with whole-genome sequencing data from the UK Biobank (2,848 cases, 62,451 controls), and from the Accelerating Medicines Partnership - Parkinsons Disease (1,963 cases, 3,093 controls). We analysed the association of rare variants in these genes with Parkinsons disease using Sequence Kernel Association Test-Optimal (SKAT-O) across variant classes (all rare variants, nonsynonymous, loss-of-function and predicted damaging variants with a Combined Annotation Dependent Depletion (CADD) score >20), with meta-analysis across cohorts. We additionally performed per-domain analyses for variants in gene segments encoding functional domains. False discovery rate correction was applied. Meta-analysis identified a significant association between rare variants in ST3GAL3 and Parkinsons disease (Pfdr=0.04). Several additional lysosomal genes showed nominal associations (P<0.05), including HGSNAT, ASAH1, CTSD, HEXA, ST3GAL4 and SGPP1. Domain-based analyses identified a strong enrichment of nonsynonymous variants within the beta-acetyl-hexosaminidase-like domain of HEXA (P = 8.0 x 10), although this signal did not survive correction for multiple testing (Pfdr=0.154). In early-onset Parkinsons disease, domain-based analyses revealed significant associations in NAGLU (Pfdr=7.3x10) and ST3GAL5 (Pfdr=0.03). Together, these results provide genetic evidence that rare variants across multiple lysosomal pathways, particularly those related to sialylation, ganglioside metabolism, ceramide biology, and lysosomal proteolysis, may contribute to Parkinsons disease susceptibility beyond GBA1, highlighting biologically coherent pathways for future replication and functional investigation.

The cerebrospinal fluid (CSF) proteome offers a direct readout of central nervous system (CNS) biology but its genetic architecture remains incompletely defined. We conducted the largest single-site CSF genome-wide association study (GWAS) to date, analysing 7,092 SomaScan proteins in 1,259 individuals. Using a covariate-adjusted model including proteomic PCs and disease status, we identified 1,971 genome-wide significant pQTLs (954 cis, 971 trans), 1,409 of which replicated in an independent CSF dataset. We discovered 264 previously unreported loci, replicated 511 associations, refined 80 known loci, and 265 proxy-based associations. Using a previously published reproducibility framework, we show that robust discovery concentrates in reliable measurements, underscoring the importance of rigorous quality control. Enrichment analyses revealed immune/complement and extracellular matrix biology. Mendelian randomization prioritised causal proteins: PILRA, TREM2, IL34, CR2, SHARPIN and ERBB1 (Alzheimers disease); BST1 and GPNMB (Parkinsons disease); STX6 (Creutzfeldt Jacobs disease); and ATXN3 and B4GALNT1 (Amyotrophic lateral sclerosis), providing a scalable framework for orthogonal target validation in neurodegeneration. HighlightsCSF A{beta}42 and p-tau, CSF total protein and Qalb are major contributors to the proteomic variance and may act as potential confounders. Most pQTLs were found in proteins classified as "reproducible" based on our CSF proteomic score. The most stringently adjusted GWAS model maximized pQTL discovery among the highest-reproducibility proteins (score 1 and A). We identified 264 novel CSF pQTLs that were not described in previous analyses, replicated 511 CSF pQTLs, 80 map refinements and 265 proxy SNPs, predominantly involved in immune-related, inflammatory, and extracellular matrix mechanisms. We found 281 CSF pQTLs that were also systemic modulators of plasma protein levels that were enriched in immune-related and extracellular matrix mechanisms. We identified and validated several causal proteins associated with AD and other neurodegenerative disorders.