Journal of Neurology, Neurosurgery, and Psychiatry最新文献

Background: Heterozygous variants in SLC12A6 have recently been shown to cause dominant Charcot-Marie-Tooth disease (CMT). We aim to characterise the phenotype of patients with previously reported and novel heterozygous variants in the gene and understand any genotype-phenotype correlation.

Methods: Patients were clinically and genetically assessed in sites from Europe, Australia, Brazil and the USA. All patients underwent whole exome or whole genome sequencing. Variants were classified using American College of Medical Genetics and Genomics criteria.

Results: Twenty-three individuals from 13 families carried nine variants classified either as pathogenic/likely pathogenic or variants of uncertain significance segregating in multiple family members, including five novel variants. Forty-eight percent (11/23) were male with a mean age of disease onset of 15.7 years (range 1-45 years). Clinical phenotype varied dramatically with genotype; Arg207His and Ser647Pro caused a severe childhood-onset, sensory and motor, conduction-slowing neuropathy, whereas Gly552Asp caused a mild, adult-onset, sensory-predominant neuropathy, Thr991Ala an infantile-onset motor neuropathy, and the Met282Lys/Gly286Cys locus a complex, axonal neuropathy.

Conclusions: Heterozygous variants in SLC12A6 can cause CMT of all clinical phenotypes, severity and age of onset, depending on the genotype. Such phenotypic diversity has not been described for any other CMT gene, and more work is needed to understand disease mechanisms to guide future therapeutic options.

Background: Chronic subdural haematoma (cSDH) is a common neurological condition. Surgery remains the preferred treatment for symptomatic patients. Delays in surgery can occur due to logistical, clinical or medication-related factors. We investigated the relationship between time to surgery and postoperative functional outcomes in symptomatic cSDH.

Method: Retrospective multicentre cohort study conducted from 2012 to 2023 across five UK neurosurgical units within the National Health Service system, with 1-year follow-up. Of the 1508 patients referred for surgical intervention for cSDH, 1015 remained for analysis. 213 were excluded due to missing data and 280 for ≥30-day wait for surgery to mitigate extreme outliers. Postoperative functional outcome was assessed using the modified Rankin Scale, categorised as 'favourable' (0-3) and 'unfavourable' (4-6). Predictors of outcome were identified using multivariable logistic regression, and the association between time to surgery and outcome was evaluated by marginal effects analysis. Factors influencing time to surgery were analysed by multivariate linear regression.

Results: Of 1015 patients, 838 (82.6%) had 'favourable' outcomes and 177 (17.4%) had 'unfavourable' outcomes. Surgical delay was significantly longer in patients with 'unfavourable' outcomes (mean 4.4 vs 2.9 days, p<0.001) and independently associated with poorer outcomes (OR=1.05 per day, p=0.002). Risk increased linearly for each additional day of delay, up to 28% by day 30. Delayed time to surgery included older age (p=0.007), antiplatelet use (p<0.001), high Glasgow Coma Scale Score and Low Frailty Score.

Conclusion: Surgical delay significantly worsens outcomes in cSDH. Older age, antiplatelet therapy, milder neurological presentation and low frailty scores were key contributors to delay.

Background: Severe forms of generalised (GD) or cervical dystonia (CD) can be effectively treated with deep brain stimulation (DBS) of the globus pallidus interna (GPi). However, objectively assessing DBS effectiveness remains challenging.

Objective: To identify objective biomarkers of GPi-DBS effectiveness using a minimalistic three-dimensional (3D) kinematic motion capture system in patients with dystonia.

Methods: This retrospective longitudinal study analysed kinematic data from 14 patients before and after GPi-DBS: 7 with GD (3 females; mean age, 34.1±16.5 years; mean Burke-Fahn-Marsden (BFM) 32.9±14.1) and 7 with CD (4 females; mean age, 46.2±9.8 years; mean BFM 10.4±4.4). Parameters included barycentre displacement length, volume, velocity, angular velocity and power spectral density (PSD) in low-frequency (delta and theta) bands. Dystonia severity was assessed using the BFM scale.

Results: In the pooled cohort, GPi-DBS significantly reduced dystonia severity, with mean BFM scores decreasing from 21.6±15.4 preoperatively to 14.1±13.1 postoperatively (p=0.011, permutation test). In subgroup analyses, BFM scores decreased significantly in the CD group (p=0.015), while a non-significant trend toward improvement was observed in the GD group (p=0.076). Kinematic analysis in the pooled cohort demonstrated a robust reduction in barycentre angular velocity (p<0.001), whereas other parameters were not significantly modified. In the CD subgroup, additional significant reductions were observed in displacement length, velocity and PSD amplitudes in both frequency bands (all p<0.01). Multivariate regression analysis demonstrated that kinematic improvements in barycentre displacement length, velocity, angular velocity and PSD in delta and theta bands were significantly associated with clinical improvements (all p<0.05).

Conclusions: 3D kinematic analysis provides objective biomarkers of GPi-DBS effectiveness in dystonia. Despite differing response patterns, kinematic features remain informative across phenotypes supporting their use in individualised outcome assessment.

Background: Weight loss is a substantial non-motor feature of Parkinson's disease (PD) associated with worse clinical outcomes, but the underlying mechanisms remain poorly understood. Thus, we investigated the mechanisms of PD-related weight loss by examining the correlation between body composition and various plasma metabolites.

Methods: We enrolled 91 patients with PD and 47 healthy controls between July 2021 and October 2023. Body composition was evaluated using bioelectrical impedance analysis. Plasma metabolite profiling was conducted via mass spectrometry, including short-chain and medium-chain fatty acids, Krebs cycle intermediates, ketone bodies and phospholipids. Subsequently, alterations in body composition in PD and their association with plasma metabolites were assessed.

Results: Patients with PD had lower body weight (p=0.003), body mass index (BMI; p=0.001) and body fat mass (p<0.001) compared with controls. Metabolomic analyses revealed that, in patients with PD, glycolysis and Krebs cycle markers (lactic acid and succinic acid) were reduced, while ketone bodies (acetoacetic acid and 3-hydroxybutyric acid), amino acid catabolism-related markers (2-hydroxybutyric acid and 2-oxobutyric acid) and acetic acid were elevated. Notably, in patients with PD, acetoacetic acid and 3-hydroxybutyric acid negatively correlated with BMI. Phosphatidylcholine (40:2) was also elevated in PD and showed higher levels in individuals at more advanced Hoehn and Yahr stages.

Conclusions: PD-related fat loss was accompanied by a pattern of lower glycolytic activity and higher levels of lipid and amino acid metabolism-related metabolites, consistent with a potential shift in energy utilisation. These findings highlight metabolic pathways as potential targets for interventions to mitigate weight loss in PD.

Background: Increased healthcare use precedes classical multiple sclerosis (MS) symptom onset. Limited evidence exists on sex and age variation. We assessed physician visit patterns pre-MS onset by sex and age.

Methods: Using data from British Columbia, Canada, we compared annual physician visit rates (overall, by reason and specialty) in the 15 years before the neurologist-determined MS symptom onset date (index) and a matched non-MS cohort, stratified by sex and age (<30, 30-49, ≥50).

Results: We included 2038 MS and 10 182 non-MS persons (74% female). Mean age (years) at index was 37.6 (females) and 38.7 (males). Compared with matched non-MS persons, females with MS showed earlier and more consistent elevations in physician visits (years -14 to -1), while males had sporadic elevations (years -5, -3 and -1). Females also had longer periods of elevated rate ratios (RRs) for ill-defined signs/symptoms (years -15 to -1), mental disorders (years -14 to -1 except year -7) and musculoskeletal conditions (years -6 to -1). Females exhibited sustained elevated visits by specialty, including general practice (all years; RR ≥1.1), psychiatry (years -12 to -1 except -8 to -6; RRs ≥1.6) and ophthalmology (years -9 to -1 except -2; RRs ≥1.4). Compared with matched non-MS counterparts, those aged 30-49 years had sustained higher RRs for psychiatry visits (years -12 to -1 except -8 and -6; RRs ≥1.9) and ophthalmology (years -9 to -1; RRs ≥1.4). Other age groups had fewer elevated RRs preindex. Across comparisons, RRs were of similar magnitude across sex and age groups.

Conclusions: Sex-specific and age-specific differences in physician visits extended up to 15 years pre-MS onset, suggesting a durable prodromal signature, most evident in females and those aged 30-49 years.

Background: The relevance of covert cerebrovascular disease (CCD) in practice is uncertain, partly because estimation of risk in whole clinical populations is difficult. Studies have had success extracting CCD from clinical text using natural language processing (NLP), though they have been limited to specific CCD phenotypes. Here, we used NLP to measure multiple clinically-reported CCD phenotypes in a large clinical cohort and estimated subsequent disease risk in health record data.

Methods: From all people with brain imaging in Scotland (2010-2018), we selected people with no prior hospitalisation for neurological disease (n=367 988). NLP of imaging reports identified: white matter hypoattenuation or hyperintensities (WMH), lacunes, cortical infarcts and cerebral atrophy. Adjusted HRs (aHRs) were estimated between each phenotype and stroke, dementia and Parkinson's disease (conditions previously associated with CCD), epilepsy and colorectal cancer (control conditions).

Results: For each phenotype, the aHR of stroke was WMH 1.4 (95% CI 1.3-1.4), lacunes 1.6 (1.5-1.6), cortical infarct 1.8 (1.7-1.9) and cerebral atrophy 1.1 (1.0-1.1). The aHR of dementia was WMH 1.3 (1.3-1.3), lacunes 1.0 (0.9-1.0), cortical infarct 1.1 (1.1-1.2) and cerebral atrophy 1.7 (1.7-1.8). The aHR of Parkinson's disease was WMH 1.1 (1.0-1.2), lacunes 1.1 (0.9-1.2), cortical infarct 0.7 (0.6-0.9) and cerebral atrophy 1.4 (1.3-1.5). The aHRs between CCD phenotypes and epilepsy and colorectal cancer were around the null.

Conclusion: CCD and atrophy have implications for future disease risk and can be identified at scale using NLP of clinical reports. Prevention of neurological disease in people with CCD should be a priority for healthcare policy makers.

Background: Higher vitamin D has consistently been associated with a lower multiple sclerosis (MS) risk, but some controversy remains about whether this is due to vitamin D itself or sunlight.

Methods: We conducted a prospective study among women participating in the Norwegian Mother, Father and Child Cohort Study, recruited in 2002-2008 and followed until 2022. We identified incident MS cases through data linkage with the Norwegian MS Registry. Total vitamin D intake from food and supplements was obtained from validated food frequency questionnaires completed in pregnancy. We estimated HRs for MS and 95% confidence intervals (CI) using Cox regression.

Results: Among 78 074 participants, 349 developed MS during follow-up. Their median daily vitamin D intake was 296 international units (IU) compared with 333 IU among women who did not develop MS. Higher total vitamin D intake was associated with a 42% lower MS risk (HR comparing top vs bottom quintile 0.58, 95% CI 0.38 to 0.89, p_trend<0.01). The results were similar when adjusting for age at delivery, total energy intake, pre-pregnancy body mass index and smoking. The associations were similar for vitamin D intake from food (HR for top vs bottom quintile 0.70, 95% CI 0.47 to 0.1.04, p_trend=0.02) and supplements (HR for ≥600 IU/day vs <200 IU/day 0.65, 95% CI 0.41 to 1.04, p_trend=0.01).

Conclusions: In this prospective study, higher vitamin D intake was associated with lower MS risk in women living in Norway, where there is insufficient sun-induced vitamin D production during most of the year. This supports the hypothesis that vitamin D itself modifies MS risk.

Background: Despite the impact of depression in multiple sclerosis (MS), the neurobiological mechanisms underlying its pathogenesis are still poorly understood. Disrupted functional connectivity (FC) within the reward circuit has been observed in major depressive disorder (MDD), highlighting its essential role in the neurobiology of depression. Here, we hypothesised that an analogous dysconnectivity may underpin depression in MS.

Methods: The present study aimed to investigate FC of key nodes of the reward circuit (nucleus accumbens, NAcc and ventral tegmental area, VTA) in MS patients with depression (MS-D; n=30, 22 females), characterising differences with MS patients without depression (MS-nD; n=30, 17 females) and MDD patients without MS (n=30, 23 females). Furthermore, dynamic causal modelling (DCM) was applied to resting-state functional magnetic resonance imaging (fMRI) data to characterise effective connectivity (EC), which refers to the causal influences of brain regions involved in the circuit.

Results: MS-D group showed reduced FC compared with both MS-nD and MDD, suggesting that the association of depression with MS may reflect dysfunction of the reward circuit. The DCM analysis showed inhibitory self-connections, a negative modulation of VTA in MS-D>MS-nD, a negative modulation between VTA, NAcc and the right amygdala as an effect of having depression and no EC differences for MS-D>MDD.

Conclusions: The present connectivity study revealed promising results for understanding the pathophysiology of depression in MS. A combined FC-EC investigation of the reward circuit may represent a potential non-invasive in vivo MRI biomarker for understanding the onset of core depressive symptoms, supporting the development of effective and personalised therapies.