Journal of Neurology, Neurosurgery, and Psychiatry最新文献

Background: The underlying risk factors for young-onset cryptogenic ischaemic stroke (CIS) remain unclear. This multicentre study aimed to explore the association between heavy alcohol consumption and CIS with subgroup analyses stratified by sex and age.

Methods: Altogether, 540 patients aged 18-49 years (median age 41; 47.2% women) with a recent CIS and 540 sex-matched and age-matched stroke-free controls were included. Heavy alcohol consumption was defined as >7 (women) and >14 (men) units per week or at least an average of two times per month ≥5 (women) and ≥7 (men) units per instance (binge drinking). A conditional logistic regression adjusting for age, sex, education, hypertension, cardiovascular diseases, diabetes, hypercholesterolaemia, current smoking, obesity, diet and physical inactivity was used to assess the independent association between alcohol consumption and CIS.

Results: Patients were twice as more often heavy alcohol users compared with controls (13.7% vs 6.7%, p<0.001), were more likely to have hypertension and they were more often current smokers, overweight and physically inactive. In the entire study population, heavy alcohol consumption was independently associated with CIS (adjusted OR 2.11; 95% CI 1.22 to 3.63). In sex-specific analysis, heavy alcohol consumption was associated with CIS in men (2.72; 95% CI 1.25 to 5.92), but not in women (1.56; 95% CI 0.71 to 3.41). When exploring the association with binge drinking alone, a significant association was shown in the entire cohort (2.43; 95% CI 1.31 to 4.53) and in men (3.36; 95% CI 1.44 to 7.84), but not in women.

Conclusions: Heavy alcohol consumption, particularly binge drinking, appears to be an independent risk factor in young men with CIS.

Background: We investigated the effectiveness of an Interdisciplinary Home-bAsed Reablement Programme (I-HARP) on improving functional independence, health and well-being of people with dementia, family carer outcomes and costs.

Method: A multicentre pragmatic parallel-arm randomised controlled trial compared I-HARP to usual care in community-dwelling people with mild to moderate dementia and their family carers in Sydney, Australia (2018-2022). I-HARP is a 4-month, home-based, dementia rehabilitation model delivered by an interdisciplinary team. Assessments were conducted at baseline (time-1), 4-month (time-2) and 12-month (time-3) follow-up. The primary outcome measure was the client's functional independence using the Disability Assessment for Dementia (DAD) scale at time-2, based on intention-to-treat analyses.

Result: Of 130 recruited client-carer dyads, 116 dyads (58/group) completed the trial. The I-HARP group were not significantly better in most outcome measures than usual care at both time-2 and time-3; with the only statistically significant difference being a reduction in home environment hazards at time-2. Post hoc subgroup analysis of 66 clients with mild dementia found significantly better functional independence in the intervention group compared with those in usual care: difference 8.99 on DAD (95% CI 1.21, 16.79) at time-2 and difference 12.16 (95% CI 1.93, 22.38) at time-3. Economic evaluation suggests potentially lower resource use in I-HARP compared with usual care, but the cost-effectiveness is uncertain.

Conclusion: Primary outcomes were not met for a population of people with dementia, with severity ranging from mild to moderate and severe. The I-HARP model appeared to benefit functional independence of participants with mild dementia, with potential cost savings.

Trial registration number: ACTRN12618000600246.

Background and objective: Between 5% and 10% of amyotrophic lateral sclerosis (ALS) cases have a family history of the disease, 30% of which do not have an identifiable underlying genetic cause after a comprehensive study of the known ALS-related genes. Based on a significantly increased incidence of ALS in a small geographical region from Spain, the aim of this work was to identify novel ALS-related genes in ALS cases with negative genetic testing.

Methods: We detected an increased incidence of both sporadic and, especially, familial ALS cases in a small region from Spain compared with available demographic and epidemiological data. We performed whole genome sequencing in a group of 12 patients with ALS (5 of them familial) from this unique area. We expanded the study to include affected family members and additional cases from a wider surrounding region.

Results: We identified a shared missense mutation (c.1586C>T; p.Pro529Leu) in the cyclic AMP regulated phosphoprotein 21 (ARPP21) gene that encodes an RNA-binding protein, in a total of 10 patients with ALS from 7 unrelated families. No mutations were found in other ALS-causing genes.

Conclusions: While previous studies have dismissed a causal role of ARPP21 in ALS, our results strongly support ARPP21 as a novel ALS-causing gene.

Background: Vitamin D (VitD) affects the risk of multiple sclerosis (MS), but the impact on disease activity is controversial. We assessed whether VitD is associated with the No-Evidence of Disease Activity-3 (NEDA-3) status at 2 years from disease-modifying treatment (DMT) start, and whether this association is causal or the result of confounding factors. Furthermore, we explored if a genetic predisposition to higher VitD levels affects the risk of disease activity.

Methods: 230 untreated relapsing-remitting MS patients underwent serum 25-OH-vitamin-D measurement, and the association between seasonally adjusted VitD and disease activity was tested. Modelling a Polygenic Risk Score from a Genome-Wide Association Study on ~400 000 individuals, we studied the impact of genetic predisposition to higher VitD on the NEDA-3 status in 1408 independent MS patients. Two-sample Mendelian randomisation (MR) was used to assess causality.

Results: Lower baseline VitD was associated with decreased probability of NEDA-3 at 2 years (p=0.019). Particularly, VitD levels <20 ng/mL conferred an over twofold risk of disease activity (OR 2.36, 95% CI 1.30 to 3.88, p=0.0037). Genetic predisposition to higher VitD levels was associated with delayed age at MS onset (p=0.018) and with a higher probability of NEDA-3 status (p=0.034). MR confirmed causality between VitD and the risk of disease activity (p=0.041).

Conclusions: VitD levels before DMT start affect the risk of disease activity in MS. Genetic predisposition to higher VitD levels confers a lower risk of disease activity and is associated with delayed MS onset. Our work prompts future prospective studies regarding VitD supplementation and lifestyle interventions to hamper disease activity in MS.

Neuroleptic-induced dystonia is a source of great concern in clinical practice because of its iatrogenic nature which can potentially lead to life-threatening conditions. Since all neuroleptics (antipsychotics) share the ability to block the dopamine D₂-type receptors (D₂Rs) that are highly enriched in the striatum, this drug-induced dystonia is thought to be caused by decreased striatal D₂R activity. However, how associations of striatal D₂R inactivation with dystonia are formed remains elusive.A growing body of evidence suggests that imbalanced activities between D₁R-expressing medium spiny neurons and D₂R-expressing medium spiny neurons (D₁-MSNs and D₂-MSNs) in the striatal striosome-matrix system underlie the pathophysiology of various basal ganglia disorders including dystonia. Given the specificity of the striatal dopamine D₁ system in 'humans', this article highlights the striatal striosome hypothesis in causing 'repetitive' and 'stereotyped' motor symptoms which are key clinical features of dystonia. It is suggested that exposure to neuroleptics may reduce striosomal D₁-MSN activity and thereby cause dystonia symptoms. This may occur through an increase in the striatal cholinergic activity and the collateral inhibitory action of D₂-MSNs onto neighbouring D₁-MSNs within the striosome subfields. The article proposes a functional pathology of the striosome-matrix dopamine system for neuroleptic-induced acute dystonia or neuroleptic-withdrawal dystonia. A rationale for the effectiveness of dopaminergic or cholinergic pharmacotherapy is also provided for treating dystonias. This narrative review covers various aspects of the relevant field and provides a detailed discussion of the mechanisms of neuroleptic-induced dystonia.

Objectives: To evaluate the validity, reliability, responsiveness and meaningful change threshold of the Inclusion Body Myositis (IBM) Functional Rating Scale (FRS).

Methods: Data from a large 20-month multicentre, randomised, double-blind, placebo-controlled trial in IBM were used. Convergent validity was tested using Spearman correlation with other health outcomes. Discriminant (known groups) validity was assessed using standardised effect sizes (SES). Internal consistency was tested using Cronbach's alpha. Intrarater reliability in stable patients and equivalence of face-to-face and telephone administration were tested using intraclass correlation coefficients (ICCs) and Bland-Altman plots. Responsiveness was assessed using standardised response mean (SRM). A receiver operator characteristic (ROC) curve anchor-based approach was used to determine clinically meaningful IBMFRS change.

Results: Among the 150 patients, mean (SD) IBMFRS total score was 27.4 (4.6). Convergent validity was supported by medium to large correlations (r_s modulus: 0.42-0.79) and discriminant validity by moderate to large group differences (SES=0.51-1.59). Internal consistency was adequate (overall Cronbach's alpha: 0.79). Test-retest reliability (ICCs=0.84-0.87) and reliability of telephone versus face-to-face administration (ICCs=0.93-0.95) were excellent, with Bland-Altman plots showing good agreement. Responsiveness in the worsened group defined by various external constructs was large at both 12 (SRM=-0.76 to -1.49) and 20 months (SRM=-1.12 to -1.57). In ROC curve analysis, a drop in at least two IBMFRS total score points was shown to represent a meaningful decline.

Conclusions: When administered by trained raters, the IBMFRS is a reliable, valid and responsive tool that can be used to evaluate the impact of IBM and its treatment on physical function, with a 2-point reduction representing meaningful decline.

Trial registration number: NCT02753530.