Annals of Neurology最新文献

Objective: Rehabilitation is thought to reduce ataxia severity in individuals with hereditary cerebellar ataxia (HCA). This multicenter, randomized controlled superiority trial aimed to examine the efficacy of a 30-week goal-directed rehabilitation program compared with 30 weeks of standard care on function, ataxia, health-related quality of life, and balance in individuals with an HCA.

Methods: Individuals with an autosomal dominant or recessive ataxia (aged ≥15 years) were enrolled at 5 sites in Australia. Participants were randomized (1:1) to receive rehabilitation (6 weeks of outpatient physiotherapy followed by a 24-week home exercise program) (n = 39) or continued their usual activity (n = 37). The primary outcome measure was the motor domain of the Functional Independence Measure (mFIM) at 7 weeks. Secondary outcomes included the Scale for the Assessment and Rating of Ataxia (SARA) and the SF-36v2, assessed at 7, 18, and 30 weeks. Outcome assessors were blinded to treatment allocation.

Results: Seventy-one participants (rehabilitation, 37; standard-care, 34) were included in the intention-to-treat analysis. At 7 weeks, mFIM (mean difference 2.26, 95% confidence interval [CI]: 0.26 to 4.26, p = 0.028) and SARA (-1.21, 95% CI: -2.32 to -0.11, p = 0.032) scores improved after rehabilitation compared with standard care. Compared with standard care, rehabilitation improved SARA scores at 30 weeks (mean difference -1.51, 95% CI: -2.76 to -0.27, p = 0.017), but not mFIM scores (1.74, 95% CI: -0.32 to 3.81, p = 0.098). Frequent adverse events in both groups were fatigue, pain, and falls.

Interpretation: Goal-directed rehabilitation improved function at 7 weeks, with improvement in ataxia and health-related quality of life maintained at 30 weeks in individuals with HCA, beyond that of standard care. ANN NEUROL 2024.

Objective: Excitotoxicity is a common hallmark of epilepsy and other neurological diseases associated with elevated extracellular glutamate levels. Thus, here, we studied the protective effects of (R)-AS-1, a positive allosteric modulator (PAM) of glutamate uptake in epilepsy models.

Methods: (R)-AS-1 was evaluated in a range of acute and chronic seizure models, while its adverse effect profile was assessed in a panel of standard tests in rodents. The effect of (R)-AS-1 on glutamate uptake was assessed in COS-7 cells expressing the transporter. WAY 213613, a selective competitive EAAT2 inhibitor, was used to probe the reversal of the enhanced glutamate uptake in the same transporter expression system. Confocal microscopy and Western blotting analyses were used to study a potential influence of (R)-AS-1 on GLT-1 expression in mice.

Results: (R)-AS-1 showed robust protection in a panel of animal models of seizures and epilepsy, including the maximal electroshock- and 6 Hz-induced seizures, corneal kindling, mesial temporal lobe epilepsy, lamotrigine-resistant amygdala kindling, as well as seizures induced by pilocarpine or Theiler's murine encephalomyelitis virus. Importantly, (R)-AS-1 displayed a favorable adverse effect profile in the rotarod, the minimal motor impairment, and the Irwin tests. (R)-AS-1 enhanced glutamate uptake in vitro and this effect was abolished by WAY 213613, while no influence on GLT-1 expression in vivo was observed after repeated treatment.

Interpretation: Collectively, our results show that (R)-AS-1 has favorable tolerability and provides robust preclinical efficacy against seizures. Thus, allosteric enhancement of EAAT2 function could offer a novel therapeutic strategy for treatment of epilepsy and potentially other neurological disorders associated with glutamate excitotoxicity. ANN NEUROL 2024.

Endovascular thrombectomy (EVT) was shown to be safe and efficacious in patients with large core stroke in multiple randomized controlled trials. However, the impact of reperfusion and other procedural metrics on EVT outcomes in this population has not been well-characterized.

Methods: From the SELECT2 trial, we evaluated the association between reperfusion status, first-pass effect (near-complete or complete reperfusion [extended thrombolysis in cerebral infarction (eTICI) 2c-3] in 1 pass), procedure time and primary technique (aspiration vs stent-retriever) with functional outcomes in patients receiving EVT across ASPECTS (3 vs 4 vs 5) and core estimate strata (<70 vs ≥70ml, <100 vs ≥100ml, and <150 vs ≥150ml).

Results: Of 180 patients who received thrombectomy, 144 (80%) achieved successful reperfusion (eTICI 2b-3) and demonstrated better clinical outcomes (adjusted generalized odds ratios [aGenOR]: 1.48, 95% confidence interval [CI]: 1.01-2.15), compared with unsuccessful reperfusion. Results were consistent across ASPECTS and core estimate strata. Additionally, complete or near-complete reperfusion (eTICI 2c-3) was associated with better functional outcome (aGenOR: 1.99, 95% CI: 1.33-2.97) in patients achieving successful reperfusion. Functional outcome point estimates favored those with first-pass-effect (42 of 167 (25%), aGenOR: 1.46, 95% CI: 0.96-2.24). Longer procedure time was associated with worse modified Rankin scale (mRS) distribution (aGenOR: 0.92, 95% CI: 0.87-0.96, p-value = 0.001 for 10 minutes increment). Aspiration-first technique was used in 43 of 154 (25%) patients and was not associated with higher reperfusion (88% vs 78%, p = 0.18) or better functional outcome (aGenOR: 0.74, 95% CI: 0.50-1.10) as compared with stent-retriever first.

Interpretation: Successful reperfusion resulted in improved clinical outcomes in large core patients across baseline ischemic core strata. Near complete or complete reperfusion was further associated with better outcomes, whereas prolonged procedures were associated with worse outcomes. Results were consistent regardless of the technique used. ANN NEUROL 2024.

There are no dramatically effective pharmacological treatments for most patients with amyotrophic lateral sclerosis, a complex disease with multiple underlying mechanisms, such as neuroinflammation, oxidative stress, mitochondrial dysfunction, microbiome alteration, and antiretroviral activity. We sifted through 15 years of reviews by a group called ALSUntangled to identify 8 alternative and off-label treatments that target ≥1 of these mechanisms, and have ≥1 human trial suggesting meaningful benefits. Given the overlapping pathological mechanisms of the highlighted products, we suggest that combinations of these treatments targeting diverse mechanisms might be worthwhile for future amyotrophic lateral sclerosis therapy development. ANN NEUROL 2024.

Objective: The limited existing evidence on sex differences in the clinical characteristics of patients with spontaneous, non-traumatic intracerebral hemorrhage (ICH) comes from small, single-center studies. Here, we performed an individual patient data meta-analysis of 3 randomized clinical trials and 1 multi-ethnic observational study of ICH to investigate the impact of sex on ICH severity and outcome.

Methods: Inclusion criteria in our study were a neuroimaging-confirmed ICH. We evaluated whether sex was associated with ICH severity (hematoma volume and expansion) and poor functional outcomes (modified Rankin Scale >3) 3 or 6 months after the ICH.

Results: A total of 4,812 ICH patients were evaluated (mean age 62, 40% female). Males with ICH were younger, more likely to be smokers and have diabetes, and less likely to be on anticoagulants (all p < 0.05). In multivariable analyses, male sex was associated with non-lobar location (odds ratio [OR]: 1.63; 95% confidence interval [CI]: [1.39-1.92]; p < 0.001), larger hemorrhages (beta: 0.16 [0.08-0.23]; p < 0.001) and a higher risk of hematoma expansion (OR: 1.43 [1.20-1.71]; p < 0.001). Despite the larger hemorrhage volume and higher risk of expansion, male sex was associated with a 24% lower risk of poor outcomes (OR: 0.76 [0.64-0.90]; p = 0.002).

Interpretation: Compared to females, males with ICH have larger bleeds and higher risk of hematoma expansion. Despite the larger bleeds and higher risk of hematoma expansion, males with ICH have lower risk of poor outcomes. Our results suggest that the biology and clinical trajectory are different in females and males with ICH, supporting sex-specific research in this condition. ANN NEUROL 2024.