Physical Activity, Fitness, and Long-Term Risk of Amyotrophic Lateral Sclerosis: A Prospective Cohort Study

体力活动，健身和肌萎缩性侧索硬化症的长期风险: 一项前瞻性队列研究

Observational studies have demonstrated an increased amyotrophic lateral sclerosis (ALS) risk among professional athletes in various sports. For moderately increased levels of physical activity and fitness, the results are diverging. Through a cohort study, we aimed to assess the relationship between indicators of physical activity and fitness (self-reported physical activity and resting heart rate) and long-term ALS risk. Indicators of high levels of physical activity and fitness are associated with a reduced risk of ALS more than 30 years later in men, but not in women.

观察性研究表明，各种运动的专业运动员中肌萎缩性侧索硬化症 (ALS) 的风险增加。对于适度增加的身体活动和健身水平，结果是不同的。通过一项队列研究，我们旨在评估身体活动和健身指标 (自我报告的身体活动和静息心率) 与长期ALS风险之间的关系。高水平的身体活动和健康指标与男性30多年后ALS风险降低有关，但女性则没有。

REF: Vaage AM, Meyer HE, Landgraff IK, Myrstad M, Holmøy T, Nakken O. Physical Activity, Fitness, and Long-Term Risk of Amyotrophic Lateral Sclerosis: A Prospective Cohort Study. Neurology. 2024;103(2):e209575. doi:10.1212/WNL.0000000000209575 PMID: 38924713

Efficacy of Atogepant in Chronic Migraine With and Without Acute Medication Overuse in the Randomized, Double-Blind, Phase 3 PROGRESS Trial

在随机，双盲，3期PROGRESS试验中，Atogepant对有或没有急性药物过度使用的慢性偏头痛的疗效

Atogepant is an oral, calcitonin gene-related peptide receptor antagonist approved for the preventive treatment of migraine. We evaluated the efficacy of atogepant for the preventive treatment of chronic migraine (CM) in participants with and without acute medication overuse. Atogepant was effective in participants with CM, with and without acute medication overuse, as evidenced by reductions in mean MMDs, MHDs, and acute medication use days; reductions in the proportion of participants meeting acute medication overuse criteria; and improvements in PROs.

Atogepant是一种口服降钙素基因相关肽受体拮抗剂，已批准用于偏头痛的预防性治疗。我们评估了atogepant在有和没有急性药物过度使用的参与者中预防性治疗慢性偏头痛 (CM) 的功效。Atogepant对有或没有急性药物过度使用的CM参与者有效，这可以通过平均MMDs，MHDs和急性药物使用天数的减少来证明; 符合急性药物过度使用标准的参与者比例的减少; 和PROs的改善。

REF: Goadsby PJ, Friedman DI, Holle-Lee D, et al. Efficacy of Atogepant in Chronic Migraine With and Without Acute Medication Overuse in the Randomized, Double-Blind, Phase 3 PROGRESS Trial. Neurology. 2024;103(2):e209584. doi:10.1212/WNL.0000000000209584 PMID: 38924724

External Validation of a Model for Persistent Perfusion Deficit in Patients With Incomplete Reperfusion After Thrombectomy: EXTEND-PROCEED

血栓切除术后不完全再灌注患者持续灌注不足模型的外部验证: 扩展-继续

We recently developed a model (PROCEED) that predicts the occurrence of persistent perfusion deficit (PPD) at 24 hours in patients with incomplete angiographic reperfusion after thrombectomy. This study aims to externally validate the PROCEED model using prospectively acquired multicenter data. The externally validated model had adequate predictive accuracy and discrimination. Depending on the acceptable threshold probability, the model accurately predicts persistent incomplete reperfusion and may advise physicians whether additional reperfusion attempts should be performed.

我们最近开发了一个模型 (进行)，该模型可预测血栓切除术后血管造影不完全再灌注患者在24小时内持续灌注不足 (PPD) 的发生。本研究旨在使用前瞻性获取的多中心数据从外部验证进行模型。外部验证的模型具有足够的预测准确性和区分度。根据可接受的阈值概率，该模型可以准确预测持续的不完全再灌注，并可以建议医生是否应该进行额外的再灌注尝试。

REF: Mujanovic A, Ng FC, Branca M, et al. External Validation of a Model for Persistent Perfusion Deficit in Patients With Incomplete Reperfusion After Thrombectomy: EXTEND-PROCEED. Neurology. 2024;103(2):e209401. doi:10.1212/WNL.0000000000209401 PMID: 38900979

Cerebral Amyloid Angiopathy–Related Inflammation and Biopsy-Positive Primary Angiitis of the CNS: A Comparative Study

脑淀粉样血管病相关炎症和中枢神经系统活检阳性原发性血管炎: 一项比较研究

Cerebral amyloid angiopathy-related inflammation (CAA-RI) and biopsy-positive primary angiitis of the CNS (BP-PACNS) have overlapping clinicoradiologic presentations. It is unknown whether clinical and radiologic features can differentiate CAA-RI from BP-PACNS and whether both diseases have different relapse rates. The objectives of this study were to compare clinicoradiologic presentations and relapse rates in patients with CAA-RI vs BP-PACNS. Clinicoradiologic features differed between patients with CAA-RI and those with BP-PACNS. Specific markers for CAA-RI were hemorrhagic signs of subarachnoid involvement, past intracerebral hemorrhage, ≥21 visible centrum semiovale perivascular spaces, and the probable CAA-RI criteria. A biopsy remains necessary for diagnosis in some cases of CAA-RI. The rate of relapse in the first 2 years after disease remission was lower in CAA-RI than in BP-PACNS.

脑淀粉样血管病相关炎症 (caa-ri) 和中枢神经系统活检阳性原发性血管炎 (bp-pacns) 具有重叠的临床放射学表现。尚不清楚临床和放射学特征是否可以区分caa-ri和bp-pacns，以及两种疾病是否具有不同的复发率。这项研究的目的是比较caa-ri与bp-pacns患者的临床放射学表现和复发率。Caa-ri患者和bp-pacns患者的临床放射学特征不同。Caa-ri的特异性标志物是蛛网膜下腔受累的出血征象，既往脑出血，≥ 21个可见的中心半卵圆血管周围空间以及可能的caa-ri标准。在某些caa-ri病例中，活检对于诊断仍然是必要的。Caa-ri在疾病缓解后前2年的复发率低于bp-pacns。

REF: Grangeon L, Boulouis G, Capron J, et al. Cerebral Amyloid Angiopathy-Related Inflammation and Biopsy-Positive Primary Angiitis of the CNS: A Comparative Study. Neurology. 2024;103(2):e209548. doi:10.1212/WNL.0000000000209548 PMID: 38900992

Pearls & Oy-sters: Frontal Lobe Syndrome Secondary to Cocaine-Induced Midline Destructive Lesions

珍珠和牡蛎: 可卡因引起的中线破坏性病变继发的额叶综合征

Cocaine-induced midline destructive lesions (CIMDL) are a rare complication of chronic intranasal cocaine use involving the centrofacial mucosal structures, often with nasal septum perforation and, in severe cases, involvement of neurocranial structures. Patients present with nasal obstruction, epistaxis, facial pain, nasal ulcerative lesions with crusting, and septal and palate perforation causing dysphagia and nasal reflux. CNS involvement is uncommon.We report a 47-year-old man with a history of nasal cocaine use who developed a subacute frontal syndrome secondary to cribriform plate destruction complicated by bilateral frontal lobe empyema and abscesses and extensive white matter involvement. The frequent presence of serum antineutrophil cytoplasmic antibodies (ANCA) in CIMDL makes this uncommon presentation challenging to differentiate from localized granulomatosis with polyangiitis. While ANCA antibodies may play a role in CIMDL, immunosuppression is not indicated and may lead to iatrogenesis.CIMDL should be considered in patients with isolated frontal lobe syndrome. Eliciting a history of cocaine use and obtaining toxicologic studies are essential in the diagnosis of CIMDL.

可卡因引起的中线破坏性病变 (CIMDL) 是慢性鼻内可卡因使用累及中面部粘膜结构的罕见并发症，通常伴有鼻中隔穿孔，在严重情况下还涉及神经颅结构。患者表现为鼻塞，鼻出血，面部疼痛，伴有结痂的鼻溃疡性病变，以及导致吞咽困难和鼻反流的鼻中隔和pa穿孔。中枢神经系统受累并不常见。我们报道了一名47岁的男子，他有鼻用可卡因史，继发于筛状板破坏，并发双侧额叶积脓，脓肿和广泛的白质受累，并发亚急性额叶综合征。CIMDL中经常存在血清抗中性粒细胞胞质抗体 (ANCA)，这使得这种罕见的表现难以与局部肉芽肿性血管炎区分开来。虽然ANCA抗体可能在CIMDL中发挥作用，但不指示免疫抑制，并且可能导致医源性增生。孤立额叶综合征患者应考虑CIMDL。获得可卡因使用史和获得毒理学研究对于CIMDL的诊断至关重要。

REF: Cabrera Muras A, Gómez Muga JJ, Antón Méndez L, Barreras García A, García-Moncó JC. Pearls & Oy-sters: Frontal Lobe Syndrome Secondary to Cocaine-Induced Midline Destructive Lesions. Neurology. 2024;103(2):e209619. doi:10.1212/WNL.0000000000209619 PMID: 38900994

Progressive Cerebrocerebellar Uncoupling in Sporadic and Genetic Forms of Amyotrophic Lateral Sclerosis

散发性和遗传形式的肌萎缩性侧索硬化症的进行性小脑解偶联

Amyotrophic lateral sclerosis (ALS) is predominantly associated with motor cortex, corticospinal tract (CST), brainstem, and spinal cord degeneration, and cerebellar involvement is much less well characterized. However, some of the cardinal clinical features of ALS, such as dysarthria, dysphagia, gait impairment, falls, and impaired dexterity, are believed to be exacerbated by coexisting cerebellar pathology. Cerebellar pathology may also contribute to cognitive, behavioral, and pseudobulbar manifestations. Our objective was to systematically assess both intracerebellar pathology and cerebrocerebellar connectivity alterations in a genetically stratified cohort of ALS. ALS is associated with accruing intracerebellar disease burden as well as progressive corticocerebellar uncoupling. Contrary to previous suggestions, we have not detected evidence of compensatory structural or functional changes in response to supratentorial degeneration. The contribution of cerebellar disease burden to dysarthria, dysphagia, gait impairment, pseudobulbar affect, and cognitive deficits should be carefully considered in clinical assessments, monitoring, and multidisciplinary interventions.

肌萎缩性侧索硬化症 (ALS) 主要与运动皮层，皮质脊髓束 (CST)，脑干和脊髓变性有关，而小脑受累的特征则少得多。然而，ALS的一些主要临床特征，如构音障碍、吞咽困难、步态障碍、跌倒和灵活性受损，被认为会因共存的小脑病理而加剧。小脑病理也可能有助于认知，行为和假性延髓表现。我们的目的是系统地评估ALS遗传分层队列中的小脑病理和小脑连接改变。ALS与增加小脑内疾病负担以及进行性皮质小脑解偶联有关。与以前的建议相反，我们尚未发现幕上变性引起的补偿性结构或功能变化的证据。在临床评估，监测和多学科干预中应仔细考虑小脑疾病负担对构音障碍，吞咽困难，步态障碍，假性延髓影响和认知缺陷的影响。

REF: Tahedl M, Tan EL, Kleinerova J, et al. Progressive Cerebrocerebellar Uncoupling in Sporadic and Genetic Forms of Amyotrophic Lateral Sclerosis. Neurology. 2024;103(2):e209623. doi:10.1212/WNL.0000000000209623 PMID: 38900989

Fluid Biomarkers in Individuals at Risk for Genetic Prion Disease up to Disease Conversion

处于遗传朊病毒疾病风险的个体的流体生物标志物直至疾病转化

To longitudinally characterize disease-relevant CSF and plasma biomarkers in individuals at risk for genetic prion disease up to disease conversion. CSF prion seeding activity may represent the earliest detectable prodromal sign in E200K carriers. Neuronal damage and neuroinflammation markers show limited sensitivity in the prodromal phase. CSF PrP levels remain stable even in the presence of RT-QuIC seeding activity.

纵向表征处于遗传性朊病毒病风险直至疾病转化的个体中与疾病相关的CSF和血浆生物标志物。CSF朊病毒接种活性可能代表E200K携带者中最早可检测到的前驱体征。神经元损伤和神经炎症标志物在前驱期显示出有限的敏感性。Csfprp水平即使在rt-quic接种活性存在下也保持稳定。

REF: Vallabh SM, Mortberg MA, Allen SW, et al. Fluid Biomarkers in Individuals at Risk for Genetic Prion Disease up to Disease Conversion. Neurology. 2024;103(2):e209506. doi:10.1212/WNL.0000000000209506 PMID: 38896810 PMCID: PMC11226308

Association of Terazosin, Doxazosin, or Alfuzosin Use and Risk of Dementia With Lewy Bodies in Men

特拉唑嗪，多沙唑嗪或阿夫唑嗪的使用与男性路易体痴呆风险的关系

Terazosin, doxazosin, and alfuzosin (Tz/Dz/Az) are α-1 adrenergic receptor antagonists that also bind to and activate a key adenosine triphosphate (ATP)-producing enzyme in glycolysis. It is hypothesized that the increase in energy availability in the brain may slow or prevent neurodegeneration, potentially by reducing the accumulation of alpha-synuclein. Recent work has suggested a potentially neuroprotective effect of the use of Tz/Dz/Az in Parkinson disease in both animal and human studies. We investigated the neuroprotective effects of Tz/Dz/Az in a closely related disease, dementia with Lewy bodies (DLB). We find an association in men who are taking Tz/Dz/Az and a lower hazard of DLB compared with similar men taking other medications. When combined with the literature of Tz/Dz/Az on Parkinson disease, our findings suggest that glycolysis-enhancing drugs may be broadly protective in neurodegenerative synucleinopathies. A future randomized trial is required to assess these associations for causality.

特拉唑嗪，多沙唑嗪和阿夫唑嗪 (Tz/Dz/Az) 是 α-1肾上腺素能受体拮抗剂，它们还结合并激活糖酵解中的关键三磷酸腺苷 (ATP) 产生酶。据推测，大脑中能量可用性的增加可能会减缓或预防神经变性，这可能是通过减少 α-突触核蛋白的积累来实现的。最近的工作表明，在动物和人类研究中，使用Tz/Dz/Az在帕金森氏病中具有潜在的神经保护作用。我们研究了Tz/Dz/Az在密切相关的疾病路易体痴呆 (DLB) 中的神经保护作用。我们发现服用Tz/Dz/Az的男性与服用其他药物的类似男性相比，DLB的风险较低。结合Tz/Dz/Az关于帕金森病的文献，我们的发现表明，糖酵解增强药物可能对神经退行性突触核蛋白病具有广泛的保护作用。需要未来的随机试验来评估这些相关性的因果关系。

REF: Hart A, Aldridge G, Zhang Q, Narayanan NS, Simmering JE. Association of Terazosin, Doxazosin, or Alfuzosin Use and Risk of Dementia With Lewy Bodies in Men. Neurology. 2024;103(2):e209570. doi:10.1212/WNL.0000000000209570 PMID: 38896813 PMCID: PMC11226317

Using the Progression Independent of Relapse Activity Framework to Unveil the Pathobiological Foundations of Multiple Sclerosis

使用独立于复发活动框架的进展来揭示多发性硬化症的病理生物学基础

Progression independent of relapse activity (PIRA), a recent concept to formalize disability accrual in multiple sclerosis (MS) independent of relapses, has gained popularity as a potential clinical trial outcome. We discuss its shortcomings and appraise the challenges of implementing it in clinical settings, experimental trials, and research. The current definition of PIRA assumes that acute inflammation, which can manifest as a relapse, and neurodegeneration, manifesting as progressive disability accrual, can be disentangled by introducing specific time windows between the onset of relapses and the observed increase in disability. The term PIRMA (progression independent of relapse and MRI activity) was recently introduced to indicate disability accrual in the absence of both clinical relapses and new brain and spinal cord MRI lesions. Assessing PIRMA in clinical practice is highly challenging because it necessitates frequent clinical assessments and brain and spinal cord MRI scans. PIRA is commonly assessed using Expanded Disability Status Scale, a scale heavily weighted toward motor disability, whereas a more granular assessment of disability deterioration, including cognitive decline, using composite measures or other tools, such as digital tools, would possess greater utility. Similarly, using PIRA as an outcome measure in randomized clinical trials is also challenging and requires methodological considerations. The underpinning pathobiology of disability accumulation, that is not associated with relapses, may encompass chronic active lesions (slowly expanding lesions and paramagnetic rim lesions), cortical lesions, brain and spinal cord atrophy, particularly in the gray matter, diffuse and focal microglial activation, persistent leptomeningeal enhancement, and white matter tract damage. We propose to use PIRA to understand the main determinant of disability accrual in observational, cohort studies, where regular MRI scans are not included, and introduce the term of "advanced-PIRMA" to investigate the contributions to disability accrual of the abovementioned processes, using conventional and advanced imaging. This is supported by the knowledge that MRI reflects the MS pathogenic mechanisms better than purely clinical descriptors. Any residual disability accrual, which remains unexplained after considering all these mechanisms with imaging, will highlight future research priorities to help complete our understanding of MS pathogenesis.

独立于复发活动的进展 (PIRA) 是一种将多发性硬化症 (MS) 中的残疾累积与复发无关的最新概念，已作为潜在的临床试验结果而受到欢迎。我们讨论了它的缺点，并评估了在临床环境，实验试验和研究中实施它的挑战。PIRA的当前定义假设可以表现为复发的急性炎症和表现为进行性残疾累积的神经变性可以通过在复发发作和观察到的残疾增加之间引入特定的时间窗来解决。最近引入了术语PIRMA (独立于复发和MRI活动的进展)，以指示在没有临床复发和新的脑和脊髓MRI病变的情况下残疾累积。在临床实践中评估PIRMA非常具有挑战性，因为它需要频繁的临床评估以及脑和脊髓MRI扫描。PIRA通常使用扩展的残疾状态量表进行评估，该量表主要针对运动障碍进行评估，而使用复合措施或其他工具 (例如数字工具) 对包括认知能力下降在内的残疾恶化进行更细粒度的评估将具有更大的实用性。同样，在随机临床试验中使用PIRA作为结果测量也是具有挑战性的，并且需要方法学上的考虑。与复发无关的残疾积累的病理生物学基础可能包括慢性活动性病变 (缓慢扩张的病变和顺磁性边缘病变)，皮质病变，脑和脊髓萎缩，尤其是在灰质中，弥漫性和局灶性小胶质细胞激活，持续性软脑膜增强和白质束损伤。我们建议使用PIRA来了解观察性队列研究中残疾累积的主要决定因素，其中不包括常规MRI扫描，并引入 “高级PIRMA” 一词来调查上述过程对残疾累积的贡献，使用常规和高级成像。这得到了MRI比纯粹的临床描述更好地反映MS致病机制的知识的支持。在考虑了所有这些成像机制后，任何残留的残疾累积都无法解释，这将突出未来的研究重点，以帮助我们完成对MS发病机理的理解。

REF: Ciccarelli O, Barkhof F, Calabrese M, et al. Using the Progression Independent of Relapse Activity Framework to Unveil the Pathobiological Foundations of Multiple Sclerosis. Neurology. 2024;103(1):e209444. doi:10.1212/WNL.0000000000209444 PMID: 38889384 PMCID: PMC11226318