Vascular resistance and resilience in ALS – an ultrahigh-resolution 7T MRI study of the motor cortex

肌萎缩侧索硬化症(ALS)是一种以运动皮质锥体细胞变性为特征的快速进展性神经肌肉疾病。散发性肌萎缩侧索硬化症的潜在原因仍然很大程度上尚不清楚，仅限于支持性措施，而没有任何因果疗法。尽管许多患者在3到5年内死于呼吸功能不全，但个别ALS的病程和预后存在很大的差异。这反映在不同的运动表型，长达10年的生存时间，以及个体患者疾病进展的停止甚至逆转。在提出的建议中，我们假设临床ALS异质性的根本原因是运动皮质的血管供应可变，这减轻了M1锥体细胞退化(阻力)或其对运动功能的影响(“韧性”)。为了解决这个问题，我们将前瞻性地检查选定的20名ALS患者和20名年龄和性别匹配的对照组，他们将接受7特斯拉超高场磁共振成像(MRI)应用血管造影(ToF-MRA)和解剖序列(MPRAGE)。根据视觉分级，大脑前动脉(运动内侧皮质)和大脑中动脉(运动外侧皮质)的分支将区分两种M1供应的血管模式：一种是“单一供应”模式，其中M1供应仅由一个单一分支的终末皮质动脉供应；另一种是“双供应”模式，即两个分支供应终末皮质动脉。我们假设“双供”模式导致两个分支的灌注区重叠，从而减轻M1锥体细胞变性或其对运动功能的影响。为了进行定量分析，将应用血管距离图，这将为每个非血管体素分配到所检查的每条动脉的距离，从而允许对分支的灌注区进行近似。基于中介模型，将评估血管供应模式和灌注区对锥体细胞变性的直接影响(使用M1皮质厚度、全局和身体部位特异性研究)，以及其严重性是否在基线MRI时和纵向上中介血管供应模式和灌注区对运动功能(全局和身体部位特异性)的影响。血管模式可以作为解释ALS表型变异的新标记物，这可能被证明是关于病程和预后的个性化患者咨询的另一个方面。此外，脑血管系统是潜在的“动态”组织，其功能可以通过生活方式和某些药物来改变。“血管疗法”可能为肌萎缩侧索硬化症的预防和治疗开辟新的途径。

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neuromuscular disorder hallmarked by pyramidal cell degeneration of the motor cortex (M1). The underlying causes of sporadic ALS remain largely unknown, limiting its treatment options to supportive measures without any causal therapies. Even though many patients die within 3 to 5 years through respiratory insufficiency, individual ALS disease course and prognosis are highly variable. This is mirrored by distinct motor phenotypes, very long survival times of up to 10 years, and cessation or even reversal of disease progression in individual patients.In the presented proposal we hypothesize that a root cause of clinical ALS heterogeneity is a variable vascular supply of the motor cortex, which mitigates M1 pyramidal cell degeneration (“resistance”) or its impact on motor function (“resilience”). To address this question, we will prospectively examine a selected cohort of 20 ALS patients and 20 age- and sex-matched controls that will undergo 7 Tesla ultra-high field magnetic resonance imaging (MRI) applying angiographic (ToF-MRA) and anatomical sequences (MPRAGE). By visual rating two vascular patterns of M1 supply will be distinguished for the branches of the anterior cerebral artery (medial motor cortex) and middle cerebral artery (lateral motor cortex), respectively: a “single supply” pattern in which the M1 supply is provided by the terminal cortical arteries of one single branch only, or a “double supply” pattern, in which two branches feed the supplying terminal cortical arteries. We assume that a “double supply” pattern results in overlapping perfusion territories of both branches which mitigate M1 pyramidal cell degeneration or its impact on motor function. For quantitative analysis vessel distance mapping will be applied, which assigns each non-vessel voxel the distance to each of the examined arteries and thus consequently allows an approximation of the branches’ perfusion territories. Based upon mediation models the direct effects of the vascular supply patterns and perfusion territories on pyramidal cell degeneration (studied using M1 cortical thickness, global and body-part specific) will be assessed, as well as whether their severity mediates the influence of vascular supply patterns and perfusion territories upon motor function (global and body-part specific), both, at the time of the baseline MRI and longitudinally.Vascular patterns could serve as a new marker to explain the phenotypic variability in ALS, which might prove useful as an additional aspect for an individualized patient counseling regarding disease course and prognosis. Additionally the cerebral vasculature is potentially “dynamic” tissue, whose functionality can be modified through lifestyle and certain drugs. A “vascular approach to therapy” might lead to new avenues in the prevention and treatment of ALS.