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

• Applicants: Dr.-Ing. Hendrik Mattern; Professorin Dr. Stefanie Schreiber; Professor Dr. Oliver Speck
• Subject Area: Clinical Neurology; Neurosurgery and Neuroradiology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 501214112

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.

• DFG Programme: Research Grants