Brain Vascular Health in ALS Is Mediated through Motor Cortex Microvascular Integrity

Abstract

Brain vascular health appears to be critical for preventing the development of amyotrophic lateral sclerosis (ALS) and slowing its progression. ALS patients often demonstrate cardiovascular risk factors and commonly suffer from cerebrovascular disease, with evidence of pathological alterations in their small cerebral blood vessels. Impaired vascular brain health has detrimental effects on motor neurons: vascular endothelial growth factor levels are lowered in ALS, which can compromise endothelial cell formation and the integrity of the blood–brain barrier. Increased turnover of neurovascular unit cells precedes their senescence, which, together with pericyte alterations, further fosters the failure of toxic metabolite removal. We here provide a comprehensive overview of the pathogenesis of impaired brain vascular health in ALS and how novel magnetic resonance imaging techniques can aid its detection. In particular, we discuss vascular patterns of blood supply to the motor cortex with the number of branches from the anterior and middle cerebral arteries acting as a novel marker of resistance and resilience against downstream effects of vascular risk and events in ALS. We outline how certain interventions adapted to patient needs and capabilities have the potential to mechanistically target the brain microvasculature towards favorable motor cortex blood supply patterns. Through this strategy, we aim to guide novel approaches to ALS management and a better understanding of ALS pathophysiology.

Age-Related Differences in Human Cortical Microstructure Depend on the Distance to the Nearest Vein

“…Additional analyses of time-of-flight MRI measurements would benefit future studies. Moreover, previous studies pointed out that hypertension and alterations in brain vasculature relate to myelin loss and M1 pathology (Jacków-Nowicka et al 2021; Tsushima, et al 2003; Dobrynina et al 2018, Li et al 2023; Schreiber et al 2023). Here, 9/17 older adults showed global signs of vascular health risk (i.e., presence of hypertension and/or signs of cerebral small vessel diseases outside S1 and M1).…”

“…Age-related differences in cortical microstructure are used to understand the neuronal mechanisms that underlie human brain ageing and neurodegeneration. Vascular supply patterns in the brain vary between individuals (Bernier et al, 2018; Huck et al, 2019), influence cortical microstructure and functional decline (Perosa et al, 2020; Vockert et al, 2021), and explain brain pathology (Schreiber et al 2023). However, the contribution of the local vascular architecture on age-related changes in cortical microstructure is poorly understood.…”

“…Quantitative T1 values (qT1) were used as validated proxy for cortical myelin content (Dinse et al, 2015; Stüber et al, 2014; Haast et al 2016), and quantitative susceptibility mapping (QSM) was used to quantify cortical iron (Langkammer et al, 2012; Deistung et al 2013; Hametner et al 2018; Acosta-Cabronero et al 2016; Betts et al 2016). We focus on primary somatosensory cortex (S1) and primary motor cortex (M1) as both areas play an important role in ageing and neurodegeneration, and venous density in S1 and M1 has been associated with myelin loss and decline of sensorimotor function in older adults (Schreiber et al 2023). Ultra-high resolution QSM images were used for vein identification, and Vessel Distance Mapping (VDM) for linking age-related changes in layer-specific cortical microstructure to the distance to the nearest vein (Mattern et al 2021a; Garcia-Garcia et al 2023).…”

Multimodal layer modelling revealsin-vivopathology in ALS

“…Increased calcium in humans may reflect similar mechanisms, including the increased activity of M1 in ALS 51 or calcifications in blood vessels related to poor brain health 52 .…”

A patient-derived amyotrophic lateral sclerosis blood-brain barrier cell model reveals focused ultrasound-mediated anti-TDP-43 antibody delivery

“…Additionally, evidence from animal and human studies indicates BBB dysfunction in ALS, and suggests cerebrovascular involvement in disease development and progression (15)(16)(17)(18). Changes in BBB ultrastructure and barrier integrity were found in preclinical models and in patients, leading to increased BBB permeability and infiltration of blood-derived proteins, erythrocytes and immune cells into the brain (16,17,(19)(20)(21)(22)(23)(24).…”