3.1.1 Ultrastructural modifications
In postmortem ALS human spinal cord, electron microscopy and immunohistochemistry revealed swelling and cytoplasmic vacuolisation of microvascular endothelial cells, degeneration of pericytes and detachment of astrocyte end-feet processes from endothelial cells (Garbuzova-Davis et al., 2012; Miyazaki et al., 2011; Sasaki, 2015; Yamadera et al., 2015). Studies also reported increased (Garbuzova-Davis et al., 2012; Waters et al., 2021) or decreased (Miyazaki et al., 2011; Ono et al., 1998) collagen content in the basement membrane of the spinal cord microvasculature in ALS patients. Reduced collagen content in the basement membrane can be to due cellular damage, whereas a thickened basement membrane could be a result of repetitive regeneration. This discrepancy in the above reports could be attributed to the different CNS regions assessed, the heterogeneity in ALS pathology, and varied quantification methods employed to assess collagen content. Further studies are required to confirm this in a more systematic manner, and assess the impact of basement thickening or thinning on CNS exposure of passively-diffusing compounds, given that brain microvascular basement membrane thickening has been associated with reduced BBB transport of passively-diffusing drugs in a mouse model of AD (Mehta, Short & Nicolazzo, 2013).