3.1.3 Leaky CNS barriers
For human post mortem studies, the leakiness of CNS barriers is often inferred from the presence of plasma-derived proteins in brain or spinal cord. Donnenfeld et al. identified IgG and C3/C4 complement in the motor cortex and spinal cord of ALS patients nearly 40 years ago (Donnenfeld, Kascsak & Bartfeld, 1984). These deposits were detected immunohistochemically in 5 of 13 ALS motor cortices and 6 of 16 ALS spinal cords, but not in non-ALS controls. Findings by Donnenfeldet al. were later confirmed by Engelhardt et al . immunohistochemically, where IgG was identified in 13 of 15 ALS spinal cords and 6 of 11 ALS motor cortices (Engelhardt & Appel, 1990). In addition to IgG, Winker et al. noted haemoglobin, fibrinogen and thrombin in the ALS cervical spinal cord (8 sporadic ALS cases, 3 familial ALS cases) but not in non-ALS controls (5 cases) (Winkler, Sengillo, Sullivan, Henkel, Appel & Zlokovic, 2013). In line with these postmortem findings, increased IgG (1.26-fold) and albumin (1.28-fold) has been reported by Leonardi et al. (Leonardi, Abbruzzese, Arata, Cocito & Vische, 1984) in ALS cerebrospinal fluid (CSF) (90 ALS cases, 50 controls) and elevated haemoglobin levels (1.86-fold) has been reported in the CSF of individuals with ALS by Waters et al. (236 ALS cases, 87 controls) (Waters et al., 2021) . Consistently, these studies demonstrate that CNS barrier permeability is generally increased in individuals with ALS, which is very likely a result of the ultrastructural abnormality and reduced expression of TJs at the ALS CNS barriers. While these modifications likely contribute to the leakiness of endogenous proteins into the CNS, the impact of these changes on the CNS access of small and large molecular weight therapeutics has yet to be undertaken clinically. This could be achieved using imaging techniques such as magnetic resonance imaging to visualise CNS access of gadolinium in ALS.