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.