Microangiopathy in temporal lobe epilepsy with diffusion MRI alterations and cognitive decline

Abstract White matter microvascular alterations in temporal lobe epilepsy (TLE) can influence local hemodynamics and are relevant to understanding acquired neurodegenerative processes and cognitive impairment associated with this condition. We quantified microvascular changes, myelin, axonal and glial/matrix labelling in the gyral core and deep temporal lobe white matter regions in surgical resections from 44 TLE patients with or without hippocampal sclerosis. We compared this pathology data with in-vivo MRI diffusion measurements in co-registered regions and neuropsychological measures of pre-operative cognitive impairment and decline. We observed increased arteriolosclerosis in TLE compared to controls (greater sclerotic index, p < 0.001) which was independent of age. Microvascular changes included increased vascular densities in some regions but uniformly reduced mean vascular size (COL4, p < 0.05 to 0.0001), and increased pericyte coverage of small vessels and capillaries particularly in deep white matter (PDGFRβ and SMA, p < 0.01) which was more marked the longer the epilepsy (p < 0.05). We noted increased glial numbers (Olig2, Iba1) but reduced myelin (MAG, PLP) in TLE compared to controls, particularly prominent in deep white matter. Gene expression analysis showed a greater reduction of myelination genes in HS than non-HS cases and with age and correlated with diffusion MRI alterations. Glial densities and vascular size were increased with increased MRI diffusivity and vascular density with Fixel-Based analysis white matter regions. Increased perivascular space associated with reduced fractional anisotropy as well as age-accelerated cognitive decline prior to surgery (p < 0.05). In summary, likely acquired microangiopathic changes in TLE, including vascular sclerosis, increased pericyte coverage and reduced small vessel size, may indicate a functional alteration in contractility of small vessels and haemodynamics that could impact on tissue perfusion. These morphological features are detectable in-vivo on white matter diffusion MRI and might explain cognitive decline in TLE.