Abstract T P79: Molecular Disorganization of Axons Adjacent to Subcortical Stroke in Hereditary Endotheliopathy With Retinopathy, Nephropathy, and Stroke; an Imaging to Molecular Neuropathology Correlation

Abstract

White matter stroke secondary to microvascular injury is common yet the molecular changes that accompany ischemic damage to white matter are poorly understood. MRI imaging studies suggest that abnormalities exist within the white matter adjacent to lacunar infarcts and this may lead to infarct progression through a functional disruption of adjacent axons. Hereditary subcortical stroke syndromes provide a unique opportunity to study the molecular mechanisms of cerebral microvascular disease and its effect on white matter. Here, we examined two autopsy cases of hereditary endotheliopathy with retinopathy, nephropathy and stroke (HERNS) syndrome with severe microvascular ischemic disease in the cerebral white matter to determine the molecular organization of myelin and axons within the cerebral white matter adjacent to lacunar infarcts in these patients. MRI imaging was used to identify regions of prior lacunar infarction or FLAIR hyperintensity. Serial paraffin-embedded sections within these regions were immunolabeled for markers of nodes of Ranvier and paranodes as well as neurofilaments and myelin basic protein and compared to normal-appearing white matter and non-diseased controls. Compared to controls, HERNS cases demonstrate lengthening of paranodes and disrupted nodal staining patterns consistent with a loss of normal axon-oligodendrocyte molecular interactions. These abnormalities of axonal microdomains are present beyond the region of infarction suggested by MRI and H&E sections and occur in areas of FLAIR hyperintensity without frank lacunar infarction. These results indicate there is a peri-infarct in white matter stroke marked by molecular disruption of axons surrounding the infarct that may serve as a new therapeutic target for this currently untreatable form of ischemic stroke.