PATHOLOGICAL CORRELATES OF WHITE MATTER HYPERINTENSITIES ON CADAVERIC MRI IN PROGRANULIN-ASSOCIATED FRONTOTEMPORAL DEMENTIA

Abstract

White matter hyperintensities (WMH) are present on magnetic resonance imaging (MRI) brain scans of patients with frontotemporal dementia (FTD) associated with progranulin (GRN) mutations. However, their histopathological correlates are unknown. Cadaveric MRI scanning provides undistorted, in situ brain images, allowing precise spatial and quantitative correlations of neuroimaging abnormalities with histology in post-mortem brain tissue. We report a patient with behavioural variant FTD and a GRN Q130fs mutation, with extensive WMH, who underwent detailed cadaveric MRI and characterisation of WMH pathological correlates. The patient underwent cadaveric in situ brain MRI (GE Signa 1.5T scanner) within 24 hours after death, including volumetric T1 and FLAIR sequences. MRI had also been performed in vivo 2.6 years earlier. Five brain regions were selected for histopathological analysis, corresponding to areas of severe or absent WMH on FLAIR MRI: right frontal pole, anterior frontal, posterior frontal, temporal and occipital lobes. Histological examination was performed using sections stained with haematoxylin and eosin, Luxol fast blue and Perl stains and immunohistochemical staining for TDP-43, Aβ, phosphorylated neurofilament (SMI31), myelin basic protein and glial fibrillary acidic protein. Vascular pathology was semi-quantitatively assessed in regions of interest using the recommendations of the Vascular Cognitive Impairment Neuropathology Guidelines. In vivo and cadaveric MRI showed progressive, asymmetric (left worse than right) frontotemporal and parietal atrophy, and asymmetric WMH, predominantly affecting frontal white matter. TDP-43 type A pathology was present in the neocortex. Brain regions with most severe WMH on MRI (frontal pole and anterior frontal lobe) displayed the most severe cortical pathology when assessed for neuronal loss, spongiosis, gliosis, myelin loss and TDP-43 burden. In regions found to have WMH on MRI, there was no or minimal vascular pathology. The severity of cortical pathology corresponded with the degree of white matter pathology in all regions analysed. Vascular pathology does not appear to underlie the extensive WMH seen in GRN-mutation associated FTD. WMH could be due to axonal degeneration secondary to cortical neuronal loss, or, given the known role of GRN in inflammatory pathways, excessive inflammation leading to demyelination. Further study of WMH histopathological correlates across a larger cohort of patients is required.