Pathological correlates of white matter hyperintensities in a case of progranulin mutation associated frontotemporal dementia

Ione O.C Woollacott,Martina Bocchetta,Carole H Sudre,Basil H Ridha,Catherine Strand,Robert Courtney,Sebastien Ourselin,M Jorge Cardoso,Jason D Warren,Martin N Rossor,Tamas Revesz,Nick C Fox,Janice L Holton,Tammaryn Lashley,Jonathan D Rohrer

doi:10.1080/13554794.2018.1506039

Abstract

ABSTRACTWhite matter hyperintensities (WMH) are often seen on MRI brain scans in frontotemporal dementia (FTD) due to progranulin (GRN) mutations, but their pathological correlates are unknown. We examined the histological changes underlying WMH in a patient with GRN mutation associated behavioral variant FTD. In vivo and cadaveric MRI showed progressive, asymmetric frontotemporal and parietal atrophy, and asymmetrical WMH predominantly affecting frontal mid-zones. We first performed segmentation and localization analyses of WMH present on cadaveric MRI FLAIR images, then selected five different brain regions directly matched to differing severities of WMH for histological analysis. We used immunohistochemistry to assess vascular pathology, degree of spongiosis, neuronal and axonal loss, TDP-43, demyelination and astrogliosis, and microglial burden and morphology. Brain regions with significant WMH displayed severe cortical and white matter pathology, and prominent white matter microglial activation and microglial dystrophy, but only mild axonal loss and minimal vascular pathology. Our study suggests that WMH in GRN mutation carriers are not secondary to vascular pathology. Whilst cortical pathology induced axonal degeneration could contribute to white matter damage, individuals with GRN mutations could develop selective white matter vulnerability and myelin loss due to chronic, regional microglial dysfunction arising from GRN haploinsufficiency.

Highlights

Cerebral white matter hyperintensities (WMH) reflect an abnormal tissue fat/water ratio within myelinated brain areas, and are visible as hyperintense lesions on T2-weighted and fluid-attenuated inversion recovery (FLAIR) MRI sequences (Wardlaw, Valdés Hernández, & Muñoz-Maniega, 2015)
WMH appear in healthy aging as periventricular and deep white matter lesions associated with demyelination, microgliosis and vacuolation (Murray et al, 2012), and in patients with small vessel cerebrovascular disease, associated with white matter axonal loss, demyelination, gliosis, and arteriosclerosis (Wardlaw et al, 2015)
We analyzed the burden, activation state and morphology of three different microglial phenotypes across multiple brain regions, which have not been described previously in frontotemporal dementia (FTD). Through this approach we demonstrate that WMH in GRN mutation associated FTD occur predominantly in frontal lobe mid-zones and are associated with significant cortical pathology and white matter demyelination and gliosis, but only mild axonal loss and minimal vascular pathology

Summary

Introduction

Cerebral white matter hyperintensities (WMH) reflect an abnormal tissue fat/water ratio within myelinated brain areas, and are visible as hyperintense lesions on T2-weighted and fluid-attenuated inversion recovery (FLAIR) MRI sequences (Wardlaw, Valdés Hernández, & Muñoz-Maniega, 2015). Research into the pathological correlates of WMH in vascular dementia and sporadic and familial Alzheimer’s disease (AD) is well-established (McAleese et al, 2015, 2017; Ryan et al, 2015; Snyder et al, 2015). Several studies have reported prominent WMH in patients with familial FTD due to progranulin (GRN) mutations (Caroppo et al, 2014; Ameur et al, 2016; Kelley et al, 2009; Le Ber et al, 2008; Paternicò et al, 2016; Pietroboni et al, 2011; Sudre et al, 2017) but the pathological changes underlying these have not previously been studied in detail

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