Genetic determinants of white matter hyperintensities and amyloid angiopathy in familial Alzheimer's disease

Abstract

Familial Alzheimer's disease (FAD) treatment trials raise interest in the variable occurrence of cerebral amyloid angiopathy (CAA); an emerging important factor in amyloid-modifying therapy. Previous pathological studies reported particularly severe CAA with postcodon 200 PSEN1 mutations and amyloid beta coding domain APP mutations. As CAA may manifest as white matter hyperintensities (WMH) on magnetic resonance imaging, particularly posteriorly, we investigated WMH in 52 symptomatic FAD patients for associations with mutation position. WMH were visually rated in 39 PSEN1 (18 precodon 200); 13 APP mutation carriers and 25 healthy controls. Ten PSEN1 mutation carriers (5 precodon 200) had postmortem examination. Increased WMH were observed in the PSEN1 postcodon 200 group and in the single APP patient with an amyloid beta coding domain (p.Ala692Gly, Flemish) mutation. WMH burden on MRI correlated with severity of CAA and cotton wool plaques in several areas. The precodon 200 group had younger ages at onset, decreased axonal density and/or integrity, and a greater T-lymphocytic response in occipital deep white matter. Mutation site contributes to the phenotypic and pathological heterogeneity witnessed in FAD.

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

“…The right hemisphere was fixed and left hemisphere frozen as per standard protocol, and the right hemisphere cut into 5mm thick coronal slices. Paraffin-embedded tissue sections from a large number of brain regions underwent routine post-mortem analysis, including examination for tau, transactive response DNA binding protein 43 (TDP-43), alpha-synuclein and amyloid beta (Aβ) deposition, neuronal, myelin and axonal loss and astrogliosis (Lashley et al, 2008; Ryan et al, 2015). The circle of Willis was examined for presence of atheroma, and other relevant cortical, subcortical and hippocampal regions (including leptomeningeal vessels) were examined for vascular pathology.…”

“…Sections were qualitatively assessed for degree of neuronal loss and spongiosis and semi-quantitatively assessed for degree of axonal loss, myelin loss, TDP-43, astrogliosis, and presence of microglia (CD68, CR3/43 and Iba1 positive cells). Semi-quantitative assessment used a multi-tier scoring system modified from a previous study (Ryan et al, 2015), where: ‘0ʹ represents no axonal loss, no white matter pallor, no TDP-43 present, no astrogliosis or no visible microglia; “+” or ‘1ʹ represents a mild degree of axonal loss, pallor of the white matter, TDP-43 burden, astrogliosis or presence of few microglia; “++” or ‘2ʹ represents a moderate degree of these changes or presence of moderate numbers of microglia; and “+++” or ‘3ʹ represents a severe degree of these changes or presence of many microglia. In addition, qualitative descriptions of microglial morphology were recorded, for example whether microglia appeared amoeboid (round), suggestive of microglial activation, or ramified (with extended processes), or any other atypical morphological appearances.…”

“…Presence of atheroma in the circle of Willis and vascular changes in other cortical and subcortical areas had been examined during routine post-mortem. Although the VCING include scores for myelin loss, all regions were also scored for white matter pallor using our modified multi-tier scoring system (Ryan et al, 2015) to allow direct comparison between this score of myelin loss and scores for non-vascular histological changes.…”

“…WMH also occur in neuroinflammatory diseases such as multiple sclerosis (Sarbu et al, 2016), and in neurodegenerative diseases (Filley & Fields, 2016). 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). However, WMH are less commonly seen in frontotemporal dementia (FTD).…”

White Matter Abnormalities Track Disease Progression in PSEN1 Autosomal Dominant Alzheimer’s Disease

“…Subtle differences in the methods of analysis, relative age of the AMC, or type of mutations included could account for these differences with our results. In this sense, a recent series [31] and several previous case reports [32][33][34] have underlined relevant differences in the WM abnormalities, both in neuroimaging and neuropathological studies, within ADAD cases, related to the site of the causal mutation in the PSEN1 or APP genes.…”