Differences in hippocampal subfield volume are seen in phenotypic variants of early onset Alzheimer's disease.

Thomas D Parker,Ross W Paterson,David M Cash,Nick C Fox,David L Thomas,Ian B Malone,Jennifer M Nicholas,Alexander J.M Foulkes,Sebastian J Crutch,Keir X.X Yong,Catherine F Slattery,Jonathan M Schott

doi:10.1016/j.nicl.2018.101632

Abstract

The most common presentation of early onset Alzheimer's disease (EOAD – defined as symptom onset <65 years) is with progressive episodic memory impairment – amnestic or typical Alzheimer's disease (tAD). However, EOAD is notable for its phenotypic heterogeneity, with posterior cortical atrophy (PCA) – characterised by prominent higher-order visual processing deficits and relative sparing of episodic memory – the second most common canonical phenotype. The hippocampus, which comprises a number of interconnected anatomically and functionally distinct subfields, is centrally involved in Alzheimer's disease and is a crucial mediator of episodic memory. The extent to which volumes of individual hippocampal subfields differ between different phenotypes in EOAD is unclear. The aim of this analysis was to investigate the hypothesis that patients with a PCA phenotype will exhibit differences in specific hippocampal subfield volumes compared to tAD. We studied 63 participants with volumetric T1-weighted MRI performed on the same 3T scanner: 39 EOAD patients [27 with tAD and 12 with PCA] and 24 age-matched controls. Volumetric estimates of the following hippocampal subfields for each participant were obtained using Freesurfer version 6.0: CA1, CA2/3, CA4, presubiculum, subiculum, hippocampal tail, parasubiculum, the molecular and granule cell layers of the dentate gryus (GCMLDG), the molecular layer, and the hippocampal amygdala transition area (HATA). Linear regression analyses comparing mean hippocampal subfield volumes between groups, adjusting for age, sex and head size, were performed. Using a Bonferonni-corrected p-value of p < 0.0025, compared to controls, tAD was associated with atrophy in all hippocampal regions, except the parasubiculum. In PCA patients compared to controls, the strongest evidence for volume loss was in the left presubiclum, right subiculum, right GCMLDG, right molecular layer and the right HATA. Compared to PCA, patients with tAD had strong evidence for smaller volumes in left CA1 and left hippocampal tail. In conclusion, these data provide evidence that hippocampal subfield volumes differ in different phenotypes of EOAD.

Highlights

Onset Alzheimer's disease (EOAD – defined as symptom onset under the age of 65) represents the most common cause of young onset dementia (Harvey et al, 2003) and often poses a significant diagnostic challenge (Rossor et al, 2010)
Detailed multi-domain cognitive testing was performed for each participant including: the mini-mental state examination (MMSE (Folstein et al, 1975)); an assessment of general intellect (vocabulary and matrices subtests of the Wechsler Abbreviated Scale of Intelligence (WASI) (Wechsler, 1999)); digit span forwards and backwards (Wechsler, 1987); episodic memory for faces and words (Short Recognition Memory Test (Warrington, 1984)); letter and category fluency; numeracy (Graded Difficulty Arithmetic (GDA) (Jackson and Warrington, 1986)); spelling (Graded Difficulty Spelling Test (GDST) (Baxter and Warrington, 1994)); the National Adult Reading Test (NART) (Nelson, 1982); visual search (letter (‘A’) cancellation) (Willison and Warrington, 1992); and the visual object and space perception (VOSP) battery (Warrington and James, 1991), which included shape detection, fragmented letters, object decision and dot-counting
There were no significant differences in Mini-mental state examination (MMSE) score, disease duration or proportion of APOE ε4 carriers when comparing typical Alzheimer's disease (tAD) and posterior cortical atrophy (PCA) patients

Summary

Introduction

Onset Alzheimer's disease (EOAD – defined as symptom onset under the age of 65) represents the most common cause of young onset dementia (Harvey et al, 2003) and often poses a significant diagnostic challenge (Rossor et al, 2010). As is the case in the more common lateonset form of Alzheimer's disease (LOAD), the most common presentation of EOAD is the amnestic led typical form of Alzheimer's. NeuroImage: Clinical 21 (2019) 101632 disease (tAD), characterised by progressive episodic memory impairment. Compared to LOAD, a higher proportion of EOAD patients present with non-amnestic atypical phenotypes (Mendez, 2012; Rossor et al, 2010; Slattery et al, 2017). The most commonly encountered atypical phenotype is that of posterior cortical atrophy (PCA), which is characterised by prominent higher-order visual processing deficits and relative sparing of episodic memory (Crutch et al, 2012, 2017). Why individuals with EOAD are more likely to develop these often markedly different phenotypes, is not clear

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