The behavioural/dysexecutive variant of Alzheimer's disease: clinical, neuroimaging and pathological features

Abstract

A 'frontal variant of Alzheimer's disease' has been described in patients with predominant behavioural or dysexecutive deficits caused by Alzheimer's disease pathology. The description of this rare Alzheimer's disease phenotype has been limited to case reports and small series, and many clinical, neuroimaging and neuropathological characteristics are not well understood. In this retrospective study, we included 55 patients with Alzheimer's disease with a behavioural-predominant presentation (behavioural Alzheimer's disease) and a neuropathological diagnosis of high-likelihood Alzheimer's disease (n = 17) and/or biomarker evidence of Alzheimer's disease pathology (n = 44). In addition, we included 29 patients with autopsy/biomarker-defined Alzheimer's disease with a dysexecutive-predominant syndrome (dysexecutive Alzheimer's disease). We performed structured chart reviews to ascertain clinical features. First symptoms were more often cognitive (behavioural Alzheimer's disease: 53%; dysexecutive Alzheimer's disease: 83%) than behavioural (behavioural Alzheimer's disease: 25%; dysexecutive Alzheimer's disease: 3%). Apathy was the most common behavioural feature, while hyperorality and perseverative/compulsive behaviours were less prevalent. Fifty-two per cent of patients with behavioural Alzheimer's disease met diagnostic criteria for possible behavioural-variant frontotemporal dementia. Overlap between behavioural and dysexecutive Alzheimer's disease was modest (9/75 patients). Sixty per cent of patients with behavioural Alzheimer's disease and 40% of those with the dysexecutive syndrome carried at least one APOE ε4 allele. We also compared neuropsychological test performance and brain atrophy (applying voxel-based morphometry) with matched autopsy/biomarker-defined typical (amnestic-predominant) Alzheimer's disease (typical Alzheimer's disease, n = 58), autopsy-confirmed/Alzheimer's disease biomarker-negative behavioural variant frontotemporal dementia (n = 59), and controls (n = 61). Patients with behavioural Alzheimer's disease showed worse memory scores than behavioural variant frontotemporal dementia and did not differ from typical Alzheimer's disease, while executive function composite scores were lower compared to behavioural variant frontotemporal dementia and typical Alzheimer's disease. Voxel-wise contrasts between behavioural and dysexecutive Alzheimer's disease patients and controls revealed marked atrophy in bilateral temporoparietal regions and only limited atrophy in the frontal cortex. In direct comparison with behavioural and those with dysexecutive Alzheimer's disease, patients with behavioural variant frontotemporal dementia showed more frontal atrophy and less posterior involvement, whereas patients with typical Alzheimer's disease were slightly more affected posteriorly and showed less frontal atrophy (P < 0.001 uncorrected). Among 24 autopsied behavioural Alzheimer's disease/dysexecutive Alzheimer's disease patients, only two had primary co-morbid FTD-spectrum pathology (progressive supranuclear palsy). In conclusion, behavioural Alzheimer's disease presentations are characterized by a milder and more restricted behavioural profile than in behavioural variant frontotemporal dementia, co-occurrence of memory dysfunction and high APOE ε4 prevalence. Dysexecutive Alzheimer's disease presented as a primarily cognitive phenotype with minimal behavioural abnormalities and intermediate APOE ε4 prevalence. Both behavioural Alzheimer's disease and dysexecutive Alzheimer's disease presentations are distinguished by temporoparietal-predominant atrophy. Based on the relative sparing of frontal grey matter, we propose to redefine these clinical syndromes as 'the behavioural/dysexecutive variant of Alzheimer's disease' rather than frontal variant Alzheimer's disease. Further work is needed to determine whether behavioural and dysexecutive-predominant presentations of Alzheimer's disease represent distinct phenotypes or a single continuum.

Keywords: Alzheimer’s disease; executive function; frontal, behaviour; frontotemporal dementia.

© The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Figures

Relatively little is known about behavioural- and dysexecutive-predominant presentations of Alzheimer’s disease, collectively known as ‘frontal’ Alzheimer’s disease. Ossenkoppele et al. compare these two syndromes, revealing classical temporoparietal atrophy and relative sparing of frontal cortex in both, and propose that they are redefined as the ‘behavioural/dysexecutive variant of Alzheimer’s disease’.

Figure 1

Clinical features. Frequency of (A) first symptoms reported by patients and caregivers, (B) self-reported medical conditions in the past history, (C) the number of core behavioural/cognitive symptoms met of diagnostic criteria for behavioural variant FTD (bvFTD; Rascovsky et al., 2011), and (D) these behavioural/cognitive features.

Figure 2

Neuropsychological performance. Composite z-scores for (A) memory, (B) executive functions, (C) language and (D) visuo-spatial functions. Differences between groups were assessed using ANOVA. *All patient groups < controls, P < 0.001; **behavioural Alzheimer’s disease (bAD; P < 0.001), typical Alzheimer’s disease (tAD; P < 0.001), behavioural Alzheimer’s disease/dysexecutive Alzheimer’s disease (bAD/deAD; P < 0.05) and behavioural variant FTD (bvFTD; P < 0.05) < dysexecutive Alzheimer’s disease; ***behavioural Alzheimer’s disease (P < 0.01) and typical Alzheimer’s disease (P < 0.001) < behavioural variant FTD; #dysexecutive Alzheimer’s disease < typical Alzheimer’s disease (P < 0.01) and behavioural variant FTD (P < 0.01) and behavioural Alzheimer’s disease/dysexecutive Alzheimer’s disease and behavioural Alzheimer’s disease < typical Alzheimer’s disease (P < 0.05) and behavioural variant FTD (P < 0.05).

Figure 3

Voxel-wise comparisons of grey matter volumes between healthy controls and the different diagnostic groups. Contrasts were adjusted for age, sex, total intracranial volume, scanner type and centre. Results are superimposed on the SPM8 single-subject template (left) and the study-specific DARTEL template (right), and displayed at P < 0.001 uncorrected. Supplementary Table 1 includes the coordinates of local maxima and their anatomical labels, T-values, P-values and cluster sizes.

Figure 4

Voxel-wise comparisons of grey matter volumes between combined behavioural/dysexecutive variant Alzheimer’s disease, typical Alzheimer’s disease and behavioural variant FTD patients. Contrasts were adjusted for age, sex, total intracranial volume, scanner type and centre. Results are superimposed on the SPM8 single-subject template (left) and the study-specific DARTEL template (right), and displayed at P < 0.001 uncorrected. Supplementary Table 1 includes the coordinates of local maxima and their anatomical labels, T-values, P-values and cluster sizes.

Figure 5

Frequency of brain atrophy. Frequency maps showing the proportion of patients within each diagnostic group with suprathreshold values (W < −1) compared to a group of healthy controls. Hot colours indicate that patients with behavioural/dysexecutive variant Alzheimer’s disease (i) strikingly overlapped with patients with typical Alzheimer’s disease; and (ii) showed greater involvement of the frontal cortex than patients with typical Alzheimer’s disease although to a lesser extent than patients with behavioural variant FTD patients. The methodology for computing these frequency maps is explained in more detail in Supplementary Fig. 1.