Distinct anatomical subtypes of the behavioural variant of frontotemporal dementia: a cluster analysis study

Abstract

The behavioural variant of frontotemporal dementia is a progressive neurodegenerative syndrome characterized by changes in personality and behaviour. It is typically associated with frontal lobe atrophy, although patterns of atrophy are heterogeneous. The objective of this study was to examine case-by-case variability in patterns of grey matter atrophy in subjects with the behavioural variant of frontotemporal dementia and to investigate whether behavioural variant of frontotemporal dementia can be divided into distinct anatomical subtypes. Sixty-six subjects that fulfilled clinical criteria for a diagnosis of the behavioural variant of frontotemporal dementia with a volumetric magnetic resonance imaging scan were identified. Grey matter volumes were obtained for 26 regions of interest, covering frontal, temporal and parietal lobes, striatum, insula and supplemental motor area, using the automated anatomical labelling atlas. Regional volumes were divided by total grey matter volume. A hierarchical agglomerative cluster analysis using Ward's clustering linkage method was performed to cluster the behavioural variant of frontotemporal dementia subjects into different anatomical clusters. Voxel-based morphometry was used to assess patterns of grey matter loss in each identified cluster of subjects compared to an age and gender-matched control group at P < 0.05 (family-wise error corrected). We identified four potentially useful clusters with distinct patterns of grey matter loss, which we posit represent anatomical subtypes of the behavioural variant of frontotemporal dementia. Two of these subtypes were associated with temporal lobe volume loss, with one subtype showing loss restricted to temporal lobe regions (temporal-dominant subtype) and the other showing grey matter loss in the temporal lobes as well as frontal and parietal lobes (temporofrontoparietal subtype). Another two subtypes were characterized by a large amount of frontal lobe volume loss, with one subtype showing grey matter loss in the frontal lobes as well as loss of the temporal lobes (frontotemporal subtype) and the other subtype showing loss relatively restricted to the frontal lobes (frontal-dominant subtype). These four subtypes differed on clinical measures of executive function, episodic memory and confrontation naming. There were also associations between the four subtypes and genetic or pathological diagnoses which were obtained in 48% of the cohort. The clusters did not differ in behavioural severity as measured by the Neuropsychiatric Inventory; supporting the original classification of the behavioural variant of frontotemporal dementia in these subjects. Our findings suggest behavioural variant of frontotemporal dementia can therefore be subdivided into four different anatomical subtypes.

Figure 1

The dendrogram created by the cluster analysis. Each of the 66 bvFTD subjects started in a cluster on his/her own and were then progressively clustered together. Individual patients are indicated by cluster and given an arbitrary number within cluster. The distance along the x-axis represents a measure of similarity between subjects, such that the closer the distance the greater the similarity between the subjects. We then applied voxel-based morphometry to the final two levels of clustering (represented by blue and red lines). TD = temporal dominant subtype, TFP = temporofrontoparietal subtype, FT = frontotemporal subtype, FD = frontal dominant subtype.

Figure 2

Three dimensional surface renderings showing patterns of grey matter loss in each of the four bvFTD subtypes that were identified from the cluster analysis compared to controls (corrected for multiple comparisons using family wise error at P < 0.05). The results are shown on a schematic version of the dendrogram in order to illustrate the relationship between patterns of atrophy and cluster position. Patterns of grey matter loss are also shown at the level of the dendrogram when the bvFTD subjects are divided into two groups.

Figure 3

Coronal slices through the template showing patterns of grey matter loss in each of the four subtypes compared to controls (corrected for multiple comparisons using family-wise error at P < 0.05).

Figure 4

Coronal slices through the template showing how patterns of grey matter loss differ between the four subtypes on direct comparison (corrected for multiple comparisons using false discovery rate at P < 0.005). Patterns of grey matter loss were assessed in each subtype compared to each other subtype. The TD subtype showed greater loss in the temporal lobes than the FD subtype, the TFP subtype showed greater loss in the parietal lobes than the TD subtype, the FT subtype showed greater loss in the frontal lobes than the TD and TFP subtypes, the FT subtype showed greater loss in the temporal lobe than the FD subtype and the FD subtype showed greater loss in the frontal lobes than the TD subtype. TD = temporal dominant subtype, TFP = temporofrontoparietal subtype, FT = frontotemporal subtype, FD = frontal dominant subtype.

Figure 5

Scatter-plot showing separation of the four bvFTD subtypes using the first two principal components in a principal components analysis. Based on the weights of the principal component analysis the first principal component (horizontal axis) captures the variability of the grey matter differences in the temporal and frontal lobes with positive projection of the first principal component indicating large frontal lobe atrophy and negative projection of the first principal component indicating large temporal lobe atrophy. The weights of the second principal component (vertical axis) capture the rest of the variability of the grey matter differences in the temporal lobe and mainly parietal lobes with positive projection indicating large temporal lobe atrophy and negative projection indicating large parietal lobe atrophy. TD = temporal dominant subtype, TFP = temporofrontoparietal subtype, FT = frontotemporal subtype, FD = frontal dominant subtype.

Figure 6

Box-plots with individual data points superimposed showing neuropsychological test scores for the domains of memory (WMS-R logical memory delayed recall; WMS-LM), language (Boston Naming test; BNT), executive function (Controlled Oral Word Association Test; COWAT) and visuospatial function (WAIS block design; WAIS-BD) for each sub cluster. The y-axis represents raw scores for each test, except for the WAIS in which age-corrected scaled scores are shown. In all cases, a low score represents impaired performance. TD = temporal-dominant subtype, TFP = temporofrontoparietal subtype, FT = frontotemporal subtype, FD = frontal-dominant subtype.