Our results show different patterns of atrophy in patients meeting criteria for bvFTD (Neary D et al., 1998
), but having different molecular pathology. Subjects with PiD, CBD, and FTLD-TDP type 1 all showed involvement of the frontal lobes, consistent with their clinical diagnosis, but showed different overall patterns of atrophy consistent with the view that molecular pathology contributes to pattern of atrophy and that imaging could help predict pathology in bvFTD.
Patterns of grey matter loss observed in subjects with CBD pathology were strikingly different from those observed in subjects with either PiD or FTLD-TDP type 1. Subjects with CBD showed less severe patterns of atrophy compared to the other groups, with loss mainly focused in an area of the posterior medial and lateral superior frontal lobe, including the supplemental motor area. While this region of the frontal lobes was also atrophic in both PiD and FTLD-TDP type 1, both of these pathologies showed more widespread and severe frontal lobe atrophy, particularly involving the prefrontal cortex, as well as the temporal lobes. Atrophy of the prefrontal cortex and temporal lobes could therefore be a useful anatomical signature to suggest the presence of either PiD or FTLD-TDP type 1 pathology in bvFTD subjects. Our results also highlighted differences across PiD and FTLD-TDP type 1 that could help differentiate these two entities further. A more widespread pattern of atrophy with more involvement of the posterior temporal and parietal lobes would suggest FTLD-TDP type 1, whereas loss more restricted to anterior regions of the brain, with frontal and anterior temporal grey matter loss would be more indicative of PiD. In addition, atrophy of the orbitofrontal and medial frontal cortex appeared to be particularly associated with PiD, whereas atrophy of the dorsolateral inferior frontal lobes was associated with FTLD-TDP type 1.
No previous studies have assessed patterns of atrophy across bvFTD subjects with these three pathologies. Our atrophy-molecular pathology correlations observed in this study do however concord with a few studies that have assessed atrophy in PiD, CBD and FTLD-TDP type 1 subjects, although these previous studies included subjects with a wide range of different clinical diagnoses. For example, frontotemporal atrophy has been observed in a group of PiD subjects with a mixture of different language and behavioral syndromes (Whitwell JL et al., 2005
); posterior frontal atrophy has been observed in CBD subjects with a mixture of different dementia and extrapyramidal syndromes (Josephs KA et al., 2008
); and parietal atrophy has been observed in FTLD-TDP type 1 subjects with a mixture of behavioral, language, pyramidal and extrapyramidal syndromes (Rohrer JD et al., 2010
; Whitwell JL et al., 2010b
). In addition to studies that include a wide range of different clinical diagnoses, one study assessing subjects with corticobasal syndrome similarly found patterns of frontotemporal and parietal atrophy in subjects with FTLD-TDP type 1, and posterior superior frontal atrophy in subjects with CBD (Whitwell JL et al., 2010a
). The fact that similar patterns of atrophy were observed across subjects with bvFTD, a mixture of different clinical diagnoses, as well as corticobasal syndrome, suggests that molecular pathologies may have characteristic patterns of atrophy. Variations of these characteristic patterns of atrophy, for example, asymmetry, may account for the differing clinical syndromes (Whitwell JL et al., 2010a
). It is well known that atrophy of the frontal lobes can result in behavioral abnormalities, and studies of bvFTD subjects that do not have pathology have also associated this syndrome with atrophy of the frontal lobes (Boccardi M et al., 2005
; Seeley WW et al., 2008
). Since the specific frontal regions affected in each pathological group differed, it is likely that the bvFTD syndrome observed in each of these groups resulted from atrophy of differing regions of the frontal lobe which explains why behavioral abnormalities observed in bvFTD are typically heterogeneous (Le Ber I et al., 2006
; Rosen HJ et al., 2005
; Snowden JS et al., 2001
). Indeed, while our clinical data was only retrospective and we observed little difference across the groups, there was some suggestion that there may be differences in specific behaviors. Executive dysfunction has been reported to be associated with tau pathology (Hu WT et al., 2007
), and indeed was more frequent in the PiD and CBD groups in our study. Decline in personal hygiene was only observed in patients with PiD at presentation but was found to be more associated with non-tau pathology when assessed over the entire disease course in another study (Hu WT et al., 2007
). This suggests that the region of atrophy associated with decline in personal hygiene may be affected early in the disease course in PiD and then later in FTLD-TDP. All subjects in this study were characterized by behavioral abnormalities and met criteria for bvFTD (Neary D et al., 1998
), yet these findings suggest that refining the clinical features of bvFTD, by possibly creating bvFTD subtypes, may improve clinical prediction of molecular pathology. Indeed, recent evidence suggests that bvFTD dominated by stereotypic and obsessive compulsive features, i.e. “stereotypic bvFTD”, is associated with one specific type of FTLD-FUS pathology (Snowden JS et al., 2011
). These results therefore support the suggestion that bvFTD is anatomically heterogeneous (Whitwell JL et al., 2009b
), and further suggests that patterns of atrophy vary across different molecular pathologies. It also supports the notion that the current diagnosis of bvFTD is heterogeneous and could be further refined. The number of subjects in the current study was small and VBM is a group-level technique. Larger prospective studies will be needed to confirm these results, determine the value of these characteristic patterns of atrophy in predicting pathology in individual bvFTD cases, and further examine the utility of splitting bvFTD based on subtle clinical differences.