In this study we have identified baseline characteristics that are predictive of the rate of functional decline over time in subjects with behavioural variant FTD. As we had hypothesized, rate of functional decline was associated with anatomically defined behavioural variant FTD subtypes. Specifically, those with predominantly frontal and frontotemporal patterns of atrophy had faster rates of decline than those with temporofrontoparietal and temporal dominant patterns of atrophy. In addition, worse executive, language and visuospatial function, less severe disinhibition, agitation/aggression and night-time behaviours, and older age at onset, predicted faster rates of decline. In many instances, the effects of the predictor variables across all behavioural variant FTD subjects were preserved across each of the four anatomical subtypes, with some variables improving prediction after adjusting for subtype. In fact, anatomical subtype appears to be the strongest predictor (combined partial R2 of 0.22) and always improved prediction beyond cognitive and behavioural measures.
We had previously identified four specific anatomical subtypes of behavioural variant FTD using a hierarchical clustering approach (Whitwell et al., 2009d
). The frontal dominant subtype was defined by predominant medial and lateral frontal lobe atrophy; the frontotemporal subtype by the presence of both frontal and temporal lobe atrophy; the temporal dominant subtype by predominant medial and lateral temporal lobe atrophy; and the temporofrontoparietal subtype by atrophy of the temporal lobes with some additional involvement of the frontal and parietal lobes. The 79 subjects with imaging in this study were categorized into the same four subtypes. As hypothesized, we found that anatomical subtype was a strong predictor of rate of CDR-SB increase. Interestingly, faster rates of CDR-SB increase were associated with the two variants that had the most severe frontal lobe involvement, i.e. the frontal dominant and frontotemporal subtypes, with the slowest rates observed in the temporofrontoparietal subtype. It is not surprising that the latter subtype showed the slowest rates since a small proportion of subjects in this subtype has been shown to have Alzheimer’s disease pathology (Whitwell et al., 2009d
), and Alzheimer’s disease typically has a slower rate of functional decline than FTD (Rascovsky et al., 2005
Examination of the region of interest volumes similarly showed that smaller frontal lobe volumes were associated with faster rates of CDR-SB increase. Conversely, subjects with less temporal lobe volume loss were associated with faster rates of CDR-SB increase than subjects with more temporal lobe volume loss. This paradoxical relationship can be explained by considering the anatomical subtypes, since subjects with less temporal lobe volume loss would have been clustered into the frontal dominant subtype and hence would have had severe frontal lobe volume loss. In fact, the Spearman correlation between combined temporal lobe volumes and combined frontal lobe volumes was −0.4 (P
0.001). We also examined the predictive effect of each frontal and temporal lobe volume on rate of CDR-SB increase, adjusting for the anatomical subtype. These models showed no significant effect of volume beyond the predictive effect of anatomical subtype. Taking all these results into consideration, one would deduce that the overall pattern of involvement of all lobes (i.e. anatomical subtype) is far superior to the assessment of specific lobar volumes in predicting functional decline.
The temporal dominant subtype is interesting and requires separate discussion. This subtype has been shown to consist primarily of subjects with a mutation in the MAPT
gene (Whitwell et al., 2009d
). In this current study, a significantly higher proportion of subjects with mutations in MAPT
were also observed in the temporal dominant subtype compared to the other behavioural variant FTD subtypes. The slow rate of decline in this subtype is therefore not surprising since we have demonstrated that the behavioural variant FTD subjects with a MAPT
mutation in this cohort had a slower rate of functional decline compared to subjects without a MAPT
mutation. The finding would also be in keeping with another study demonstrating longer survival in subjects with MAPT
mutations compared to subjects without (Chiu et al., 2010
). Indeed, the majority of subjects with a MAPT
mutation have severe medial temporal and less lateral temporal and temporal pole volume loss (Josephs et al., 2009
; Whitwell et al., 2009a
), which explains the association between CDR-SB increase and medial temporal lobe volume.
In addition to the finding of anatomical subtype predicting functional decline, we also found that performance on neuropsychological tests of executive, language and visuospatial function could predict rate of CDR-SB increase. The results demonstrate that subjects with poorer performance on these tests at baseline have a faster rate of CDR-SB increase. In addition, these variables added to our ability to predict CDR-SB increase beyond the effect of anatomical subtype. Hence, this indicates that the effects of these neuropsychological variables are not being driven by anatomical subtype. It remains to be determined whether the trend observed across all subjects is preserved within each anatomical subtype, although there was strong evidence that the effect occurs in the frontal dominant and temporofrontoparietal subtypes; the largest two subtypes with increased power to detect effects. One previous survival study in behavioural variant FTD found that language performance, but not executive or memory performance, was associated with shorter survival (Garcin et al., 2009
). However, it is difficult to compare these results to ours since it is unknown whether survival correlates to functional decline in behavioural variant FTD. It should be pointed out that, although it may be tempting to treat the neuropsychological measures as totally independent, there is overlap between specific tests used to assess the different domains. For example, we found that there was a moderate correlation between the Controlled Oral Word Association Test and category fluency tests (r
0.001) in our cohort. Therefore, although we aimed to reduce this overlap by using two neuropsychological tests to calculate a composite score for each domain, it would be impossible to eliminate all overlap due to the inter-relationship of these domains. This may help to explain why our visuospatial composite predictor variable was associated with rates of CDR increase, since visuospatial function has some dependency on executive function. Alternatively, the visuospatial association may be driven by a subset of behavioural variant FTD cases, but it is unlikely to be driven by differences across the anatomical subtypes since we previously showed that visuospatial function does not differ across subtypes (Whitwell et al., 2009d
Three of the NPI-Q variables predicted rate of CDR-SB increase, including: disinhibition, agitation/aggression and night-time behaviours. Surprisingly, the data showed that subjects with less severe behaviours had a faster rate of CDR-SB increase, a pattern that appeared to hold true within each subtype for disinhibition and to a certain degree agitation/aggression. However, only the effect of disinhibition persisted after adjusting for anatomical subtype, suggesting that disinhibition is not being driven by anatomical subtype. It is therefore likely that this is a real effect and that patients who are less disinhibited at baseline will indeed have a faster rate of CDR-SB increase. It is unlikely however that disinhibition is protective, more likely that it is associated with some aspect, or a subtype, of the disease that progress more slowly, such as MAPT
mutations, which have been shown to be associated with disinhibition (Pickering-Brown et al., 2008
). In fact, a moderate correlation was observed between disinhibition scores and executive composite scores (r
0.009), with less disinhibition being associated with worse performance on executive testing. The interpretation of the disinhibition results are also complicated by the fact that behavioural features change over time in behavioural variant FTD. For example, there is some evidence that behavioural variant FTD subjects who are initially disinhibited commonly later develop features of apathy (Le Ber et al., 2006
We found a trend for age at onset to be predictive of rate of functional decline; more specifically, for older subjects to have a faster rate of CDR-SB increase. A simple explanation for this could be that this result is being driven by the anatomical subtype since the temporal dominant subtype tends to be younger (Whitwell et al., 2009d
) than the other subtypes and shows a slower rate of CDR-SB increase. This explanation is unlikely, however, as we found that the effect of age on CDR-SB increase was independent of anatomical subtype. Age at onset was also normally distributed and hence there were no outlier subjects that likely influenced the model. One previous survival study in behavioural variant FTD found that older age at onset was associated with poor prognosis (Chiu et al., 2010
), which appears to support our result. We did not find education to be predictive of rate of functional decline as previously reported by one study that followed FTD subjects for 20 months on average (Perneczky et al., 2009
). This discrepancy is probably driven by the fact that our study assessed functional change over many years using a mixed effects model in behavioural variant FTD subjects, as opposed to 20 months in all variants of FTD using linear regression.
A testament of how important anatomical subtype is clinically was the fact that anatomical subtype showed predictive value beyond all cognitive and behavioural variables. Furthermore, the anatomical subtype was the strongest predictor, since the combined partial R2 for the shift and slope effects was 0.22, hence accounting for a relative large per cent of the variability in CDR-SB scores over time. These findings suggest that imaging is equal, or possibly better, than clinical measures as a predictor of functional decline in behavioural variant FTD. It is likely however that the best prediction will result from a combination of demographic, clinical and imaging predictors.
Although we were primarily interested in identifying predictors of rate of CDR-SB increase we also assessed the effect of predictor variables on the actual CDR-SB score at any give time. This is referred to as a shift effect and is essentially represented by a vertical shift in the estimated trend lines in the direction of the y
-axis. We identified multiple predictors that had a shift effect including: gender, CDR-SB at baseline, MMSE, executive composite, visuospatial composite, apathy/indifference, anatomical subtype and all frontal and temporal volumes. A number of these, as discussed above, also had an effect on the rate of CDR-SB increase. Gender did not affect the rate of CDR-SB increase but we demonstrate that for a given disease duration, females perform worse on CDR-SB than males. We also demonstrate an association between CDR-SB and MMSE, with poorer functional performance related to poorer cognitive performance. Similarly, poorer functional performance was related to more severe apathy/indifference. Relationships between functional, cognitive and behavioural measures have been previously reported in behavioural variant FTD (Rascovsky et al., 2005
) and are likely to result from damage to the same frontal and temporal regions. Furthermore, functional decline may result from a combination of both cognitive and behavioural impairment. Anatomical subtype also had an effect on shift, in addition to slope. The frontal dominant and frontotemporal subtypes had the highest actual CDR-SB scores, as well as the fastest rates of CDR-SB increase. Although the rate of CDR-SB increase was higher in the temporal dominant subtype than the temporofrontoparietal subtype, the actual CDR-SB scores were lower in the temporal dominant subtype. This is possibly explained by the fact that the temporal dominant subtype has significant language impairment (Whitwell et al., 2009d
) that unfortunately would not be detected with the CDR.
The average rate of CDR-SB increase in this cohort was 1.8 points per year and on an individual basis the majority of subjects showed <2 points increase per year. These estimates of CDR-SB change were calculated from multiple CDR assessments, up to 18. This calculation was based on statistically driven analyses that determined that a linear model was the best fit to explain our data points. Given that our institution is a tertiary care centre, our subjects had established disease by the time of initial presentation. It is unclear whether a non-linear trajectory would be observed if data were available earlier in the disease course. Other studies have reported somewhat similar rates of CDR-SB increase of 1.6–2.7 points per year in behavioural variant FTD. In these other studies however, rates were calculated as a change in CDR-SB over two time points only, usually one year apart (Brambati et al., 2007
; Knopman et al., 2008
; Gordon et al., 2010
We also found that 11% of subjects had an increase of >6 points per year, and 9% had no change or a decrease, i.e. stable or improving, CDR-SB over time. The former suggests that there is a subset of subjects with behavioural variant FTD with a dramatic rate of functional decline, i.e. ‘fast progressors’, while the later suggests that a subset show no apparent functional decline over time, i.e. slow progressors. While the concept of slow progressors has been well described by one group in the literature (Davies et al., 2006
), nothing has been previously reported on ‘fast progressors’. The results of this study shed light on features that will help to predict rate of functional decline in behavioural variant FTD and hence may be useful in identifying these ‘fast progressors’. Importantly, our cut-off of >6 points per year is not meant to be used to strictly define this group of subjects, but merely represents a reference point on the continuum to illustrate that some subjects with behavioural variant FTD progress very quickly. One subgroup of our subjects with behavioural variant FTD that showed a relatively faster rate of CDR-SB increase were the subjects with GRN
mutations. This subgroup was actually declining, on average, twice as fast as the rest of the cohort.
We have identified clinical and imaging characteristics that are useful to predict rate of functional decline in behavioural variant FTD. These findings will have important scientific implications, as well as clinical implications to physicians, patients and their families, since they allow improved prognostic estimates, in a disease that severely affects the ‘young.’ The strengths of our study are the large number of subjects, especially for a relatively rare disease, the fact that the subjects were prospectively recruited and had standardized and validated independent clinical and neuropsychological assessments collected over a 15-year period, and the application of advanced statistical techniques. Most important, our estimate of CDR-SB change was based on multiple CDR scores per subject.