In a group of clinically well-characterized patients with bvFTD presentation, 18 with confirmed postmortem pathology, just over half (58%) of the cases exhibited all five core clinical features necessary for a clinical diagnosis of bvFTD when examined for the first time. Although common, core features were far from ubiquitous, with prevalence ranging between 70% and 100%. This finding is in keeping with another study of patients with bvFTD showing that a third exhibited all core features at presentation, although they indicated that most patients with FTD would show the core features over the course of the disease.14
In contrast, only two (insidious onset and progression, decline in personal conduct) of the five core features were present in all of our patients as they progressed. At presentation, some degree of insight was maintained in a fifth of patients and emotional blunting was not observed in a similar proportion of cases over the course of the disease.
Using a more lenient threshold that employed the “best” clusters of either four or three core features improved case detection considerably at initial presentation, although it still missed 15% of cases in this sample. Importantly, of the six cases who showed two or three core features over the entire course of the disease, four had neuropathologically confirmed FTD changes. Postmortem examination was not conducted on the other two cases. These findings indicate that strict application of the clinical diagnostic criteria will miss a significant proportion of patients who harbor FTD pathology. From a clinical viewpoint, any delay in establishing the correct diagnosis raises the risk of inappropriate management or administration of therapeutic intervention that may at best be ineffective and at worst have significant adverse effects. These findings support the removal of the distinction between core and supportive features in favor of a probable/possible diagnostic hierarchy5
similar to clinical diagnostic criteria currently applied to other dementia syndromes.18–20
Recent evidence points to the existence of patients who show typical bvFTD clinical behavioral changes but who do not show progression over many years. Current diagnostic criteria do not differentiate well between true bvFTD and phenocopy cases, although impairment on tests of executive function,21
prominent atrophy on MRI,11,15
and impaired ADL appear to be the best discriminators. A recent analysis21
showed that a cluster of frontal executive tasks (Trails B, verbal fluency, digit span backward, and Hayling test of inhibitory control) could identify true bvFTD from phenocopy cases. In addition, high-quality MR T1 images acquired in the coronal plane are recommended when a diagnosis of bvFTD is suspected.11,15
Our study also confirmed that disruption in ADL is common in bvFTD. ADL disturbance was present in 40% of cases at presentation but three quarters experienced decline in this area with disease progression. These findings are consistent with those from Cambridge showing that decline in ADL proficiency was much more common in bvFTD compared to the other subtypes of FTD (i.e., semantic dementia and progressive nonfluent aphasia) and affected basic, as well as instrumental (complex), ADLs at an early stage.22
The current clinical criteria contain a large number of supportive features, many of which have a low prevalence. At presentation, only mental inflexibility, distractibility, and hyperorality were present in at least half of the patients. Over time, decline in hygiene and perseverative or stereotypical behavior also became more common. In contrast, some features such as utilization behavior were rare even with increasing disease severity. In other words, absence of these features does not rule out a diagnosis of bvFTD.
One limitation of our study is the absence of a comparison group with another non-FTD form of dementia, which is required to evaluate specificity as well as sensitivity. Unfortunately, the Cambridge clinic was heavily oriented toward FTD syndromes particularly after 1997. Since the cohort was seen over a long time period, we did not have the benefit of consistent evaluation of ADL, which should be included in future prospective studies. The only other large study examining clinical features in pathologically verified cases compared Alzheimer disease with bvFTD, semantic dementia, and progressive nonfluent aphasia, but did not have longitudinal clinical data; it was, therefore, not entirely comparable to the present work.16
Another possible limitation is that presence of clinical features was established retrospectively by examining existing information (i.e., clinical files, correspondence, questionnaires, and other instruments). When a feature was not mentioned, it was rated absent, which may have underestimated the prevalence of some of the features. Importantly, however, the fact that a comprehensive and systematic assessment was conducted using a standardized approach17
at initial presentation and during subsequent visits supports the view that absence of a feature is likely to reflect true absence rather than simple omission of recording the feature.
When first assessed in the clinic, only a proportion of patients with definite bvFTD will fulfill all current core criteria. This may reflect difficulty in the interpretation or the application of some features, notably emotional blunting and the presence, or absence, of insight. In addition, some of the supportive features (hyperorality, mental inflexibility, distractibility, and stereotypic behavior) are sufficiently common to consider their inclusion in revised diagnostic criteria, as recently suggested.5,23