This study accessed patients with clinically well-diagnosed bvFTD in the NACC database, who had presenting clinical information and subsequently neuropathologic assessments. Among those with the clinical diagnosis of bvFTD, the initial presenting clinical symptoms and signs varied depending on whether the underlying neuropathology was AD, FTLD with τ-positive neuronal inclusions, or FTLD with τ-negative findings. These findings revealed reasons why clinicians across different medical centers misdiagnose bvFTD and suggested differentiating clinical features for τ-positive vs τ-negative FTLD.
Despite published and validated diagnostic criteria for bvFTD,2,4
clinicians continue to misdiagnose patients with early-onset AD as having bvFTD. In this study, the neuropathology of AD is present in about 1 out of every 5 clinically diagnosed bvFTD cases, which is compatible with the results from other series.6,13,14
In a major report of 114 cases of bvFTD, there are 19 (16.7%) with AD on autopsy via Consortium to Establish a Registry for Alzheimer’s Disease criteria.6,15
That report, unlike this one, is not a prevalence study because it combined groups with FTLD pathology and with clinical FTD with non-FTLD pathology. Other investigators report AD pathology in 12% of a small cohort of patients with bvFTD,14
and AD pathology via NIA/Reagan criteria with or without neocortical Lewy bodies in 20% of another cohort of patients with bvFTD.13
Similar to our study, patients with bvFTD and FTLD pathology have been less likely to present with cognitive complaints when compared with the subgroup with AD pathology, whereas those with AD pathology have been more likely to present with cognitive difficulties, particularly impairments in episodic memory.6
Also similar to our study, others have found that over 70% of patients with bvFTD have poor planning and lack of judgment16
The results reported here add to the existing literature by indicating that patients with AD neuropathology may be clinically misdiagnosed with bvFTD when they are of early onset and have prominent neuropsychiatric features (delusions, hallucinations, agitation) despite greater memory difficulty and more intact personality and executive functions. In addition, clinicians may confuse the frontal clinical variant of AD with executive deficits as bvFTD.17
Neuropathologists commonly characterize FTLD by intraneuronal inclusions containing 1 of 2 misfolded, hyperphosphorylated, and ubiquinated proteins, τ or transactive response DNA-binding protein of 43 kD (TDP-43).18
Most of the τ-negative, ubiquitin-positive patients have TDP-43, although a smaller percentage have inclusions with fused in sarcoma (FUS) or no inclusions at all.19
During life, it has not been possible to reliably distinguish those patients with bvFTD who have underlying τ-negative or τ-positive pathology without the benefit of brain biopsy. Yet, determining the underlying pathology, whether τ-positive or τ-negative FTLD, or another pathology such as AD, may become increasingly important with the potential development of rational drug therapies targeted to specific pathologic conditions.
Estimates vary as to the proportions of τ-positive vs τ-negative pathology among patients with bvFTD. Of approximately 128 patients with bvFTD reported in a pooled study, 58 (45%) are τ-positive and 70 (55%) are τ-negative, mostly with TDP-43.3,13,20–22
Among the τ-positive cases in this pooled sample, the neuropathology of Pick disease occurs in about 70% of cases, with CBD in another 20%, and PSP in many of the remainder.3,6,13,20–22
In our study, we could not tell the percentages of the individual τ pathologies; there are overlapping categories, the classification of 17.4% with Pick disease does not reflect the true percentage of Pick disease pathology, and there is more PSP pathology than usually reported. Moreover, in the subset of the NACC neuropathology dataset analyzed here, there is a relatively smaller proportion of τ-positive cases (31.1%) and a correspondingly larger proportion of τ-negative cases (68.9%).
Distinguishing τ-positive from τ-negative patients during life can be difficult, primarily because the clinical manifestations depend more on the neuroanatomical localization than on type of neuronal inclusions.23
Some investigators report that, compared to τ-negative patients, τ-positive patients tend to have an extrapyramidal disorder suggestive of CBD, PSP, or parkinsonism,6
which would indicate that extrapyramidal changes on motor examination might predict an underlying tauopathy. However, τ-negative patients could also have extrapyramidal changes, and the current NACC series fails to reveal consistent differences in motor findings or total UPDRS scores.13,21,22,24
One study indicates a particular tendency to executive problems in planning and judgment among τ-positive patients.25
In contrast, other studies report greater social or behavioral changes, impaired regulation of personal conduct, poor personal hygiene, and apathy among τ-negative patients.6,25,26
Our finding of a greater proportion of τ-positive patients with initial behavioral and personality changes is seemingly in contradiction with these reports. The personality changes in the NACC are informant responses to whether the patients exhibited uncharacteristic as well as bizarre behavior, and this could reflect a general change in comportment from any cause, particularly since τ-positive patients tend to exhibit more advanced prefrontal-temporal atrophy on presentation than do τ-negative patients.27
Consistent with our findings, there may be greater abnormalities in speech and cognition, including language, among τ-negative patients.6,26
Clearly much more work is needed in order to establish the nature of potential clinical differences between patients with bvFTD who have τ-positive or τ-negative FTLD pathology.
This study had several potential limitations. First, although the NACC UDS and neuropathology datasets archive data from a large number of participants, data collection was performed by multiple clinicians and neuropathologists at different research centers, raising the possibility of variability in diagnostic interpretation across centers. However, NACC evaluations were standardized and reliability training was required across sites. Furthermore, the concordance of the NACC findings with prior single-site studies reinforced the generalizability of our results. Second, the NACC database lacked detailed neuropathologic information on localization of pathology and on histopathologic subtyping of τ, TDP-43, and FUS. Nevertheless, all of the cases included in this study were either τ-positive or τ-negative, the focus of this report. Third, given the limited overlap in subjects between the NACC UDS and neuropathology datasets, and the exploratory nature of our analyses, we did not adjust for multiple comparisons, and missing data for salient signs and symptoms was interpreted as negative results. The number of comparisons per domain and category, however, were all 12 or less, thus mitigating the effects of multiple comparisons, and the number of missing values for the analyzed variables was either none or a few per variable without a clear bias for any group. Finally, much of the data were informant-derived and influenced by their interpretation of questions such as “personality change.” Nevertheless, the informants were usually the primary caregivers who know the patients the best and who could most reliably report on their earliest symptomatic changes.
Among patients with clinically diagnosed bvFTD, there are differences in signs and symptoms at presentation between neuropathologically defined subgroups. Patients clinically diagnosed with bvFTD may have AD pathology, rather than FTLD pathology, if they have an early age at onset and prominent neuropsychiatric features despite greater memory difficulties and relatively intact personality and executive functions. Conversely, clinically diagnosed bvFTD is most likely to be caused by FTLD pathology if patients have early executive dysfunction and personality changes. Although this study did not include the new, more sensitive International Consensus Criteria for bvFTD, those criteria have unclear specificity for distinguishing bvFTD-FTLD from bvFTD-AD, particularly in the presence of early neuropsychiatric features.2
In this series, among those with FTLD pathology, patients with τ-positive bvFTD tend to earlier behavioral and personality changes, and τ-negative patients tend to more cognitive and speech abnormalities. These findings offer clues to recognition of pathologic subtypes of bvFTD during life, an important step for the development of pathophysiologically targeted clinical drug trials.