We performed a detailed analysis of clinicopathological features in 90 consecutive patients with a neuropathological diagnosis of FTD and compared these features with an additional 24 patients clinically diagnosed with FTLD but with pathology not typically associated with FTD. We found a broad spectrum of distinct neuropathological findings, including tauopathies (46.5%) and FTLD-U (28.9%). Moreover, we observed clinical and neuropsychological differences among the pathological subgroups that provide hints at the underlying pathology. These clinicopathological correlations presumably reflect differences in the pathogenesis of disorders that affect a similar regional topography in the brain. Together with other biomarkers, these clinical data will contribute to a more accurate antemortem diagnosis of FTD patients.
The spectrum of pathologies in our study was similar to several recently published series.7,37,42,43
In all but one of these studies, FTLD-U was the single most common neuropathological diagnosis. However, in our series, the tauopathies as a group were more abundant than FTLD-U. In addition, similar to Lipton and colleagues’ results,42
we found that DLDH represents only a small fraction of our neuropathological diagnoses, accounting for less than 4% of our FTD cohort. These data stand in contrast with older reports that up to 60% of FTD patients have DLDH pathology.1,12,13
There were also some notable differences in the relative proportions of the tauopathies PiD, PSP, and CBD that may reflect differences in the clinic populations evaluated at UPenn and UCSF, as well as the institutions at which these prior studies were performed. For instance, Hodges and colleagues7
reported PiD as the most common pathology, present in almost one third of their FTLD patient population, whereas both Lipton and colleagues’42
and Knopman and coworkers’37
reports, PSP was the most common tauopathy, present in 29% and 24% of their respective patient cohorts. In our analysis, CBD was the most common tauopathy, diagnosed in 19.3% of patients, similar to Kertesz and colleagues’ study43
in which CBD accounted for 20% of their FTLD cohort. In contrast with these recent studies, we also found AD pathology in 16.7% of the patients with the clinical diagnosis of FTLD.7,42
The basis for this discrepancy between our study and previous reports is unclear. One possibility is the variability in inclusion criteria and/or subject selection. For instance, patients with AD and other unrelated pathologies were specifically excluded from analysis in some previous studies. Alternatively, AD may be challenging to distinguish from progressive aphasia because verbal memory is difficult to ascertain in these circumstances. For example, two recent studies describing the pathology associated with semantic dementia and progressive aphasia reported AD pathology in 11 and 38% of subjects, respectively.44,45
In our cohort, 44% of FTLD patients with AD pathology manifested progressive aphasia. A final possibility relates to the description of a frontal variant of AD that is distinct both clinically and pathologically from typical AD.19
Knopman and coworkers37
also reported AD pathology in 12% of a small, pathologically confirmed, FTD cohort, whereas Kertesz and colleagues43
reported AD or Lewy body variant of AD in 20% of their patients. Thus, the broad spectrum of pathologies presenting clinically with FTLD emphasizes the importance of identifying clinical features and molecular biomarkers that can provide more precise antemortem predictions of the specific underlying pathology.
The demographic characteristics of our FTD cohort are similar to several large clinical series, and we did not find significant differences in the demographics of tauopathy, FTLD-U/DLDH, and AD pathological subgroups.7,37-39
These data contrast with recent studies that found a significant difference between groups with and without tau pathology in the age at diagnosis and/or the age at death.7,43
These discrepancies may be due in part to the inclusion of patients with clinical MND who have an underlying pathology of FTLD-U, because these individuals manifest both a younger age at onset and shorter disease duration.41,46
In our analysis, differences between tauopathy and FTLD-U/ DLDH groups in age at onset and disease duration disappeared once clinical MND was considered. Notably, the age at onset of FTLD patients with AD pathology was 60.3 years, which is virtually identical to the entire FTD cohort (mean age at onset, 60.4 years). The age of disease onset of this subgroup of AD patients is significantly earlier than patients with both a clinical and pathological diagnosis of AD,47
including those observed at the UPenn AD Center. Although a biological explanation of the early age at onset in the AD patients presenting clinically with FTLD is unknown, this early age at onset might have contributed to the clinical categorization of these patients as FTLD.
The clinical signs and symptoms at presentation showed some distinct patterns in the pathological subgroups that may help to determine the underlying pathology in cases of FTD. Thus, FTLD-U was always the neuropathological diagnosis in cases with a clinical diagnosis of both FTLD and MND. Recent studies also reported a similar association of combined MND and FTLD with FTLD-U pathology in 100% of patients (n = 9).7,48
However, notably, MND was diagnosed in only 18.2% of FTLD-U cases and was never a presenting symptom. This rare but statistically reliable prediction of a specific underlying pathology is in contrast with the associations between other clinical features and an underlying pathology. For instance, the presence of clinically diagnosed social/behavioral and/or language dysfunction was statistically more prevalent in the subgroup with FTLD-U or DLDH compared with patients with tau or AD pathology. The clinical presentation of progressive aphasia has been associated with tau-negative pathologies such as FTLD-U,43,44
whereas other reports have related progressive nonfluent aphasia with PiD7
We did not find a specific clinical association of a language disorder with any of the pathological subgroups. In contrast, the AD patients clinically diagnosed with FTLD were more likely to manifest deficits in other domains of cognition such as impaired memory and executive function when compared with both the tauopathy and FTLD-U/DLDH subgroups. Furthermore, patients with a tauopathy more frequently manifest extrapyramidal features consistent with the presence of both CBD and PSP in this subgroup. These observations parallel the findings of a smaller series, associating extrapyramidal features such as rigidity with CBD and the pyramidal features of clinical MND with FTLD-U.7
These statistical associations were derived in part from clustering across pathologies sharing an immunohistochemical profile. However, the tau-negative pathologies such as FTLD-U and DLDH, although sharing the absence of tau pathology, differ in many important ways including the absence of ubiquitin-immunoreactive inclusions. Another limitation to a clinically based histopathological diagnosis is that our FTD cohort of patients tended to decline to a common phenotype with global impairment, rendering a clinical diagnosis less transparent at later stages of disease. These clinical findings are supported by the widespread distribution of pathology at the time of autopsy in all pathological subgroups of FTD without a specific predilection for the frontal lobes. This is in contrast with Johnson and colleagues’19
observations, which showed a significantly higher load of tau pathology in the frontal lobe of FTLD subjects with AD pathology. However, in this study, we used a semiquantitative assessment of tau pathology, whereas in Johnson and colleagues’19
report, tau pathology was assessed using area-occupied volumetric measurements. Nonetheless, similar to Kertesz and colleagues’43
description, additional clinical features emerge with disease progression in our study and lead to the finding that the FTD phenotypes, albeit initially distinct, converge over time in a single patient. Thus, clinical features detected at the first clinical examination rather than at later time points may contribute in a statistical sense to distinguishing the pathological subgroups of FTD.
A limited battery of neuropsychological tests showed some statistical associations with pathological subgroups of FTD, thus suggesting that antemortem neuropsychological evaluation also may contribute to identifying the underlying pathology of FTLD cases. However, quantitative neuropsychological findings that discriminate among pathologically defined subgroups must be interpreted with caution because of their modest statistical significance and the limited scope of the assessment available across clinics during the decade when data were collected. Nevertheless, psychometric testing may be helpful in distinguishing the pathological subgroups with particular attention to the domains of memory and language. Thus, AD patients clinically diagnosed with FTLD were impaired in episodic memory compared with both the tauopathy and FTLD-U/DLDH subgroups, as well as a test of attention relative to patients with FTLD-U/DLDH pathology. Conversely, tauopathy and FTLD-U/DLDH patients showed greater deficits on tests of verbal fluency and confrontational naming, respectively. Additional work clearly is necessary with larger panels of psychometric testing to further refine the neuropsychological profile of the pathological subgroups of FTLD patients.
In summary, the relation between FTLD and the pathology underlying this family of clinical syndromes is complex. Clinical and neuropsychological features of FTLD patients early in the course of disease are associated with an underlying pathology. However, these associations are statistical effects found in group analyses, and the particular clinical features observed in any individual patient rarely predict the specific underlying pathology with reliability. This study highlights the need for additional radiological49
and/or biological markers such as cerebrospinal fluid tau50
that, in association with clinical and neuropsychological features, can consistently delineate the specific pathology underlying a patient with the clinical diagnosis of FTLD.