We report comprehensive, prospective longitudinal clinical and neuroimaging data for a patient with typical nfvPPA [3
] who was PiB+ and who was found to have Pick’s disease and AD at autopsy. We discuss her neuroimaging and clinical features and argue that positivity of AD biomarkers should not exclude the presence of FTLD pathology in patients with a typical nfvPPA clinical syndrome.
In FC, motor speech impairment was so severe that soon after her first presentation to our clinic she became functionally mute. She also showed mild agrammatism (verbal and written initially and written only later) but it was mild. Detailed evaluation of FC’s motor speech impairment was performed only at year one, when she was still able to produce some words. AOS was characterized by effortful groping, slow rate, sequencing errors, sound distortions and dysprosody. Dysarthria was mixed and difficult to classify. FC therefore showed a pattern of impairment typical of nfvPPA in which both AOS and dysarthria often co-occur [4
]. The severity and rapid progression of the motor speech impairment in FC were remarkable. She also showed progressive bucco-facial apraxia and some swallowing difficulties that worsened over time. The dissociation between the severe motor speech impairment and the relative sparing of comprehension (even at the sentence level) in FC raises the question of whether she could be classified as “anarthric” or as having an “anterior opercular syndrome” as first described in the European literation of the 1990s” [36
] and recently revived by Deramecourt [18
]. Anarthric patients are thought to have pure motor speech impairment with dysarthria and bucco-facial apraxia with spared language comprehension and no agrammatism. Direct comparison of FC with less recent patients from the literature is difficult as formal language assessment was often limited and modern concepts such as AOS were often not applied. Nevertheless, we believe that at first presentation FC most closely resembled the “anarthric” rather than the “agrammatic” picture As disease progressed, FC showed clearer signs of grammatical impairment highlighting the fact that in many patients the boundaries between the anarthric and agrammatic forms can be ill-defined. For this reason, recent diagnostic criteria include both motor speech deficits and agrammatism as possible core symptoms necessary for nfvPPA diagnosis. Whether each of these two core features is predictive of specific anatomo-pathological substrates is under investigation [17
]. It is worth noting that while many patients with nvfPPA and severe motor speech deficit evolve to develop a corticobasal syndrome [6
], FC’s non-speech motor deficits were never significant enough to warrant that syndromic diagnosis.
Consistent with a diagnosis of nfvPPA with primarily motor speech impartment, FC’s neuroimaging findings showed damage to the left frontal operculum/anterior insular region [6
]. Interestingly, the left precentral regions corresponding to the face, mouth, and pharyngeal motor representations [42
] were the most affected. Longitudinal VBM showed that atrophy became prominent also in other parts of the motor control network spreading to superior premotor cortex, SMA and basal ganglia as previously shown in nfvPPA [6
]. Severe involvement of all these structures likely caused complete mutism in FC, stressing the concept that motor speech production is sustained by the interaction of multiple cortical and subcortical structures [44
The prominence of the motor speech impairment in FC predicted an underlying tauopathy. While we predicted underlying CBD, the lack of general motor involvement even late in the course argued against this formulation. No clinical feature suggested AD pathology. In particular, FC’s memory was spared until very late in the disease when all her cognitive functions declined. The posterior temporo-parietal regions typically involved in AD were not significantly atrophied on VBM or hypomethabolic on PET-FDG at year 5 (eight years from disease’s onset). Hippocampal damage became apparent on VBM only five years after initial diagnosis (eight from first symptom). We were therefore surprised when the patient showed a PET-PiB positive scan. The literature on PET-PiB and FTD-spectrum clinical syndrome is still limited. The published data show that PiB positivity is in general infrequent in FTD and pathologically-confirmed patients that can elucidate the nature of the finding are rare [20
]. In particular, FC is the first patient with nfvPPA to have pathologically confirmed FTLD despite a positive PiB-PET scan. She was also included in a previous series from our group [22
]. Recently, we encountered another patient with PIB positive nfvPPA, but the patient showed a more mixed clinical picture and remains alive at the time of this writing [20
]. Another clinical series was recently reported in which only two of eight nfvPPA patients were found to be positive [21
]. Concerning our patient, many possible ante-mortem explanations could be hypothesized for her PiB positivity. Though FC filled all the criteria for definite nfvPPA, PiB-PET positivity could suggest an atypical presentation of AD. In PPA, the logopenic-variant (lvPPA) has been most often associated with PIB+ and AD pathology [2
] but in our patient both clinical and MRI/FDG-PET data excluded an lvPPA diagnosis. On the other hand, few patients with nfvPPA and underlying AD pathology have been described. High frequency of AD pathology has been reported in language-impaired patients with clinical syndromes classified as having a “nonfluent” presentation that are sometimes, but not always, consistent with lvPPA [12
Grossmann also followed nine patients with nfvPPA longitudinally, and noted AD pathology in three patients at autopsy [48
]. We might also interpret FC’s PiB positivity as a an incidental finding, since up to a third of cognitively normal elderly population shows positive PiB-PET scan [49
] or as a preclinical phase of AD, taking into account that cognitively normal individuals with positive PiB-PET scan have a greater risk of progression to symptomatic AD after 3–4 years of follow up [51
]. PIB positivity would therefore not exclude FTLD pathology as the cause of FC’s aphasia syndrome but might instead highlight an overlapping amyloid pathology that in our patient appears to have been “clinically silent” until later stages of the disease. The clinical course of FC’s disease was characterized by a general cognitive decline only in the last years of disease. Post-mortem pathological findings of Pick’s disease with AD co-pathology (Braak stage V) further support the latter hypothesis.
To our knowledge, this is the first prospective, longitudinal description of nfvPPA patient in which in-vivo evidence of brain amyloidosis detected with PiB-PET scan was correlated with pathological diagnosis in the same patient. The principal pathological diagnosis in our patient was Pick’s disease. We conclude that in-vivo biomarker evidence of brain amyloidosis (PiB-PET scan) should not be considered conclusive evidence that AD is responsible for a typical FTD syndrome.