In this study we applied PIB and FDG-PET to a clinically well characterized cohort of PPA patients in order to investigate in vivo the relationships between language phenotype, amyloid deposition and glucose metabolism in this disorder. The main findings were: 1) elevated PIB uptake was most frequently found in the logopenic variant of PPA (LPA, 4/4 patients), suggesting that this variant of progressive aphasia is often associated with underlying AD; 2) elevated PIB was uncommon in PNFA (1/6) and SD (1/5), suggesting that these PPA variants are not often associated with AD pathology; 3) patterns of glucose hypometabolism in PPA were focal and varied by clinical syndrome, while amyloid distribution in PIB-positive cases was diffuse and similar to AD.
LPA has only recently been introduced as a PPA variant, and patients with this clinical syndrome may still be misdiagnosed as having PNFA due to their decreased rate of speech.12, 23
However, the language features of LPA are distinguished from PNFA by the absence of apraxia of speech and dysarthria, the relative sparing of grammar in spontaneous speech, and the severe difficulty with repetition, especially of long sentences with unpredictable content.12
These language features are most similar to vascular “conduction aphasia,” and may be caused by deficits in auditory working memory.12, 23, 59
Furthermore, the atrophy and glucose metabolism patterns in PNFA and LPA are distinct, with left temporoparietal lesions in LPA and left fronto-insular lesions in PNFA.12
While FTLD-related pathology has most often been implicated in PNFA,5, 6
ten of fourteen patients retrospectively classified as LPA in recent clinicopathological series were found to have AD pathology on autopsy,9, 27
consistent with our finding that this language phenotype is predictive of underlying Aβ amyloidosis. Thus, accurately differentiating between LPA and PNFA has important implications for predicting underlying histopathology, and recognizing LPA as a unique variant of PPA may help identify PPA patients who are potential candidates for emerging anti-Aβ therapies.
We also found evidence of elevated PIB in one of six patients classified as PNFA and one of five subjects classified as SD. A retrospective review of these patients’ clinical data did not reveal atypical features (Supplementary Table
). Furthermore, their FDG uptake patterns conformed to their clinical syndromes, and did not show the temporoparietal hypometabolism found in LPA or AD (). While PIB appears to be highly specific for Aβ,30, 60
elevated PIB on PET does not exclude the presence of non-Aβ co-pathology. It is therefore possible that in addition to fibrillar Aβ, the PIB-positive PNFA and SD patients have co-morbid FTLD as the main pathology driving their aphasia syndrome, while Aβ pathology in these patients may be “clinically silent” or “age-related” (in the form of amyloid plaques, cerebral amyloid angiopathy, or both).31, 61
Alternatively, these patients may truly have AD pathology presenting with a PNFA or SD clinical and anatomic phenotype, as described in previous series.9, 62
Though we did not find PIB-negative cases of LPA in this study, it is likely that this syndrome can also be caused by FTLD-spectrum pathologies that asymmetrically affect temporoparietal cortex. As in all neurodegenerative diseases, deducing histopathology based on clinical phenotype in PPA relies on probabilistic relationships between clinical syndromes, anatomic patterns and underlying pathology. These relationships hold true at a group level, but are not always predictive at an individual level. Ultimately, biological markers such as PIB-PET may be needed to guide disease-specific treatment in individual patients presenting with PPA. Given the specificity of PIB for fibrillar Aβ60, 63
and the strong correlations between in vivo
PIB-PET signal and in vitro
measures of Aβ found on autopsy,31, 32
PIB-PET may be a useful clinical tool for excluding AD pathology in patients presenting with any of the PPA variants.
Clarifying the relationships between the distribution of amyloid plaques, clinical symptoms and neuronal dysfunction is of utmost importance given the effort to develop treatments targeting Aβ plaques in AD.10
The ability to image Aβ pathology in vivo
with PIB in patients with “focal” neurodegeneration such as PPA provides a unique opportunity to study these relationships and to compare them to the those found in AD. The pathology literature has been equivocal in this regard, with some investigators reporting a disproportionately high burden of plaques and tangles in left temporal and inferior parietal cortex in AD presenting as PPA,5, 64, 65
and others reporting a diffuse, “typical” pattern of AD pathology.6, 64
In a single case, Ng and colleagues found a higher burden of left hemisphere amyloid in a PIB-positive patient with PPA compared to patients with typical AD.66
In contrast, we found that amyloid deposition in PPA was diffuse, involved language and non-language areas alike, and was qualitatively indistinguishable from the pattern seen in matched AD patients (). Because most of our patients were imaged 5–6 years after the onset of their symptoms, we cannot exclude the possibility that amyloid deposition was more focal earlier in their disease course. However, at the time of imaging all patients with PIB-positive PPA in our study had a language-predominant syndrome in spite of the diffuse distribution of amyloid.
In contrast to the global pattern of PIB binding, FDG patterns in PPA were distinct and closely followed the clinical syndromes (, ). In comparison to AD, hippocampal glucose metabolism was spared in PI B-positive PPA (), mirroring the clinical sparing of episodic memory (). FDG uptake in language-related areas was more asymmetric (in favor of left hemisphere hypometabolism) in PPA than in AD (), and the region of greatest hypometabolism in each PPA subtype closely followed the language phenotype, regardless of PIB-positivity (, ).
The dissociation between PIB uptake and glucose metabolism found in our study is consistent with previous post-mortem and PIB studies in AD that have not found strong correlations between Aβ plaque distribution and clinical presentation, plaque load and disease severity, or plaque load and glucose metabolism in many brain regions (most notably frontal cortex and striatum).62, 67–72
There are many potential explanations for why patients with essentially identical Aβ plaque distribution patterns can have such discrepant clinical presentations and patterns of glucose metabolism. Patients may have discrete patterns of neurofibrillary tangles or soluble Aβ species (neither of which are imaged with PIB) that more closely match their clinical symptoms and metabolic patterns. Indeed, Mesulam and colleagues reported increased left hemisphere tangle pathology in AD presenting as PPA, while Aβ pathology was symmetric between hemispheres.27
Alternatively, the incongruity between amyloid deposition and clinical phenotype may be caused by differential vulnerability of specific neural networks to a similar burden of Aβ pathology in different patients. While in most patients the hippocampal-medial temporal-posterior cingulate network may be most vulnerable to Aβ pathology,73
resulting in the classical amnestic presentation of AD, in selected patients the language network may be most vulnerable, resulting in the clinical presentation of PPA. Differential vulnerability may be due to a combination of genetic, developmental and environmental factors that lead to decreased reserve or increased susceptibility to the neurotoxicity of Aβ. Further studies are needed to better elucidate the biological mechanisms of atypical presentations of AD.
Our study has a number of limitations. Histopathological confirmation is not available in any of our subjects (PPA or AD). While preliminary studies suggest strong correlations between in vivo
PIB-PET signal and in vitro
measures of Aβ found on autopsy,31, 32
further work is needed to validate the accuracy of PIB-PET in predicting underlying AD. As discussed above, we cannot exclude FTLD co-pathology in patients found to be PIB-positive, although the relatively young ages of our patients, particularly in the LPA group (), decreases the probability of “age-related” amyloid to some degree. The relatively small number of patients studied in each PPA subgroup limits our precision in estimating the prevalence of Aβ amyloidosis in each variant, and limits our power to detect subtle differences in PIB and FDG uptake between PPA variants and between PPA and AD. Furthermore, the PIB data for one LPA patient was excluded from quantitative analyses for technical reasons, and the significance of tracer lateralization in another LPA patient who is left-handed is difficult to interpret due to the ambiguity of hemisphere dominance. Despite these limitations, our study demonstrates that PIB-PET is a promising diagnostic tool for excluding Aβ amyloidosis in PPA, and a useful research tool for studying the relationships between Aβ amyloid, clinical presentation, and neuronal structure and function.
In summary, using PIB-PET we have demonstrated an association between the logopenic variant of PPA and Aβ amyloidosis. Furthermore, we found that language phenotype in PPA is closely related to metabolic changes that are focal and anatomically distinct between PPA subtypes, but not to amyloid deposition patterns that are diffuse and similar to AD. Combining PIB-PET with careful clinical characterization and structural and functional imaging may improve in vivo predictions of underlying pathology in PPA, and help elucidate the relationships between amyloid deposition, clinical presentation and functional and structural changes in focal cortical presentations of AD. Further studies with larger numbers of patients followed to autopsy are needed to confirm our findings.