Alzheimer and frontotemporal pathology in subsets of primary progressive aphasia

Abstract

Objective: To identify predictors of Alzheimer's disease (AD) versus frontotemporal lobar degeneration pathology in primary progressive aphasia (PPA), and determine whether the AD pathology is atypically distributed to fit the aphasic phenotype.

Methods: Neuropsychological and neuropathological analyses of 23 consecutive PPA autopsies. All had qualitative determination of neurofibrillary tangle (NFT) density. Additional quantitation was done in four of the PPA/AD cases and four AD cases with the typical amnestic dementia of the Alzheimer type.

Results: The sample contained mostly logopenic, agrammatic, and mixed forms of PPA. All six agrammatics had frontotemporal lobar degeneration (five of six with tauopathy). Seven of the 11 logopenics had AD. In logopenics, lower memory scores increased the probability of AD, but there were exceptions. The PPA/AD group showed predominance of entorhinal NFT typical of the amnestic dementia of the Alzheimer type. In the small subgroup examined quantitatively, neocortical NFTs were more numerous in the left hemisphere of PPA/AD. However, the asymmetry was low and inconsistent. Neuritic plaques did not display consistent asymmetry. Apolipoprotein E4, a major risk factor for typical AD, did not predict AD pathology in PPA.

Interpretation: Subtyping PPA helps to predict AD versus frontotemporal lobar degeneration pathology at the group level. However, our results and the literature also indicate that no clinical predictor is completely reliable in individual patients. The inconsistent concordance of NFT distribution with the asymmetric atrophy and the nonamnestic phenotype also raises the possibility that the AD markers encountered at autopsy in PPA may not always reflect the nature of the initiating neurodegenerative process.

Fig. 1

Coronal magnetic resonance imaging (MRI) scan of Case 8 done 1 year after onset. The left perisylvian cistern is wider (asterisk), indicating more atrophy on that side. Postmortem examination also showed asymmetry, with greater microvacuolation in the left neocortex. However, there were no asymmetries of neurofibrillary tangle (NFT) distribution. Visual inspection of the MRI also showed that perisylvian atrophy was more severe than medial temporal atrophy. However, the NFT density did not show a perisylvian over entorhinal predominance. This patient illustrates the inconsistency of correlation between atrophy patterns and NFT distribution in primary progressive aphasia/Alzheimer’s disease (PPA/AD).