Asymmetry and heterogeneity of Alzheimer's and frontotemporal pathology in primary progressive aphasia

Abstract

Fifty-eight autopsies of patients with primary progressive aphasia are reported. Twenty-three of these were previously described (Mesulam et al., 2008) but had their neuropathological diagnoses updated to fit current criteria. Thirty-five of the cases are new. Their clinical classification was guided as closely as possible by the 2011 consensus guidelines (Gorno-Tempini et al., 2011). Tissue diagnoses included Alzheimer's disease in 45% and frontotemporal lobar degeneration (FTLD) in the others, with an approximately equal split between TAR DNA binding protein 43 proteinopathies and tauopathies. The most common and distinctive feature for all pathologies associated with primary progressive aphasia was the asymmetric prominence of atrophy, neuronal loss, and disease-specific proteinopathy in the language-dominant (mostly left) hemisphere. The Alzheimer's disease pathology in primary progressive aphasia displayed multiple atypical features. Males tended to predominate, the neurofibrillary pathology was more intense in the language-dominant hemisphere, the Braak pattern of hippocampo-entorhinal prominence was tilted in favour of the neocortex, and the APOE e4 allele was not a risk factor. Mean onset age was under 65 in the FTLD as well as Alzheimer's disease groups. The FTLD-TAR DNA binding protein 43 group had the youngest onset and fastest progression whereas the Alzheimer's disease and FTLD-tau groups did not differ from each other in either onset age or progression rate. Each cellular pathology type had a preferred but not invariant clinical presentation. The most common aphasic manifestation was of the logopenic type for Alzheimer pathology and of the agrammatic type for FTLD-tau. The progressive supranuclear palsy subtype of FTLD-tau consistently caused prominent speech abnormality together with agrammatism whereas FTLD-TAR DNA binding protein 43 of type C consistently led to semantic primary progressive aphasia. The presence of agrammatism made Alzheimer's disease pathology very unlikely whereas the presence of a logopenic aphasia or word comprehension impairment made FTLD-tau unlikely. The association of logopenic primary progressive aphasia with Alzheimer's disease pathology was much more modest than has been implied by results of in vivo amyloid imaging studies. Individual features of the aphasia, such as agrammatism and comprehension impairment, were as informative of underlying pathology as more laborious subtype diagnoses. At the single patient level, no clinical pattern was pathognomonic of a specific neuropathology type, highlighting the critical role of biomarkers for diagnosing the underlying disease. During clinical subtyping, some patients were unclassifiable by the 2011 guidelines whereas others simultaneously fit two subtypes. Revisions of criteria for logopenic primary progressive aphasia are proposed to address these challenges.

Keywords: Alzheimers disease; ApoE e4; aphasia; frontotemporal lobar degeneration; hemispheric lateralization.

Figure 1

Clinicopathological correlations. A template for classifying all 58 autopsy cases on the basis of single word comprehension and grammaticality of verbal output. All patients had fulfilled the criteria for the root diagnosis of PPA. Classification is based on the single available clinical evaluation for the 23 cases of the Mesulam et al. (2008) cohort and the initial evaluation for the new cohort of 35 cases. The ‘logopenic’ group includes aphasias characterized by word retrieval and naming impairments (regardless of repetition status) but without grammar or word comprehension abnormalities. It therefore incorporates both logopenic PPA and logopenic PPA without repetition impairment. The ‘agrammatic’ group is essentially identical to the agrammatic PPA designation according to the Gorno-Tempini et al. (2011) guidelines. The percentages indicate the distribution of pathology types. AD = Alzheimer pathology; DLBD = diffuse Lewy body disease.

Figure 2

Atypical distribution of Alzheimer pathology in Patient P6. The photomicrographs show neurofibrillary tangles and neuritic plaques in thioflavin-S stained tissue. Magnification is ×100 except in the entorhinal area where it is ×40. Lesions are much denser in the language-dominant left superior temporal gyrus (STG). Furthermore, the principles of Braak staging do not apply in any strict fashion as neocortex contains more lesions than entorhinal cortex and the CA1 region of the hippocampus.

Figure 3

Atypical distribution of Alzheimer pathology in Patient P9. Top: Quantitative imaging within 7 months before death shows focal peak atrophy sites in the left temporoparietal junction (TPJ). Bottom: The number of neurofibrillary tangles per cubic millimetre is greater in language-related neocortical areas than in entorhinal cortex (ENTO) and more in the language-dominant left hemisphere than in the right. Data taken from Gefen et al. (2012). PPA-L* = logopenic PPA with intact repetition at the initial evaluation 2 years after onset; STG = superior temporal gyrus.

Figure 4

Asymmetry of proteinopathy in frontotemporal lobar degenerations causing PPA. (A) Number of abnormal TDP-43 precipitates in Patient P21 in posterior inferoparietal cortex (PIPL), anterior inferoparietal cortex (AIPL), superior temporal gyrus (STG), inferior temporal gyrus (ITG) and entorhinal cortex (EC). Data taken from Gliebus et al. (2010). (B) Asymmetry of tauopathy shown by immunohistochemistry in the inferior frontal gyrus (IFG) of Patient P28 with FTLD-tau (Pick-type). (C) Asymmetry of tauopathy shown by immunohistochemistry in the inferior frontal gyrus of Patient P29 with FTLD-tau (corticobasal degeneration-type). (D) Tau-positive astrocytic plaque characteristic of corticobasal degeneration (CBD) pathology in Patient P29.

Figure 5

Similar appearance of asymmetry in PPA caused by Alzheimer’s disease and FTLD-tau. Arrows point to areas of prominent atrophy in the left inferior frontal gyrus of Patient P7 who had Alzheimer pathology (A) and Patient P29 who had frontotemporal lobar degeneration with tauopathy of the corticobasal degeneration-type (B). The asterisks mark the relatively spared contralateral inferior frontal gyrus of the right hemisphere. AD = Alzheimer’s disease; CBD = corticobasal degeneration.

Figure 6

Conflicting asymmetry in PPA with TDP-type A and Alzheimer’s disease pathologies in right-handed Patient P16. Top: TDP-43 precipitates show rightward preponderance in the superior temporal gyrus (STG). Bottom: Thioflavin-S positive neurofibrillary tangles and neuritic plaques of Alzheimer pathology show the reverse asymmetry, in a pattern that is more concordant with the aphasic phenotype in a right-handed person. AD = Alzheimer’s disease.