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.

Aphasic variant of Alzheimer disease

“…At the Northwestern Alzheimer's Disease Brain Bank, 26% of the control population (n 5 190) has at least one e4 allele, whereas this frequency increases to 59% in those with an amnestic dementia during life and AD at autopsy (n 5 75). 1 The 27% frequency of e4 allele carriers in the 19 PPA participants with biomarker evidence or autopsy-confirmed AD reported in the current investigation is similar to control values. These data are consistent with previous reports 23,24 suggesting the e4 allele of APOE is not a risk factor for clinical PPA or AD pathology in PPA.…”

“…These proportions are in line with those of an autopsy series of 58 PPA cases examined at various severity stages, in which 69% of all cases with AD pathology as the primary diagnosis had logopenic aphasia. 1 These results seem at odds with another study, also of PPA participants with autopsy or biomarker evidence of AD, where a complete overlap with PPA-L was reported. 25 However, in that study, grammatical ability was not reported and 5/14 participants presented with additional nonverbal memory impairments.…”

“…In the series of 58 autopsies, for example, only 56% of PPA-L cases were associated with a primary neuropathologic diagnosis of AD. 1 Investigations addressing this question with amyloid-PET scans have also yielded variable results. One study reported that 92% of PPA-L participants had positive amyloid scans.…”

“…The PPA diagnosis was based on 3 core criteria: (1) progressive language disorder of recent onset not attributable to elementary motor or perceptual deficits; (2) absence of consequential impairments in episodic memory, visuospatial skills, or comportment for approximately 2 years as ascertained by medical records, structured interviews with family members, and results of nonlanguage tests (table e-1 at Neurology.org); and (3) diagnostic investigations consistent with a neurodegenerative etiology. 1,4,5 Standard protocol approvals, registrations, and patient consents. Northwestern University's Institutional Review Board approved this study.…”

Diffuse leukoencephalopathy with spheroids presenting as primary progressive aphasia

“…This is a novel report of PPA secondary to DLS. Previous clinicopathologic correlates of PPA have reported 9 underlying pathologies, including Alzheimer pathology; frontotemporal lobar degeneration (FTLD)-tau of the corticobasal degeneration type, progressive supranuclear palsy type, and Pick type; FTLD-TDP types A, B, and C; mixed AD and dementia with Lewy body pathology 6 ; and sporadic Creutzfeldt-Jakob disease. 7 The hemispheric asymmetry is the common denominator for neuropathologic entities underlying PPA.…”