Typical and atypical pathology in primary progressive aphasia variants

Abstract

Objective To characterize in vivo signatures of pathological diagnosis in a large cohort of patients with primary progressive aphasia (PPA) variants defined by current diagnostic classification. Methods Extensive clinical, cognitive, neuroimaging, and neuropathological data were collected from 69 patients with sporadic PPA, divided into 29 semantic (svPPA), 25 non-fluent (nfvPPA), 11 logopenic (lvPPA), and 4 mixed PPA. Patterns of grey matter (GM) and white matter (WM) atrophy at presentation were assessed and tested as predictors of pathological diagnosis using support vector machine (SVM) algorithms. Results A clinical diagnosis of PPA was associated with frontotemporal lobar degeneration (FTLD) with TDP inclusions in 40.5%, FTLD-tau in 40.5%, and Alzheimer’s disease (AD) pathology in 19% of cases. Each variant was associated with one typical pathology: 24/29 (83%) svPPA showed FTLD-TDP type C, 22/25 (88%) nfvPPA showed FTLD-tau, and all 11 lvPPA had AD. Within FTLD-tau, 4R-tau pathology was commonly associated with nfvPPA, whereas Pick’s disease was observed in a minority of subjects across all variants except for lvPPA. Compared with pathologically typical cases, svPPA-tau showed significant extrapyramidal signs, greater executive impairment, and severe striatal and frontal GM and WM atrophy. nfvPPA-TDP patients lacked general motor symptoms or significant WM atrophy. Combining GM and WM volumes, SVM analysis showed 92.7% accuracy to distinguish FTLD-tau and FTLD-TDP pathologies across variants. Interpretation Each PPA clinical variant is associated with a typical and most frequent cognitive, neuroimaging, and neuropathological profile. Specific clinical and early anatomical features may suggest rare and atypical pathological diagnosis in vivo.

Advances in progressive supranuclear palsy: new diagnostic criteria, biomarkers, and therapeutic approaches

“…1,14 Other vPSP syndromes named according to their predominant clinical features may account for about one third of earlier presentations in aggregate and include PSP with predominant parkinsonism (PSP-P), 16 pure akinesia with gait freezing (formerly PAGF, now PSP-PGF), 17 corticobasal syndrome (PSP-CBS), 14,18 primary progressive apraxia of speech or non-fluent variant primary progressive aphasia (nfvPPA; when caused by PSP: PSP with predominant speech/language disorder or PSP-SL), 19–21 behavioral variant frontotemporal dementia (bvFTD, when caused by PSP: PSP with predominant frontal presentation or PSP-F), 14,22 and PSP with predominant cerebellar ataxia (PSP-C) (Figure 2). 23 …”

“…19,20 A recent longitudinal study of 13 subjects with primary progressive AOS (PPAOS), which is similar to nfvPPA, found that five subjects developed a syndrome similar to PSP-RS about five years after onset, 19 and 22/25 nfvPPA in a larger series had tau pathology, most commonly 4R tau. 21 Similar to PSP-CBS, the new PSP criteria designate PSP-SL as possible PSP, but probable 4R tauopathy because determining which PSP-SL cases have PSP pathology based on clinical findings is impossible during life. 9 …”

“…31 Greater cortical tau pathology has been documented in PSP syndromes with more cortical symptoms during life, such as PSP-CBS, 32 PSP-SL, 21 and PSP-F. On the other hand, brainstem predominant PSP syndromes, such as PSP-P and PSP-PGF, have less cortical tau pathology and more severe degeneration in globus pallidus, subthalamic nucleus and substantia nigra when compared with PSP-RS. 1 Studies using brain tissue from human PSP patients have shown that inoculation of tau transgenic mice with this tissue can recapitulate PSP tau inclusions in mouse brains or identify specific strains of transmissible tau in cell culture models.…”

A clinicopathological approach to the diagnosis of dementia

“…2) and hypoperfusion or hypometabolism in the posterior perisylvian region and/or parietal lobe on MRI, single-photon emission CT (SPECT) and PET supports this diagnosis 66,67 . In addition, AD biomarkers (CSF or PET) have high utility for increasing confidence in the diagnosis, as well as for distinguishing lvPPA from FTD language syndromes that are much less frequently caused by AD pathology 76 (see FTD section below).…”

“…However, this condition is more frequently associated with AD 166 , although cases of tauopathy have also been reported 76 .…”