Typical and atypical pathology in primary progressive aphasia variants
Open accessAbstract
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 nonfluent (nfvPPA), 11 logopenic (lvPPA), and 4 mixed PPA. Patterns of gray 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 transactive response DNA‐binding protein (TDP) inclusions in 40.5%, FTLD‐tau in 40.5%, and Alzheimer disease (AD) pathology in 19% of cases. Each variant was associated with 1 typical pathology; 24 of 29 (83%) svPPA showed FTLD‐TDP type C, 22 of 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 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. Ann Neurol 2017;81:430–443
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Semantic variant primary progressive aphasia is strongly associated with TDP-43 type C neuropathology.
“[with the exception of svPPA, which is strongly associated with TAR DNA-binding protein 43 (TDP-43) type C neuropathology] (Spinelli et al., 2017).”
From Neuroinflammation and protein aggregation co-localize across the frontotemporal dementia spectrum (2020) · cites this paper as Spinelli et al., 2017
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- Authors
- Spinelli, E. G., Mandelli, M. L., Miller, Z. A., Santos‐Santos, M. A., Wilson, S. M., Agosta, F., Grinberg, L. T., Huang, E. J., Trojanowski, J. Q., Meyer, M., Henry, M. L., Comi, G., Rabinovici, G., Rosen, H. J., Filippi, M., Miller, B. L., Seeley, W. W., & Gorno‐Tempini, M. L.
- Affiliations
- Vita-Salute San Raffaele University (IT)
- University of California, San Francisco (US)
- University of Pennsylvania (US)
- The University of Texas at Austin (US)
- Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute Vita‐Salute San Raffaele University Milan Italy
- Corresponding author
- Gorno‐Tempini, Maria Luisa
- ORCID
- Venue
- Annals of Neurology
- Publisher
- Wiley
- Published
- 2017-03
- Volume
- 81
- Issue
- 3
- Pages
- 430-443
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- PMC
- PMC5421819
- OpenAlex
- W2582619151
- Cited by
- 409
- References
- 2
- Citations by year
- 2026: 25 · 2025: 51 · 2024: 35 · 2023: 36 · 2022: 53 · 2021: 50 · 2020: 73 · 2019: 42 · 2018: 29 · 2017: 15
- FWCI
- 35.73
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Annals of Neurology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Archivio Istituzionale della Ricerca - Università Vita-Salute San Raffaele (submittedVersion, other-oa)
- Funders
- National Institute of Neurological Disorders and Stroke (R01 NS050915)
- National Institute on Deafness and Other Communication Disorders (K24 DC015544)
- National Institute on Aging (P50 AG03006, P50 AG023501, P01 AG019724)
- Larry L. Hillblom Foundation
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- primary progressive aphasia, semantic variant PPA, logopenic variant PPA, frontotemporal lobar degeneration, FTLD-TDP, FTLD-tau, Alzheimer disease pathology, Pick's disease, 4R tau, gray matter atrophy, white matter atrophy, neuropathological diagnosis, support vector machine classification, extrapyramidal signs
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Atrophy, Female, Humans, Male, Middle Aged, tau Proteins, Aphasia, Primary Progressive, Pick Disease of the Brain, Frontotemporal Lobar Degeneration, Primary Progressive Nonfluent Aphasia, Support Vector Machine, White Matter, Gray Matter
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