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Typical and atypical pathology in primary progressive aphasia variants
Spinelli EG, Mandelli ML, Miller ZA, Santos-Santos MA, Wilson SM, Agosta F, Grinberg LT, Huang EJ et al.. Annals of neurology, 2017-03-20
Topic: Brain proteins, microglia and lab models
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.
Key findings
- 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.
- Interpretation Each PPA clinical variant is associated with a typical and most frequent cognitive, neuroimaging, and neuropathological profile.
Why it matters
In 69 patients with primary progressive aphasia, each language variant was usually linked to one underlying pathology, and all 11 with the logopenic variant had Alzheimer's disease pathology. This helps predict what pathology a living patient may have, but it does not test any treatment or cure.
Study details
- Participants69
- Effect size40.5%; 92.7%
- Evidence strengthModerate
How this study scored 62/100
Published in a leading specialty journal. Scored zero for study design and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Annals of neurology) |
| Journal's citation record | 3 / 4 | Annals of Neurology: journal h-index 437 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 3 / 5 | Rated “moderate” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 2 / 5 | 2017 — within 10 year(s) of the newest study here |
| Sample size | 1 / 4 | 69 participants |
| Effect reported | 2 / 3 | Effect reported as a number, without an interval or test |
| Studied in people | 3 / 3 | Studied in people (participant count stated) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 6 / 7 | Cited 415 times (OpenAlex, 2026-10-10) |
| Citations per year | 4 / 5 | 37.7 citations a year over 11 year(s) since 2017 |
| Impact for its field and year | 5 / 6 | Cited 32.4× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 3 / 6 | Cited by 21 other studies in this library |
| Still being cited | 3 / 4 | Cited 111 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Maria‐Luisa Gorno‐Tempini: h-index 33 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | University of California, San Francisco: institution h-index 1,915 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 7 institution(s) in 2 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 28133816) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 62 / 100 | — |
What each of these 20 components measures, and what this score is not →
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APA 7th
Spinelli, E. G., Mandelli, M. L., Miller, Z. A., Santos-Santos, M. A., Wilson, S. M., Agosta, F., et al. (2017). Typical and atypical pathology in primary progressive aphasia variants. Annals of neurology. https://doi.org/10.1002/ana.24885
Vancouver
Spinelli EG, Mandelli ML, Miller ZA, Santos-Santos MA, Wilson SM, Agosta F, et al. Typical and atypical pathology in primary progressive aphasia variants. Annals of neurology. 2017. doi:10.1002/ana.24885. PMID: 28133816.
BibTeX
@article{spinelli2017-28133816,
author = {Spinelli, E. G. and Mandelli, M. L. and Miller, Z. A. and Santos-Santos, M. A. and Wilson, S. M. and Agosta, F. and Grinberg, L. T. and Huang, E. J. and others},
title = {{Typical and atypical pathology in primary progressive aphasia variants}},
journal = {Annals of neurology},
year = {2017},
doi = {10.1002/ana.24885},
pmid = {28133816},
url = {https://doi.org/10.1002/ana.24885}
}
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