Clinical and Imaging Features of Sporadic and Genetic Frontotemporal Lobar Degeneration TDP-43 A and B - PubMed (original) (raw)

. 2025 May;12(5):947-957.

doi: 10.1002/acn3.70014. Epub 2025 Mar 10.

Rhiana Schafer 1, Ashlin R K Roy 1, Andrzej Sokolowski 1, Noah G Cryns 1, Dana Leichter 1, Argentina Lario Lago 1, Eliana Marisa Ramos 2, Yann Cobigo 1, Salvatore Spina 1, Lea T Grinberg 1 3, Daniel H Geschwind 2 4 5, Maria L Gorno-Tempini 1, Joel H Kramer 1, Howard J Rosen 1, Bruce L Miller 1, William W Seeley 1 3, David C Perry 1

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Clinical and Imaging Features of Sporadic and Genetic Frontotemporal Lobar Degeneration TDP-43 A and B

Sean Coulborn et al. Ann Clin Transl Neurol. 2025 May.

Abstract

Objective: Certain frontotemporal lobar degeneration subtypes, including TDP-A and B, can either occur sporadically or in association with specific genetic mutations. It is uncertain whether syndromic or imaging features previously associated with these patient groups are subtype or genotype specific. Our study sought to discern the similarities and differences between sporadic and genetic TDP-A and TDP-B.

Methods: We generated individual atrophy maps and extracted mean atrophy scores for regions of interest-frontotemporal, occipitoparietal, thalamus, and cerebellum-in 54 patients with FTLD-TDP types A or B. We calculated asymmetry as the absolute difference in atrophy between right and left frontotemporal regions, and dorsality as the difference in atrophy between dorsal and ventral frontotemporal regions. We used ANCOVAs adjusted for disease severity to compare atrophy extent or imbalance, neuropsychological tests, and behavioral measures.

Results: For some regions, volumetric differences were found either between TDP subtypes (e.g., worse occipitoparietal and cerebellum atrophy in TDP-A than B), or within subtypes depending on genetic status (e.g., worse thalamic and occipitoparietal atrophy in C9orf72-associated TDP-B than sporadic TDP-B). While progranulin mutation-associated TDP-A and sporadic TDP-A cases can be strongly asymmetric, TDP-A and TDP-B associated with C9orf72 tended to be symmetric. TDP-A was more dorsal in atrophy than TDP-B, regardless of genetic status.

Interpretation: While some neuroimaging features are FTLD-TDP subtype-specific and do not significantly differ based on genotype, other features differ between sporadic and genetic forms within the same subtype and could decrease accuracy of classification algorithms that group genetic and sporadic cases.

Keywords: c9orf72; frontotemporal dementia; frontotemporal lobar degeneration; progranulin.

© 2025 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

FIGURE 1

FIGURE 1

Clinical Syndrome and Mutation Status Distribution within Subtypes. Abbreviations: AD‐D, Alzheimer's disease type (amnestic multidomain) dementia; ALS, Amyotrophic lateral sclerosis; bvFTD, behavioral variant frontotemporal dementia; C9orf72, chromosome 9 open reading frame 72; CBS, corticobasal syndrome; GRN, progranulin gene; lvPPA, logopenic variant primary progressive aphasia; MCI, mild cognitive impairment; MND, motor neuron disease; nfvPPA, nonfluent variant primary progressive aphasia; PPA (U), primary progressive aphasia (unclassified); svPPA, semantic variant primary progressive aphasia; TBK‐1, TANK‐binding kinase 1 gene; TARDBP, TAR DNA binding protein gene.

FIGURE 2

FIGURE 2

Boxplots representing atrophy (W‐scores) across participants stratified by genotype (C9orf72, GRN, sporadic) and FTLD‐TDP subtype (TDP‐A and TDP‐B) for (A) frontotemporal; (B) occipitoparietal; (C) thalamic; and (D) cerebellar regions, and for (E) absolute value of asymmetry (right–left); and (F) dorsality (negative values depicting dorsal predominant atrophy, positive showing ventral predominant atrophy). X in the center of each box represents the mean. *p < 0.050; ***p < 0.001. NS, non‐significant.

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