TDP-43 subtypes are associated with distinct atrophy patterns in frontotemporal dementia
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BACKGROUND: We sought to describe the antemortem clinical and neuroimaging features among patients with frontotemporal lobar degeneration with TDP-43 immunoreactive inclusions (FTLD-TDP). METHODS: Subjects were recruited from a consecutive series of patients with a primary neuropathologic diagnosis of FTLD-TDP and antemortem MRI. Twenty-eight patients met entry criteria: 9 with type 1, 5 with type 2, and 10 with type 3 FTLD-TDP. Four patients had too sparse FTLD-TDP pathology to be subtyped. Clinical, neuropsychological, and neuroimaging features of these cases were reviewed. Voxel-based morphometry was used to assess regional gray matter atrophy in relation to a group of 50 cognitively normal control subjects. RESULTS: Clinical diagnosis varied between the groups: semantic dementia was only associated with type 1 pathology, whereas progressive nonfluent aphasia and corticobasal syndrome were only associated with type 3. Behavioral variant frontotemporal dementia and frontotemporal dementia with motor neuron disease were seen in type 2 or type 3 pathology. The neuroimaging analysis revealed distinct patterns of atrophy between the pathologic subtypes: type 1 was associated with asymmetric anterior temporal lobe atrophy (either left- or right-predominant) with involvement also of the orbitofrontal lobes and insulae; type 2 with relatively symmetric atrophy of the medial temporal, medial prefrontal, and orbitofrontal-insular cortices; and type 3 with asymmetric atrophy (either left- or right-predominant) involving more dorsal areas including frontal, temporal, and inferior parietal cortices as well as striatum and thalamus. No significant atrophy was seen among patients with too sparse pathology to be subtyped. CONCLUSIONS: FTLD-TDP subtypes have distinct clinical and neuroimaging features, highlighting the relevance of FTLD-TDP subtyping to clinicopathologic correlation.
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TDP-43 pathological burden may further contribute toward the exclusive effects within FTD subjects.
“Transactive response DNA binding protein 43 kDa (TDP‐43) pathological burden may further contribute toward the exclusive effects within FTD subjects, as type two TDP‐43 sub‐types have previously exhibited distinct atrophy patterns involving the mPFC. 62”
From High vulnerability of medial prefrontal pyramidal neurons in post-stroke, vascular, Alzheimer's disease, and aging-related dementias (2026) · cites this paper as [62]
The Results report that type 2 FTLD-TDP was associated with significant atrophy in the medial prefrontal cortex, and the Discussion describes distinct atrophy patterns across TDP-43 subtypes. The paper does not establish that pathological burden contributes to the citing study’s “exclusive effects” within FTD subjects. (LLM, conf=0.85)
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“probability of underlying pathologies, a differential diagnosis between the two conditions is clinically relevant (Rohrer et al., 2010; Spinelli et al., 2017).”
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“…the exclusive effects within FTD subjects, as type two TDP-43 sub-types have previously exhibited distinct atrophy patterns involving the mPFC. 62 However, only a small subset of PSP cases, which predominantly comprised the FTD group, have reported TDP-43 intracellular inclusions subsequently…”
- Authors
- Rohrer, J. D., Geser, F., Zhou, J., Gennatas, E. D., Sidhu, M., Trojanowski, J. Q., DeArmond, S. J., Miller, B. L., & Seeley, W. W.
- Affiliations
- University of California, San Francisco (US)
- Corresponding author
- Seeley, W.W.
- Venue
- Neurology
- Published
- 2010-12-14
- Volume
- 75
- Issue
- 24
- Pages
- 2204-2211
- ISSN
- 0028-3878 (ISSN-L)
- 1526-632X
- PMC
- PMC3013589
- OpenAlex
- W2002632820
- Cited by
- 187
- References
- 34
- Citations by year
- 2026: 5 · 2025: 9 · 2024: 11 · 2023: 7 · 2022: 13 · 2021: 15 · 2020: 12 · 2019: 11 · 2018: 10 · 2017: 8 · 2016: 12 · 2015: 16 · 2014: 9 · 2013: 17 · 2012: 17
- FWCI
- 10.69
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Neurology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Wellcome Trust
- National Institutes of Health (5u01ag024904-10)
- National Institute on Aging (P50-AG23501, RC1AG035427, P01 AG 17586-10, UO1AG029213-01, P30AG036468, 1 U01 AG 024904-05, P30AG010124, P01AG009215, P30 AG 10124-18, P01AG017586, AG17586, AG-10124, R01AG033017, 1P01 AG-19724-07, U01AG029213, AG023501, P01-AG19724, P01 AG 09215-20, P01AG019724, P50AG023501)
- National Institute of Neurological Disorders and Stroke (P50NS053488, RC2NS069368)
- 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
- FTLD-TDP, frontotemporal lobar degeneration, semantic dementia, progressive nonfluent aphasia, corticobasal syndrome, behavioral variant frontotemporal dementia, clinicopathological correlation, voxel-based morphometry
- MeSH terms
- Aged, Aged, 80 and over, Aphasia, Atrophy, Brain, Inclusion Bodies, DNA-Binding Proteins, Female, Frontal Lobe, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Temporal Lobe, Thalamus, Frontotemporal Lobar Degeneration, Frontotemporal Dementia
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