Transactive response DNA-binding protein of 43 kDa (TDP-43) type-A is associated with frontotemporal lobar degeneration (FTLD). In primary age-related tauopathy (PART), TDP-type-α displays similar features to FTLD-TDP type-A. We compared antemortem MRI volumes of amygdala nuclei and hippocampal subfields between 16 PART-TDP-α and 12 FTLD-TDP-A autopsy-confirmed cases. Hippocampal tail and CA1 body volumes were smaller in PART-TDP-α group, which also had smaller lateral and central amygdala nuclei compared to FTLD-TDP-A group, but differences were non-significant after FDR correction. There is no evidence suggesting that TDP-43 type-A in FTLD affects hippocampal and amygdala volume loss differently than TDP-43 type-α in PART.
NeumannMLeeEBMackenzieIR. Frontotemporal lobar degeneration TDP-43-immunoreactive pathological subtypes: clinical and mechanistic significance. Adv Exp Med Biol2021; 1281: 201–217.
2.
JosephsKAMurrayMETosakulwongN, et al.Pathological, imaging and genetic characteristics support the existence of distinct TDP-43 types in non-FTLD brains. Acta Neuropathol2019; 137: 227–238.
3.
JosephsKAWhitwellJLWeigandSD, et al.TDP-43 is a key player in the clinical features associated with Alzheimer's disease. Acta Neuropathol2014; 127: 811–824.
4.
YoussefHGattoRGPhamNTT, et al.TDP-43 is associated with subiculum and cornu ammonis 1 hippocampal subfield atrophy in primary age-related tauopathy. J Alzheimers Dis2024; 99: 1023–1032.
5.
NelsonPTDicksonDWTrojanowskiJQ, et al.Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report. Brain2019; 142: 1503–1527.
6.
YoussefHWeissmannCUrukG, et al.Looking into abnormal co-expressions of tau and TDP-43 in the realm of mixed dementia types: a double-punch scenario. Brain Sci2025; 15: 716.
7.
YoussefHGattoRGPhamNTT, et al.Multiple neuropathologies underly hippocampal subfield atrophy in a case with a slowly progressive amnestic syndrome: challenging the notion of pure LATE-NC. Neuropathology2025; 45: e70000.
8.
JosephsKAMackenzieIFroschMP, et al.LATE To the PART-y. Brain2019; 142: e47.
9.
KatsumataYWuXAungKZ, et al.Pure LATE-NC: frequency, clinical impact, and the importance of considering APOE genotype when assessing this and other subtypes of non-Alzheimer's pathologies. Acta Neuropathol2024; 148: 66.
10.
MackenzieIRNeumannM. Reappraisal of TDP-43 pathology in FTLD-U subtypes. Acta Neuropathol2017; 134: 79–96.
11.
NeumannMKwongLKLeeEB, et al.Phosphorylation of S409/410 of TDP-43 is a consistent feature in all sporadic and familial forms of TDP-43 proteinopathies. Acta Neuropathol2009; 117: 137–149.
12.
FormanMSMackenzieIRCairnsNJ, et al.Novel ubiquitin neuropathology in frontotemporal dementia with valosin-containing protein gene mutations. J Neuropathol Exp Neurol2006; 65: 571–581.
13.
JosephsKAStrohADuggerB, et al.Evaluation of subcortical pathology and clinical correlations in FTLD-U subtypes. Acta Neuropathol2009; 118: 349–358.
JosephsKAMurrayMETosakulwongN, et al.Brain atrophy in primary age-related tauopathy is linked to transactive response DNA-binding protein of 43kDa. Alzheimers Dement2019; 15: 799–806.
16.
WhitwellJLJackCRJrParisiJE, et al.Does TDP-43 type confer a distinct pattern of atrophy in frontotemporal lobar degeneration?Neurology2010; 75: 2212–2220.
17.
RohrerJDGeserFZhouJ, et al.TDP-43 subtypes are associated with distinct atrophy patterns in frontotemporal dementia. Neurology2010; 75: 2204–2211.
18.
BocchettaMIglesiasJECashDM, et al.Amygdala subnuclei are differentially affected in the different genetic and pathological forms of frontotemporal dementia. Alzheimers Dement (Amst)2019; 11: 136–141.
19.
CairnsNJBigioEHMackenzieIR, et al.Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration. Acta Neuropathol2007; 114: 5–22.
20.
CraryJFTrojanowskiJQSchneiderJA, et al.Primary age-related tauopathy (PART): a common pathology associated with human aging. Acta Neuropathol2014; 128: 755–766.
21.
JackCRJrBennettDABlennowK, et al.NIA-AA Research framework: toward a biological definition of Alzheimer's disease. Alzheimers Dement2018; 14: 535–562.
22.
KimDKimHSChoiSM, et al.Primary age-related tauopathy: an elderly brain pathology frequently encountered during autopsy. J Pathol Transl Med2019; 53: 159–163.
23.
MackenzieIRNeumannMBigioEH, et al.Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration: an update. Acta Neuropathol2010; 119: 1–4.
24.
ZhangYJXuYFCookC, et al.Aberrant cleavage of TDP-43 enhances aggregation and cellular toxicity. Proc Natl Acad Sci U S A2009; 106: 7607–7612.
25.
ZhangXSunBWangX, et al.Phosphorylated TDP-43 staging of primary age-related tauopathy. Neurosci Bull2019; 35: 183–192.
26.
JosephsKAMurrayMEWhitwellJL, et al.Updated TDP-43 in Alzheimer's disease staging scheme. Acta Neuropathol2016; 131: 571–585.
27.
JackCRJrLoweVJSenjemML, et al.11C Pib and structural MRI provide complementary information in imaging of Alzheimer's disease and amnestic mild cognitive impairment. Brain2008; 131: 665–680.
28.
IglesiasJEAugustinackJCNguyenK, et al.A computational atlas of the hippocampal formation using ex vivo, ultra-high resolution MRI: application to adaptive segmentation of in vivo MRI. Neuroimage2015; 115: 117–137.
29.
SayginZMKliemannDIglesiasJE, et al.High-resolution magnetic resonance imaging reveals nuclei of the human amygdala: manual segmentation to automatic atlas. Neuroimage2017; 155: 370–382.
30.
FischlB. Freesurfer. Neuroimage2012; 62: 774–781.
31.
BocchettaMIglesiasJEScelsiMA, et al.Hippocampal subfield volumetry: differential pattern of atrophy in different forms of genetic frontotemporal dementia. J Alzheimers Dis2018; 64: 497–504.
32.
WesselingACalandriILBouwmanMMA, et al.Amygdalar and hippocampal volume loss in limbic-predominant age-related TDP-43 encephalopathy. Brain2025; 148: 3913–3923.
33.
GefenTAhmadianSSMaoQ, et al.Combined pathologies in FTLD-TDP types A and C. J Neuropathol Exp Neurol2018; 77: 405–412.
34.
GallagherMDSuhEGrossmanM, et al.TMEM106B Is a genetic modifier of frontotemporal lobar degeneration with C9orf72 hexanucleotide repeat expansions. Acta Neuropathol2014; 127: 407–418.
35.
IidaMAFarrellKWalkerJM, et al.Predictors of cognitive impairment in primary age-related tauopathy: an autopsy study. Acta Neuropathol Commun2021; 9: 134.
36.
BuciucMWhitwellJLBakerMC, et al.Old age genetically confirmed frontotemporal lobar degeneration with TDP-43 has limbic predominant TDP-43 deposition. Neuropathol Appl Neurobiol2021; 47: 1050–1059.
37.
WhitwellJLJosephsKAMurrayME, et al.MRI Correlates of neurofibrillary tangle pathology at autopsy: a voxel-based morphometry study. Neurology2008; 71: 743–749.
38.
JackCRJrDicksonDWParisiJE, et al.Antemortem MRI findings correlate with hippocampal neuropathology in typical aging and dementia. Neurology2002; 58: 750–757.
39.
JosephsKAMartinPRWeigandSD, et al.Protein contributions to brain atrophy acceleration in Alzheimer's disease and primary age-related tauopathy. Brain2020; 143: 3463–3476.
40.
MenesesAKogaSO'LearyJ, et al.TDP-43 Pathology in Alzheimer's disease. Mol Neurodegener2021; 16: 84.
41.
KawakamiIAraiTHasegawaM. The basis of clinicopathological heterogeneity in TDP-43 proteinopathy. Acta Neuropathol2019; 138: 751–770.
42.
LeeSMAsressSHalesCM, et al.TDP-43 cytoplasmic inclusion formation is disrupted in C9orf72-associated amyotrophic lateral sclerosis/frontotemporal lobar degeneration. Brain Commun2019; 1: fcz014.
43.
LeeEBLeeVMTrojanowskiJQ. Gains or losses: molecular mechanisms of TDP43-mediated neurodegeneration. Nat Rev Neurosci2011; 13: 38–50.
44.
JoMLeeSJeonYM, et al.The role of TDP-43 propagation in neurodegenerative diseases: integrating insights from clinical and experimental studies. Exp Mol Med2020; 52: 1652–1662.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
