Pathological, imaging and genetic characteristics support the existence of distinct TDP-43 types in non-FTLD brains

Keith A. Josephs, Melissa E. Murray, Nirubol Tosakulwong, Stephen D. Weigand, Amanda M. Serie, Ralph B. Perkerson, Billie J. Matchett, Clifford R. Jack, David S. Knopman, Ronald C. Petersen, Joseph E. Parisi, Leonard Petrucelli, Matthew Baker, Rosa Rademakers, Jennifer L. Whitwell, Dennis W. Dickson

Research output: Contribution to journalArticlepeer-review

21 Scopus citations


TDP-43 is present in a high proportion of aged brains that do not meet criteria for frontotemporal lobar degeneration (FTLD). We determined whether there are distinct TDP-43 types in non-FTLD brains. From a cohort of 553 brains (Braak neurofibrillary tangle (NFT) stage 0–VI), excluding cases meeting criteria for FTLD, we identified those that had screened positive for TDP-43. We reviewed 14 different brain regions in these TDP-43 positive cases and classified them into those with “typical” TDP-43 immunoreactive inclusions (TDP type-α), and those in which TDP-43 immunoreactivity was adjacent to/associated with NFTs in the same neuron (TDP type-β). We compared pathological, genetic (APOE4, TMEM106B and GRN variants), neuroimaging and clinical data between types, as well as compared neuroimaging between types and a group of TDP-43 negative cases (n = 309). Two-hundred forty-one cases were classified as TDP type-α (n = 131, 54%) or TDP type-β (n = 110, 46%). Type-α cases were older than type-β at death (median 89 years vs. 87 years; p = 0.02). Hippocampal sclerosis was present in 78 (60%) type-α cases and 16 (15%) type-β cases (p < 0.001). Type-α cases showed a pattern of widespread TDP-43 deposition commonly extending into temporal, frontal and brainstem regions (84% TDP-43 stage 4–6) while in type-β cases deposition was predominantly limbic, located in amygdala, entorhinal cortex and subiculum of the hippocampus (84% TDP-43 stages 1–3) (p < 0.001). There was a difference in the frequency of TMEM106B protective (GG) and risk (CC) haplotypes (SNP rs3173615 encoding p.T185S) in type-α cases compared to type-β cases (GG/CG/CC: 8%/42%/50% vs. 24%/49%/27%; p = 0.01). Type-α cases had smaller amygdala (− 10.6% [− 17.6%, − 3.5%]; p = 0.003) and hippocampal (− 14.4% [− 21.6%, − 7.3%]; p < 0.001) volumes on MRI at death compared to type-β cases, although both types had smaller amygdala and hippocampal volumes compared to TDP-43 negative cases (− 7.77%, − 21.6%; p < 0.001). These findings demonstrate that there is distinct heterogeneity of TDP-43 deposition in non-FTLD brains.

Original languageEnglish (US)
Pages (from-to)227-238
Number of pages12
JournalActa neuropathologica
Issue number2
StatePublished - Feb 11 2019


  • Alzheimer’s disease
  • FTLD
  • Frontotemporal lobar degeneration
  • Hippocampus
  • MRI
  • TDP-43
  • TDP-43 type
  • TMEM106B
  • Type-β

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience


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