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

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

Abstract

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.

Keywords

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

Notes

Acknowledgements

This study was funded by the following grants from the US National Institutes of Health (National Institute on Aging): R01 AG037491, P50 AG16574, U01 AG006786 and R35 NS097261 (National Institute of Neurological Disorders and Stroke). We thank the families of the patients who donated their brains to science and thus allowed completion of this study.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Keith A. Josephs
    • 1
    Email author
  • Melissa E. Murray
    • 5
  • Nirubol Tosakulwong
    • 2
  • Stephen D. Weigand
    • 2
  • Amanda M. Serie
    • 5
  • Ralph B. Perkerson
    • 5
  • Billie J. Matchett
    • 5
  • Clifford R. JackJr.
    • 3
  • David S. Knopman
    • 1
  • Ronald C. Petersen
    • 1
  • Joseph E. Parisi
    • 4
  • Leonard Petrucelli
    • 5
  • Matthew Baker
    • 5
  • Rosa Rademakers
    • 5
  • Jennifer L. Whitwell
    • 3
  • Dennis W. Dickson
    • 5
  1. 1.Department of NeurologyMayo ClinicRochesterUSA
  2. 2.Department of Health Sciences ResearchMayo ClinicRochesterUSA
  3. 3.Department of RadiologyMayo ClinicRochesterUSA
  4. 4.Laboratory Medicine and PathologyMayo ClinicRochesterUSA
  5. 5.Department of NeuroscienceMayo ClinicJacksonvilleUSA

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