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

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

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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.

Original languageEnglish (US)
JournalActa Neuropathologica
DOIs
StateAccepted/In press - Jan 1 2019

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Amygdala
Frontotemporal Lobar Degeneration
Brain
Neuroimaging
Hippocampus
Entorhinal Cortex
Neurofibrillary Tangles
Sclerosis
Haplotypes
Brain Stem
Single Nucleotide Polymorphism
Neurons

Keywords

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

ASJC Scopus subject areas

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

Cite this

@article{1b690e5f867d4c278e3a7d4bc0b35f39,
title = "Pathological, imaging and genetic characteristics support the existence of distinct TDP-43 types in non-FTLD brains",
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 = "Alzheimer’s disease, Frontotemporal lobar degeneration, FTLD, Hippocampus, MRI, TDP-43, TDP-43 type, TMEM106B, Type-β",
author = "Josephs, {Keith Anthony} and Murray, {Melissa E} and Nirubol Tosakulwong and Weigand, {Stephen D.} and Serie, {Amanda M.} and Perkerson, {Ralph B.} and Matchett, {Billie J.} and Jack, {Clifford R Jr.} and Knopman, {David S} and Petersen, {Ronald Carl} and Parisi, {Joseph E} and Leonard Petrucelli and Matthew Baker and Rademakers, {Rosa V} and Whitwell, {Jennifer Lynn} and Dickson, {Dennis W}",
year = "2019",
month = "1",
day = "1",
doi = "10.1007/s00401-018-1951-7",
language = "English (US)",
journal = "Acta Neuropathologica",
issn = "0001-6322",
publisher = "Springer Verlag",

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TY - JOUR

T1 - Pathological, imaging and genetic characteristics support the existence of distinct TDP-43 types in non-FTLD brains

AU - Josephs, Keith Anthony

AU - Murray, Melissa E

AU - Tosakulwong, Nirubol

AU - Weigand, Stephen D.

AU - Serie, Amanda M.

AU - Perkerson, Ralph B.

AU - Matchett, Billie J.

AU - Jack, Clifford R Jr.

AU - Knopman, David S

AU - Petersen, Ronald Carl

AU - Parisi, Joseph E

AU - Petrucelli, Leonard

AU - Baker, Matthew

AU - Rademakers, Rosa V

AU - Whitwell, Jennifer Lynn

AU - Dickson, Dennis W

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

KW - Alzheimer’s disease

KW - Frontotemporal lobar degeneration

KW - FTLD

KW - Hippocampus

KW - MRI

KW - TDP-43

KW - TDP-43 type

KW - TMEM106B

KW - Type-β

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U2 - 10.1007/s00401-018-1951-7

DO - 10.1007/s00401-018-1951-7

M3 - Article

JO - Acta Neuropathologica

JF - Acta Neuropathologica

SN - 0001-6322

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