124 Citations (Scopus)

Abstract

TDP-43 immunoreactivity occurs in 19-57 % of Alzheimer's disease (AD) cases. Two patterns of TDP-43 deposition in AD have been described involving hippocampus (limbic) or hippocampus and neocortex (diffuse), although focal amygdala involvement has been observed. In 195 AD cases with TDP-43, we investigated regional TDP-43 immunoreactivity with the aim of developing a TDP-43 in AD staging scheme. TDP-43 immunoreactivity was assessed in amygdala, entorhinal cortex, subiculum, hippocampal dentate gyrus, occipitotemporal, inferior temporal and frontal cortices, and basal ganglia. Clinical, neuroimaging, genetic and pathological characteristics were assessed across stages. Five stages were identified: stage I showed scant-sparse TDP-43 in the amygdala only (17 %); stage II showed moderate-frequent amygdala TDP-43 with spread into entorhinal and subiculum (25 %); stage III showed further spread into dentate gyrus and occipitotemporal cortex (31 %); stage IV showed further spread into inferior temporal cortex (20 %); and stage V showed involvement of frontal cortex and basal ganglia (7 %). Cognition and medial temporal volumes differed across all stages and progression across stages correlated with worsening cognition and medial temporal volume loss. Compared to 147 AD patients without TDP-43, only the Boston Naming Test showed abnormalities in stage I. The findings demonstrate that TDP-43 deposition in AD progresses in a stereotypic manner that can be divided into five distinct topographic stages which are supported by correlations with clinical and neuroimaging features. Given these findings, we recommend sequential regional TDP-43 screening in AD beginning with the amygdala.

Original languageEnglish (US)
Pages (from-to)441-450
Number of pages10
JournalActa Neuropathologica
Volume127
Issue number3
DOIs
StatePublished - Mar 2014

Fingerprint

Alzheimer Disease
Amygdala
Pathology
Hippocampus
Dentate Gyrus
Frontal Lobe
Temporal Lobe
Basal Ganglia
Neuroimaging
Cognition
Parahippocampal Gyrus
Entorhinal Cortex
Neocortex

Keywords

  • Alzheimer disease
  • Amygdala
  • MRI
  • Staging
  • TDP-43
  • TDP-43 type

ASJC Scopus subject areas

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

Cite this

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title = "Staging TDP-43 pathology in Alzheimer's disease",
abstract = "TDP-43 immunoreactivity occurs in 19-57 {\%} of Alzheimer's disease (AD) cases. Two patterns of TDP-43 deposition in AD have been described involving hippocampus (limbic) or hippocampus and neocortex (diffuse), although focal amygdala involvement has been observed. In 195 AD cases with TDP-43, we investigated regional TDP-43 immunoreactivity with the aim of developing a TDP-43 in AD staging scheme. TDP-43 immunoreactivity was assessed in amygdala, entorhinal cortex, subiculum, hippocampal dentate gyrus, occipitotemporal, inferior temporal and frontal cortices, and basal ganglia. Clinical, neuroimaging, genetic and pathological characteristics were assessed across stages. Five stages were identified: stage I showed scant-sparse TDP-43 in the amygdala only (17 {\%}); stage II showed moderate-frequent amygdala TDP-43 with spread into entorhinal and subiculum (25 {\%}); stage III showed further spread into dentate gyrus and occipitotemporal cortex (31 {\%}); stage IV showed further spread into inferior temporal cortex (20 {\%}); and stage V showed involvement of frontal cortex and basal ganglia (7 {\%}). Cognition and medial temporal volumes differed across all stages and progression across stages correlated with worsening cognition and medial temporal volume loss. Compared to 147 AD patients without TDP-43, only the Boston Naming Test showed abnormalities in stage I. The findings demonstrate that TDP-43 deposition in AD progresses in a stereotypic manner that can be divided into five distinct topographic stages which are supported by correlations with clinical and neuroimaging features. Given these findings, we recommend sequential regional TDP-43 screening in AD beginning with the amygdala.",
keywords = "Alzheimer disease, Amygdala, MRI, Staging, TDP-43, TDP-43 type",
author = "Josephs, {Keith Anthony} and Murray, {Melissa E} and Whitwell, {Jennifer Lynn} and Parisi, {Joseph E} and Leonard Petrucelli and Jack, {Clifford R Jr.} and Petersen, {Ronald Carl} and Dickson, {Dennis W}",
year = "2014",
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T1 - Staging TDP-43 pathology in Alzheimer's disease

AU - Josephs, Keith Anthony

AU - Murray, Melissa E

AU - Whitwell, Jennifer Lynn

AU - Parisi, Joseph E

AU - Petrucelli, Leonard

AU - Jack, Clifford R Jr.

AU - Petersen, Ronald Carl

AU - Dickson, Dennis W

PY - 2014/3

Y1 - 2014/3

N2 - TDP-43 immunoreactivity occurs in 19-57 % of Alzheimer's disease (AD) cases. Two patterns of TDP-43 deposition in AD have been described involving hippocampus (limbic) or hippocampus and neocortex (diffuse), although focal amygdala involvement has been observed. In 195 AD cases with TDP-43, we investigated regional TDP-43 immunoreactivity with the aim of developing a TDP-43 in AD staging scheme. TDP-43 immunoreactivity was assessed in amygdala, entorhinal cortex, subiculum, hippocampal dentate gyrus, occipitotemporal, inferior temporal and frontal cortices, and basal ganglia. Clinical, neuroimaging, genetic and pathological characteristics were assessed across stages. Five stages were identified: stage I showed scant-sparse TDP-43 in the amygdala only (17 %); stage II showed moderate-frequent amygdala TDP-43 with spread into entorhinal and subiculum (25 %); stage III showed further spread into dentate gyrus and occipitotemporal cortex (31 %); stage IV showed further spread into inferior temporal cortex (20 %); and stage V showed involvement of frontal cortex and basal ganglia (7 %). Cognition and medial temporal volumes differed across all stages and progression across stages correlated with worsening cognition and medial temporal volume loss. Compared to 147 AD patients without TDP-43, only the Boston Naming Test showed abnormalities in stage I. The findings demonstrate that TDP-43 deposition in AD progresses in a stereotypic manner that can be divided into five distinct topographic stages which are supported by correlations with clinical and neuroimaging features. Given these findings, we recommend sequential regional TDP-43 screening in AD beginning with the amygdala.

AB - TDP-43 immunoreactivity occurs in 19-57 % of Alzheimer's disease (AD) cases. Two patterns of TDP-43 deposition in AD have been described involving hippocampus (limbic) or hippocampus and neocortex (diffuse), although focal amygdala involvement has been observed. In 195 AD cases with TDP-43, we investigated regional TDP-43 immunoreactivity with the aim of developing a TDP-43 in AD staging scheme. TDP-43 immunoreactivity was assessed in amygdala, entorhinal cortex, subiculum, hippocampal dentate gyrus, occipitotemporal, inferior temporal and frontal cortices, and basal ganglia. Clinical, neuroimaging, genetic and pathological characteristics were assessed across stages. Five stages were identified: stage I showed scant-sparse TDP-43 in the amygdala only (17 %); stage II showed moderate-frequent amygdala TDP-43 with spread into entorhinal and subiculum (25 %); stage III showed further spread into dentate gyrus and occipitotemporal cortex (31 %); stage IV showed further spread into inferior temporal cortex (20 %); and stage V showed involvement of frontal cortex and basal ganglia (7 %). Cognition and medial temporal volumes differed across all stages and progression across stages correlated with worsening cognition and medial temporal volume loss. Compared to 147 AD patients without TDP-43, only the Boston Naming Test showed abnormalities in stage I. The findings demonstrate that TDP-43 deposition in AD progresses in a stereotypic manner that can be divided into five distinct topographic stages which are supported by correlations with clinical and neuroimaging features. Given these findings, we recommend sequential regional TDP-43 screening in AD beginning with the amygdala.

KW - Alzheimer disease

KW - Amygdala

KW - MRI

KW - Staging

KW - TDP-43

KW - TDP-43 type

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U2 - 10.1007/s00401-013-1211-9

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JO - Acta Neuropathologica

JF - Acta Neuropathologica

SN - 0001-6322

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