Tau aggregation influences cognition and hippocampal atrophy in the absence of beta-amyloid: a clinico-imaging-pathological study of primary age-related tauopathy (PART)

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Abstract

We investigate whether there is any association between the Braak neurofibrillary tangle (NFT) stage and clinical and MRI features in definite primary age-related tauopathy (PART). We analysed 52 cases with a Braak NFT tangle stage >0 and ≤IV, and a Thal phase of 0 (no beta-amyloid present). Twenty-nine (56%) were female. Median age at death was 88 years (IQR 82–92 years). Fifteen (29%) were TDP-positive (75% TDP stage I), 16 (31%) had argyrophilic grain disease and three (6%) had alpha-synuclein-positive Lewy bodies. TDP-43 inclusion when present were rare and predominantly perivascular. Of the 15 with TDP-43, three showed a moderate number of inclusions and also had hippocampal sclerosis, neuronal intranuclear inclusions and fine neurites of the CA1 region of the hippocampus. Four cases (8%) had an apolipoprotein epsilon 4 (APOE4) allele. There was a significant correlation between age at death and Braak NFT stage (r = 0.32, p = 0.02). After accounting for age at clinical examination, there were significant associations between Braak NFT stage, and WAIS-R Block Design and Trail Making Tests A and B, with higher Braak stage associated with poorer performances. Thirty of the 52 cases had completed an antemortem volumetric head MRI. Two separate MRI analyses revealed an association between higher Braak NFT stage and grey matter atrophy in the head of the left hippocampus. There were no significant clinical or radiologic associations with TDP-43. Findings from this study demonstrate that aggregated tau distribution is associated with poorer cognitive performance, as well as atrophy, in the absence of beta-amyloid. These findings support the parcellation of definite PART as a useful construct. The relatively low frequencies of APOE4, TDP-43, Lewy bodies, and hippocampal sclerosis, and the rarity and morphology of TDP-43 lesions are noted contrasts to what is typically observed in Alzheimer’s disease of the old.

Original languageEnglish (US)
Pages (from-to)1-11
Number of pages11
JournalActa Neuropathologica
DOIs
StateAccepted/In press - Feb 3 2017

Fingerprint

Tauopathies
Neurofibrillary Tangles
Amyloid
Cognition
Atrophy
Lewy Bodies
Apolipoproteins
Sclerosis
Hippocampus
Trail Making Test
Intranuclear Inclusion Bodies
alpha-Synuclein
Neurites
Alzheimer Disease
Alleles
Head

Keywords

  • Alzheimer’s disease
  • Beta-amyloid
  • Cognition
  • Hippocampus
  • MRI
  • Neurofibrillary tangles
  • PART
  • Tauopathy
  • TDP-43

ASJC Scopus subject areas

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

Cite this

@article{0964c613322d47a28cbe675d6bb25201,
title = "Tau aggregation influences cognition and hippocampal atrophy in the absence of beta-amyloid: a clinico-imaging-pathological study of primary age-related tauopathy (PART)",
abstract = "We investigate whether there is any association between the Braak neurofibrillary tangle (NFT) stage and clinical and MRI features in definite primary age-related tauopathy (PART). We analysed 52 cases with a Braak NFT tangle stage >0 and ≤IV, and a Thal phase of 0 (no beta-amyloid present). Twenty-nine (56{\%}) were female. Median age at death was 88 years (IQR 82–92 years). Fifteen (29{\%}) were TDP-positive (75{\%} TDP stage I), 16 (31{\%}) had argyrophilic grain disease and three (6{\%}) had alpha-synuclein-positive Lewy bodies. TDP-43 inclusion when present were rare and predominantly perivascular. Of the 15 with TDP-43, three showed a moderate number of inclusions and also had hippocampal sclerosis, neuronal intranuclear inclusions and fine neurites of the CA1 region of the hippocampus. Four cases (8{\%}) had an apolipoprotein epsilon 4 (APOE4) allele. There was a significant correlation between age at death and Braak NFT stage (r = 0.32, p = 0.02). After accounting for age at clinical examination, there were significant associations between Braak NFT stage, and WAIS-R Block Design and Trail Making Tests A and B, with higher Braak stage associated with poorer performances. Thirty of the 52 cases had completed an antemortem volumetric head MRI. Two separate MRI analyses revealed an association between higher Braak NFT stage and grey matter atrophy in the head of the left hippocampus. There were no significant clinical or radiologic associations with TDP-43. Findings from this study demonstrate that aggregated tau distribution is associated with poorer cognitive performance, as well as atrophy, in the absence of beta-amyloid. These findings support the parcellation of definite PART as a useful construct. The relatively low frequencies of APOE4, TDP-43, Lewy bodies, and hippocampal sclerosis, and the rarity and morphology of TDP-43 lesions are noted contrasts to what is typically observed in Alzheimer’s disease of the old.",
keywords = "Alzheimer’s disease, Beta-amyloid, Cognition, Hippocampus, MRI, Neurofibrillary tangles, PART, Tauopathy, TDP-43",
author = "Josephs, {Keith Anthony} and Murray, {Melissa E} and Nirubol Tosakulwong and Whitwell, {Jennifer Lynn} and Knopman, {David S} and Machulda, {Mary Margaret} and Weigand, {Stephen D.} and Boeve, {Bradley F} and Kantarci, {Kejal M} and Leonard Petrucelli and Val Lowe and Jack, {Clifford R Jr.} and Petersen, {Ronald Carl} and Parisi, {Joseph E} and Dickson, {Dennis W}",
year = "2017",
month = "2",
day = "3",
doi = "10.1007/s00401-017-1681-2",
language = "English (US)",
pages = "1--11",
journal = "Acta Neuropathologica",
issn = "0001-6322",
publisher = "Springer Verlag",

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TY - JOUR

T1 - Tau aggregation influences cognition and hippocampal atrophy in the absence of beta-amyloid

T2 - a clinico-imaging-pathological study of primary age-related tauopathy (PART)

AU - Josephs, Keith Anthony

AU - Murray, Melissa E

AU - Tosakulwong, Nirubol

AU - Whitwell, Jennifer Lynn

AU - Knopman, David S

AU - Machulda, Mary Margaret

AU - Weigand, Stephen D.

AU - Boeve, Bradley F

AU - Kantarci, Kejal M

AU - Petrucelli, Leonard

AU - Lowe, Val

AU - Jack, Clifford R Jr.

AU - Petersen, Ronald Carl

AU - Parisi, Joseph E

AU - Dickson, Dennis W

PY - 2017/2/3

Y1 - 2017/2/3

N2 - We investigate whether there is any association between the Braak neurofibrillary tangle (NFT) stage and clinical and MRI features in definite primary age-related tauopathy (PART). We analysed 52 cases with a Braak NFT tangle stage >0 and ≤IV, and a Thal phase of 0 (no beta-amyloid present). Twenty-nine (56%) were female. Median age at death was 88 years (IQR 82–92 years). Fifteen (29%) were TDP-positive (75% TDP stage I), 16 (31%) had argyrophilic grain disease and three (6%) had alpha-synuclein-positive Lewy bodies. TDP-43 inclusion when present were rare and predominantly perivascular. Of the 15 with TDP-43, three showed a moderate number of inclusions and also had hippocampal sclerosis, neuronal intranuclear inclusions and fine neurites of the CA1 region of the hippocampus. Four cases (8%) had an apolipoprotein epsilon 4 (APOE4) allele. There was a significant correlation between age at death and Braak NFT stage (r = 0.32, p = 0.02). After accounting for age at clinical examination, there were significant associations between Braak NFT stage, and WAIS-R Block Design and Trail Making Tests A and B, with higher Braak stage associated with poorer performances. Thirty of the 52 cases had completed an antemortem volumetric head MRI. Two separate MRI analyses revealed an association between higher Braak NFT stage and grey matter atrophy in the head of the left hippocampus. There were no significant clinical or radiologic associations with TDP-43. Findings from this study demonstrate that aggregated tau distribution is associated with poorer cognitive performance, as well as atrophy, in the absence of beta-amyloid. These findings support the parcellation of definite PART as a useful construct. The relatively low frequencies of APOE4, TDP-43, Lewy bodies, and hippocampal sclerosis, and the rarity and morphology of TDP-43 lesions are noted contrasts to what is typically observed in Alzheimer’s disease of the old.

AB - We investigate whether there is any association between the Braak neurofibrillary tangle (NFT) stage and clinical and MRI features in definite primary age-related tauopathy (PART). We analysed 52 cases with a Braak NFT tangle stage >0 and ≤IV, and a Thal phase of 0 (no beta-amyloid present). Twenty-nine (56%) were female. Median age at death was 88 years (IQR 82–92 years). Fifteen (29%) were TDP-positive (75% TDP stage I), 16 (31%) had argyrophilic grain disease and three (6%) had alpha-synuclein-positive Lewy bodies. TDP-43 inclusion when present were rare and predominantly perivascular. Of the 15 with TDP-43, three showed a moderate number of inclusions and also had hippocampal sclerosis, neuronal intranuclear inclusions and fine neurites of the CA1 region of the hippocampus. Four cases (8%) had an apolipoprotein epsilon 4 (APOE4) allele. There was a significant correlation between age at death and Braak NFT stage (r = 0.32, p = 0.02). After accounting for age at clinical examination, there were significant associations between Braak NFT stage, and WAIS-R Block Design and Trail Making Tests A and B, with higher Braak stage associated with poorer performances. Thirty of the 52 cases had completed an antemortem volumetric head MRI. Two separate MRI analyses revealed an association between higher Braak NFT stage and grey matter atrophy in the head of the left hippocampus. There were no significant clinical or radiologic associations with TDP-43. Findings from this study demonstrate that aggregated tau distribution is associated with poorer cognitive performance, as well as atrophy, in the absence of beta-amyloid. These findings support the parcellation of definite PART as a useful construct. The relatively low frequencies of APOE4, TDP-43, Lewy bodies, and hippocampal sclerosis, and the rarity and morphology of TDP-43 lesions are noted contrasts to what is typically observed in Alzheimer’s disease of the old.

KW - Alzheimer’s disease

KW - Beta-amyloid

KW - Cognition

KW - Hippocampus

KW - MRI

KW - Neurofibrillary tangles

KW - PART

KW - Tauopathy

KW - TDP-43

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U2 - 10.1007/s00401-017-1681-2

DO - 10.1007/s00401-017-1681-2

M3 - Article

C2 - 28160067

AN - SCOPUS:85011715950

SP - 1

EP - 11

JO - Acta Neuropathologica

JF - Acta Neuropathologica

SN - 0001-6322

ER -