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01-05-2017 | Original Paper

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

Authors: Keith A. Josephs, Melissa E. Murray, Nirubol Tosakulwong, Jennifer L. Whitwell, David S. Knopman, Mary M. Machulda, Stephen D. Weigand, Bradley F. Boeve, Kejal Kantarci, Leonard Petrucelli, Val J. Lowe, Clifford R. Jack Jr, Ronald C. Petersen, Joseph E. Parisi, Dennis W. Dickson

Published in: Acta Neuropathologica | Issue 5/2017

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.

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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)
Authors: Keith A. Josephs
Melissa E. Murray
Nirubol Tosakulwong
Jennifer L. Whitwell
David S. Knopman
Mary M. Machulda
Stephen D. Weigand
Bradley F. Boeve
Kejal Kantarci
Leonard Petrucelli
Val J. Lowe
Clifford R. Jack Jr
Ronald C. Petersen
Joseph E. Parisi
Dennis W. Dickson
Publication date: 01-05-2017
Publisher: Springer Berlin Heidelberg
Published in: Acta Neuropathologica / Issue 5/2017
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-017-1681-2

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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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