Acta Neuropathologica

, Volume 133, Issue 5, pp 705–715 | Cite as

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

  • Keith A. JosephsEmail author
  • 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. JackJr
  • Ronald C. Petersen
  • Joseph E. Parisi
  • Dennis W. Dickson
Original Paper


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.


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



This study was supported by the US National Institute of Aging (NIA) Grants R01 AG037491 (PI: KAJ), P50 AG16574 (PI: RCP), U01 AG006786 (PI: RCP), R01 AG11378 (PI: CRJ) and R01 AG041851 (PI: CRJ). We wish to thank Kris Johnson, Linda Rousseau, Virginia Phillips and Monica Casey-Castenedes for pathological support.


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Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Keith A. Josephs
    • 1
    • 2
    Email author
  • Melissa E. Murray
    • 7
  • Nirubol Tosakulwong
    • 3
  • Jennifer L. Whitwell
    • 4
  • David S. Knopman
    • 1
  • Mary M. Machulda
    • 5
  • Stephen D. Weigand
    • 3
  • Bradley F. Boeve
    • 1
  • Kejal Kantarci
    • 4
  • Leonard Petrucelli
    • 7
  • Val J. Lowe
    • 4
  • Clifford R. JackJr
    • 4
  • Ronald C. Petersen
    • 1
  • Joseph E. Parisi
    • 6
  • Dennis W. Dickson
    • 7
  1. 1.Behavioral Neurology, Department of NeurologyMayo ClinicRochesterUSA
  2. 2.Movement Disorders, Department of NeurologyMayo Clinic, College of MedicineRochesterUSA
  3. 3.Biostatistics, Department of Health Science ResearchMayo ClinicRochesterUSA
  4. 4.Radiology Research, Department of RadiologyMayo ClinicRochesterUSA
  5. 5.Department of Psychiatry and PsychologyMayo ClinicRochesterUSA
  6. 6.Neuropathology, Laboratory Medicine and PathologyMayo ClinicRochesterUSA
  7. 7.Department of NeuroscienceMayo ClinicJacksonvilleUSA

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