Tau aggregation influences cognition and hippocampal atrophy in the absence of beta-amyloid: a clinico-imaging-pathological study of primary age-related tauopathy (PART).
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.
Behavioral Neurology, Department of Neurology, Mayo Clinic, Rochester, MN, USA. josephs.keith@mayo.edu.|Movement Disorders, Department of Neurology, Mayo Clinic, College of Medicine, Rochester, MN, USA. josephs.keith@mayo.edu.
Keith A
KA
Josephs
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
Melissa E
ME
Murray
Biostatistics, Department of Health Science Research, Mayo Clinic, Rochester, MN, USA.
Nirubol
N
Tosakulwong
Radiology Research, Department of Radiology, Mayo Clinic, Rochester, MN, USA.
Jennifer L
JL
Whitwell
Behavioral Neurology, Department of Neurology, Mayo Clinic, Rochester, MN, USA.
David S
DS
Knopman
Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.
Mary M
MM
Machulda
Biostatistics, Department of Health Science Research, Mayo Clinic, Rochester, MN, USA.
Stephen D
SD
Weigand
Behavioral Neurology, Department of Neurology, Mayo Clinic, Rochester, MN, USA.
Bradley F
BF
Boeve
Radiology Research, Department of Radiology, Mayo Clinic, Rochester, MN, USA.
Kejal
K
Kantarci
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
Leonard
L
Petrucelli
Radiology Research, Department of Radiology, Mayo Clinic, Rochester, MN, USA.
Val J
VJ
Lowe
Radiology Research, Department of Radiology, Mayo Clinic, Rochester, MN, USA.
Clifford R
CR
Jack
Behavioral Neurology, Department of Neurology, Mayo Clinic, Rochester, MN, USA.
Ronald C
RC
Petersen
Neuropathology, Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
Joseph E
JE
Parisi
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
Dennis W
DW
Dickson
D000367:Age Factors; D000369:Aged, 80 and over; D058227:Amyloidogenic Proteins / Q000378:metabolism; D001284:Atrophy; D003071:Cognition / Q000502:physiology*; D005260:Female; D006624:Hippocampus / Q000473:pathology*; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D016874:Neurofibrillary Tangles / Q000473:pathology*; D024801:Tauopathies / Q000175:diagnosis / Q000473:pathology*; D016875:tau Proteins / Q000378:metabolism*
D058227:Amyloidogenic Proteins; C054369:MAPT protein, human; D016875:tau Proteins
Alzheimer’s disease; Beta-amyloid; Cognition; Hippocampus; MRI; Neurofibrillary tangles; PART; TDP-43; Tauopathy