title: Tau PET patterns mirror clinical and neuroanatomical variability in Alzheimer's disease.
abstract: SEE SARAZIN ET AL DOI101093/BRAIN/AWW041 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: The advent of the positron emission tomography tracer (18)F-AV1451 provides the unique opportunity to visualize the regional distribution of tau pathology in the living human brain. In this study, we tested the hypothesis that tau pathology is closely linked to symptomatology and patterns of glucose hypometabolism in Alzheimer's disease, in contrast to the more diffuse distribution of amyloid-β pathology. We included 20 patients meeting criteria for probable Alzheimer's disease dementia or mild cognitive impairment due to Alzheimer's disease, presenting with a variety of clinical phenotypes, and 15 amyloid-β-negative cognitively normal individuals, who underwent (18)F-AV1451 (tau), (11)C-PiB (amyloid-β) and (18)F-FDG (glucose metabolism) positron emission tomography, apolipoprotein E (APOE) genotyping and neuropsychological testing. Voxel-wise contrasts against controls (at P < 0.05 family-wise error corrected) showed that (18)F-AV1451 and (18)F-FDG patterns in patients with posterior cortical atrophy ('visual variant of Alzheimer's disease', n = 7) specifically targeted the clinically affected posterior brain regions, while (11)C-PiB bound diffusely throughout the neocortex. Patients with an amnestic-predominant presentation (n = 5) showed highest (18)F-AV1451 retention in medial temporal and lateral temporoparietal regions. Patients with logopenic variant primary progressive aphasia ('language variant of Alzheimer's disease', n = 5) demonstrated asymmetric left greater than right hemisphere (18)F-AV1451 uptake in three of five patients. Across 30 FreeSurfer-defined regions of interest in 16 Alzheimer's disease patients with all three positron emission tomography scans available, there was a strong negative association between (18)F-AV1451 and (18)F-FDG uptake (Pearson's r = -0.49 ± 0.07, P < 0.001) and less pronounced positive associations between (11)C-PiB and (18)F-FDG (Pearson's r = 0.16 ± 0.09, P < 0.001) and (18)F-AV1451 and (11)C-PiB (Pearson's r = 0.18 ± 0.09, P < 0.001). Voxel-wise linear regressions thresholded at P < 0.05 (uncorrected) showed that, across all patients, younger age was associated with greater (18)F-AV1451 uptake in wide regions of the neocortex, while older age was associated with increased (18)F-AV1451 in the medial temporal lobe. APOE ϵ4 carriers showed greater temporal and parietal (18)F-AV1451 uptake than non-carriers. Finally, worse performance on domain-specific neuropsychological tests was associated with greater (18)F-AV1451 uptake in key regions implicated in memory (medial temporal lobes), visuospatial function (occipital, right temporoparietal cortex) and language (left > right temporoparietal cortex). In conclusion, tau imaging-contrary to amyloid-β imaging-shows a strong regional association with clinical and anatomical heterogeneity in Alzheimer's disease. Although preliminary, these results are consistent with and expand upon findings from post-mortem, animal and cerebrospinal fluid studies, and suggest that the pathological aggregation of tau is closely linked to patterns of neurodegeneration and clinical manifestations of Alzheimer's disease.
authors.affiliation: Memory and Aging Center, University of California San Francisco, San Francisco, CA, USA Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, CA, USA Department of Neurology and Alzheimer Center, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands r.ossenkoppele@vumc.nl.
authors.forename: Rik
authors.initials: R
authors.lastname: Ossenkoppele
authors.affiliation: Memory and Aging Center, University of California San Francisco, San Francisco, CA, USA Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, CA, USA.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Schonhaut
authors.affiliation: Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, CA, USA MedTech West and the Department of Clinical Neuroscience and Rehabilitation, University of Gothenburg, Sweden.
authors.forename: Michael
authors.initials: M
authors.lastname: Schöll
authors.affiliation: Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, CA, USA.
authors.forename: Samuel N
authors.initials: SN
authors.lastname: Lockhart
authors.affiliation: Memory and Aging Center, University of California San Francisco, San Francisco, CA, USA Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, CA, USA.
authors.forename: Nagehan
authors.initials: N
authors.lastname: Ayakta
authors.affiliation: Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
authors.forename: Suzanne L
authors.initials: SL
authors.lastname: Baker
authors.affiliation: Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
authors.forename: James P
authors.initials: JP
authors.lastname: O'Neil
authors.affiliation: Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
authors.forename: Mustafa
authors.initials: M
authors.lastname: Janabi
authors.affiliation: Memory and Aging Center, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Andreas
authors.initials: A
authors.lastname: Lazaris
authors.affiliation: Memory and Aging Center, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Averill
authors.initials: A
authors.lastname: Cantwell
authors.affiliation: Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, CA, USA.
authors.forename: Jacob
authors.initials: J
authors.lastname: Vogel
authors.affiliation: Memory and Aging Center, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Miguel
authors.initials: M
authors.lastname: Santos
authors.affiliation: Memory and Aging Center, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Zachary A
authors.initials: ZA
authors.lastname: Miller
authors.affiliation: Memory and Aging Center, University of California San Francisco, San Francisco, CA, USA Rocky Mountain Alzheimer's Disease Center, Departments of Neurosurgery and Neurology, University of Colorado Denver Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: Brianne M
authors.initials: BM
authors.lastname: Bettcher
authors.affiliation: Memory and Aging Center, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Keith A
authors.initials: KA
authors.lastname: Vossel
authors.affiliation: Memory and Aging Center, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Joel H
authors.initials: JH
authors.lastname: Kramer
authors.affiliation: Memory and Aging Center, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Maria L
authors.initials: ML
authors.lastname: Gorno-Tempini
authors.affiliation: Memory and Aging Center, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Miller
authors.affiliation: Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, CA, USA Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Jagust
authors.affiliation: Memory and Aging Center, University of California San Francisco, San Francisco, CA, USA Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, CA, USA.
authors.forename: Gil D
authors.initials: GD
authors.lastname: Rabinovici
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism; D000544:Alzheimer Disease / Q000000981:diagnostic imaging / Q000378:metabolism*; D000682:Amyloid / Q000378:metabolism*; D000814:Aniline Compounds; D001057:Apolipoproteins E / Q000235:genetics; D052160:Benzothiazoles / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D002243:Carbolines / Q000378:metabolism; D016022:Case-Control Studies; D060825:Cognitive Dysfunction / Q000000981:diagnostic imaging / Q000378:metabolism*; D005260:Female; D019788:Fluorodeoxyglucose F18 / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D059906:Neuroimaging; D009483:Neuropsychological Tests; D049268:Positron-Emission Tomography; D013844:Thiazoles; D016875:tau Proteins / Q000378:metabolism*
chemical_list: C475519:2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole; D000682:Amyloid; D000814:Aniline Compounds; D001057:Apolipoproteins E; D052160:Benzothiazoles; D002243:Carbolines; D013844:Thiazoles; D016875:tau Proteins; D019788:Fluorodeoxyglucose F18; D005947:Glucose; C000591008:7-(6-fluoropyridin-3-yl)-5H-pyrido(4,3-b)indole
keywords: APOE; AV1451 PET; Alzheimer’s disease; cognition; tau