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Longitudinal tau PET in ageing and Alzheimer’s disease
Open accessAbstract
See Hansson and Mormino (doi:10.1093/brain/awy065) for a scientific commentary on this article.Our objective was to compare different whole-brain and region-specific measurements of within-person change on serial tau PET and evaluate its utility for clinical trials. We studied 126 individuals: 59 cognitively unimpaired with normal amyloid, 37 cognitively unimpaired with abnormal amyloid, and 30 cognitively impaired with an amnestic phenotype and abnormal amyloid. All had baseline amyloid PET and two tau PET, MRI, and clinical assessments. We compared the topography across all cortical regions of interest of tau PET accumulation rates and the rates of four different whole-brain or region-specific meta-regions of interest among the three clinical groups. We computed sample size estimates for change in tau PET, cortical volume, and memory/mental status indices for use as outcome measures in clinical trials. The cognitively unimpaired normal amyloid group had no observable tau accumulation throughout the brain. Tau accumulation rates in cognitively unimpaired abnormal amyloid were low [0.006 standardized uptake value ratio (SUVR), 0.5%, per year] but greater than rates in the cognitively unimpaired normal amyloid group in the basal and mid-temporal, retrosplenial, posterior cingulate, and entorhinal regions of interest. Thus, the earliest elevation in accumulation rates was widespread and not confined to the entorhinal cortex. Tau accumulation rates in the cognitively impaired abnormal amyloid group were 0.053 SUVR (3%) per year and greater than rates in cognitively unimpaired abnormal amyloid in all cortical areas except medial temporal. Rates of accumulation in the four meta-regions of interest differed but only slightly from one another. Among all tau PET meta-regions of interest, sample size estimates were smallest for a temporal lobe composite within cognitively unimpaired abnormal amyloid and for the late Alzheimer's disease meta-region of interest within cognitively impaired abnormal amyloid. The ordering of the sample size estimates by outcome measure was MRI < tau PET < cognitive measures. At a group-wise level, observable rates of short-term serial tau accumulation were only seen in the presence of abnormal amyloid. As disease progressed to clinically symptomatic stages (cognitively impaired abnormal amyloid), observable rates of tau accumulation were seen uniformly throughout the brain providing evidence that tau does not accumulate in one area at a time or in start-stop, stepwise sequence. The information captured by rate measures in different meta-regions of interest, even those with little topographic overlap, was similar. The implication is that rate measurements from simple meta-regions of interest, without the need for Braak-like staging, may be sufficient to capture progressive within-person accumulation of pathologic tau. Tau PET SUVR measures should be an efficient outcome measure in disease-modifying clinical trials.
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“Longitudinal deposition in tau PET is associated with baseline levels tau and Aβ deposition is a necessary antecedent for spread of tau beyond the temporal lobe in AD [189, 190] (Fig. 3).”
From The use of neuroimaging techniques in the early and differential diagnosis of dementia (2023) · cites this paper as [189]
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“Brain imaging has helped to improve the biological classification of AD by allowing proposed classifications based on pathology, like the ATN staging, to be applied in vivo and opened a new window of therapeutic intervention at preclinical stages.”
From The use of neuroimaging techniques in the early and differential diagnosis of dementia (2023) · cites this paper as [189]
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“Longitudinal deposition in tau PET is associated with baseline levels tau and Aβ deposition is a necessary antecedent for spread of tau beyond the temporal lobe in AD [189, 190] (Fig. 3).”
From The use of neuroimaging techniques in the early and differential diagnosis of dementia (2023) · cites this paper as [189]
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“Such imaging has also improved our understanding of the role of mixed pathologies in dementia [102, 175, 189, 247].”
From The use of neuroimaging techniques in the early and differential diagnosis of dementia (2023) · cites this paper as [189]
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“In contrast, cross-sectional and longitudinal human cohort studies of biomarkers support a scenario in which amyloid pathology (Aβ42 lowering in CSF, positive amyloid PET imaging) precedes tau pathology (tau-PET and phospho-Tau elevation in CSF) and then neurodegeneration 126-128 .”
From The amyloid hypothesis in Alzheimer disease: new insights from new therapeutics (2022) · cites this paper as [127]
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“Antemortem diagnosis also relies heavily on the presence of Aβ and tau, either as measured in the spinal fluid or imaged using positron emission tomography (PET) [7–10].”
From Systems-based proteomics to resolve the biology of Alzheimer’s disease beyond amyloid and tau (2021) · cites this paper as [7]
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“However, that fact that elevated rates in CU A + relative to CU A were not confined to the entorhinal cortex suggests that early tau accumulation may not be as spatially restricted as implied in Braak staging (Braak and Braak, 1991).”
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- Bejanin, Do neurodegeneration or amyloid pathology contribute to the relationship between AV-1451 and cognitive symptoms in Alzhimer's disease?, 252
- La Joie, Relationships between AV1451-PET and CSF biomarkers in a heterogeneous clinical sample, 258
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Metadata
- Authors
- Jack, C. R., Wiste, H. J., Schwarz, C. G., Lowe, V. J., Senjem, M. L., Vemuri, P., Weigand, S. D., Therneau, T. M., Knopman, D. S., Gunter, J. L., Jones, D. T., Graff-Radford, J., Kantarci, K., Roberts, R. O., Mielke, M. M., Machulda, M. M., & Petersen, R. C.
- Affiliations
- Mayo Clinic (US)
- Department of Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
- Corresponding author
- Jack, Clifford R
- ORCID
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2018-03-12
- Volume
- 141
- Issue
- 5
- Pages
- 1517-1528
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- PMC
- PMC5917767
- OpenAlex
- W2791135917
- Cited by
- 452
- References
- 54
- Citations by year
- 2026: 36 · 2025: 56 · 2024: 61 · 2023: 49 · 2022: 55 · 2021: 75 · 2020: 56 · 2019: 46 · 2018: 18
- FWCI
- 37.75
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Brain (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- NIH (R01 AG011378, R01 AG041851, U01 AG006786, R01 AG034676, R01 NS097495, P50 AG016574)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Medical Imaging Techniques and Applications
- Keywords
- tau PET, Alzheimer's disease, amyloid PET, within-person change, sample size determination, clinical trial outcome measures, amyloid-beta, entorhinal cortex, temporal lobe, cognitive impairment, cortical volume, memory decline, brain atrophy
- MeSH terms
- Aged, Aged, 80 and over, Aging, Alzheimer Disease, Brain, Female, Humans, Longitudinal Studies, Magnetic Resonance Imaging, Male, Middle Aged, Psychiatric Status Rating Scales, tau Proteins, Positron-Emission Tomography, Cognitive Dysfunction
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