Tau PET in autosomal dominant Alzheimer’s disease: relationship with cognition, dementia and other biomarkers

Gordon, Brian A.; Blazey, Tyler; Christensen, Jon; Dincer, Aylin; Flores, Shaney; Keefe, Sarah; Chen, Charles; Su, Yi; McDade, Eric; Wang, Guoqiao; Li, Yan; Hassenstab, Jason; Aschenbrenner, Andrew J.; Hornbeck, Russ C.; Jack, Clifford R.; Ances, Beau M.; Berman, Sarah B.; Brosch, Jared R.; Galasko, Douglas; Gauthier, Serge; Lah, James J.; Masellis, Mario; Dyck, Christopher H. van; Mintun, Mark A.; Klein, Gregory; Ristić, Smiljana; Cairns, Nigel J.; Marcus, Daniel S.; Xiong, Chengjie; Holtzman, David M.; Raichle, Marcus E.; Morris, John C.; Bateman, Randall J.; Benzinger, Tammie L.S.

doi:10.1093/brain/awz019

Cited by 143 publications

(178 citation statements)

References 70 publications

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“…The spread of tau beyond the MTL to the parietal lobe and other regions may be a critical milestone in the progression of AD. The early changes observed in the MPL in this study coincide with a recent report of the earliest tau deposition found in medial parietal regions (precuneus and isthmus cingulate) in autosomal dominant AD (Gordon et al, 2019). Considering that a 0.2 SD increase in MPL tau can potentially be detected several years before A-positivity (Figure 4), these data support the use of primary prevention trials against A where treatment is initiated years before the current threshold for A-positivity, if treatment efficacy relies on early intervention, prior to the development of tau pathology.…”

Section: A Pet and Estimation Of Tfa+supporting

confidence: 91%

Time between milestone events in the Alzheimer’s disease amyloid cascade

Insel

Donohue

Berron

et al. 2020

Preprint

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Objective: Estimate the time-course of the spread of key pathological markers and the onset of cognitive dysfunction in Alzheimer's disease.Methods: In a cohort of 336 older adults, ranging in cognitive functioning, we estimated the time of initial changes of A, tau, and decreases in cognition with respect to the time of A-positivity.Results: Small effect sizes of change in CSF A42 and regional A PET were estimated to occur several decades before A-positivity. Increases in CSF tau occurred 11-12 years before A-positivity. Temporoparietal tau PET showed increases 4-5 years before Apositivity. Subtle cognitive dysfunction was observed 7-9 years before A-positivity.Conclusions: Increases in tau and cognitive dysfunction occur years before the presence of significant A. Explicit estimates of the time for these events provide a clearer picture of the time course of the amyloid cascade and identify potential windows for specific treatments. O. 2017. Earliest accumulation of β-amyloid occurs within the default-mode network and concurrently affects brain connectivity. Nat Commun 8.

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Section: A Pet and Estimation Of Tfa+supporting

confidence: 91%

Time between milestone events in the Alzheimer’s disease amyloid cascade

Insel

Donohue

Berron

et al. 2020

Preprint

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“…Based on prior cross-sectional and longitudinal literature we expected that higher baseline tau PET, worse baseline cognitive performance, older age, APOE ε4, greater white matter hyperintensity, and lower cortical thickness might independently predict higher tau accumulation rates in unimpaired individuals ( Lim et al , 2014 ; Cho et al , 2016 a , 2019 ; Scholl et al , 2016 ; Donohue et al , 2017 ; Maass et al , 2017 ; Mishra et al , 2017 ; Mormino et al , 2017 ; Chiotis et al , 2018 ; Gordon et al , 2019 ; Knopman et al , 2019 ; Pontecorvo et al , 2019 ). The fact that these were not independent predictors in this analysis ( Fig.…”

Section: Discussionmentioning

confidence: 99%

Predicting future rates of tau accumulation on PET

Jack

Wiste

Weigand

et al. 2020

Brain

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Clinical trials with anti-tau drugs will need to target individuals at risk of accumulating tau. Our objective was to identify variables available in a research setting that predict future rates of tau PET accumulation separately among individuals who were either cognitively unimpaired or cognitively impaired. All 337 participants had: a baseline study visit with MRI, amyloid PET, and tau PET exams, at least one follow-up tau PET exam; and met clinical criteria for membership in one of two clinical diagnostic groups: cognitively unimpaired (n = 203); or cognitively impaired (n = 134, a combined group of participants with either mild cognitive impairment or dementia with Alzheimer’s clinical syndrome). Our primary analyses were in these two clinical groups; however, we also evaluated subgroups dividing the unimpaired group by normal/abnormal amyloid PET and the impaired group by clinical phenotype (mild cognitive impairment, amnestic dementia, and non-amnestic dementia). Linear mixed effects models were used to estimate associations between age, sex, education, APOE genotype, amyloid and tau PET standardized uptake value ratio (SUVR), cognitive performance, cortical thickness, and white matter hyperintensity volume at baseline, and the rate of subsequent tau PET accumulation. Log-transformed tau PET SUVR was used as the response and rates were summarized as annual per cent change. A temporal lobe tau PET meta-region of interest was used. In the cognitively unimpaired group, only higher baseline amyloid PET was a significant independent predictor of higher tau accumulation rates (P < 0.001). Higher rates of tau accumulation were associated with faster rates of cognitive decline in the cognitively unimpaired subgroup with abnormal amyloid PET (P = 0.03), but among the subgroup with normal amyloid PET. In the cognitively impaired group, younger age (P = 0.02), higher baseline amyloid PET (P = 0.05), APOE ε4 (P = 0.05), and better cognitive performance (P = 0.05) were significant independent predictors of higher tau accumulation rates. Among impaired individuals, faster cognitive decline was associated with faster rates of tau accumulation (P = 0.01). While we examined many possible predictor variables, our results indicate that screening of unimpaired individuals for potential inclusion in anti-tau trials may be straightforward because the only independent predictor of high tau rates was amyloidosis. In cognitively impaired individuals, imaging and clinical variables consistent with early onset Alzheimer’s disease phenotype were associated with higher rates of tau PET accumulation suggesting this may be a highly advantageous group in which to conduct proof-of-concept clinical trials that target tau-related mechanisms. The nature of the dementia phenotype (amnestic versus non-amnestic) did not affect this conclusion.

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“…The ROIs were defined according to areas of early vs late neurodegeneration and tau deposition in the literature and our previous work. 3,14,[28][29][30][31]…”

Section: Mri Scanningmentioning

confidence: 99%

Association of Longitudinal Changes in Cerebrospinal Fluid Total Tau and Phosphorylated Tau 181 and Brain Atrophy With Disease Progression in Patients With Alzheimer Disease

Llibre‐Guerra

Schindler

et al. 2019

JAMA Netw Open

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IMPORTANCE The amyloid/tau/neurodegeneration (A/T/N) framework uses cerebrospinal fluid (CSF) levels of total tau (tTau) as a marker of neurodegeneration and CSF levels of phosphorylated tau 181 (pTau181) as a marker of tau tangles. However, it is unclear whether CSF levels of tTau and pTau181 have similar or different trajectories over the course of Alzheimer disease. OBJECTIVES To examine the rates of change in CSF levels of tTau and pTau181 across the Alzheimer disease course and how the rates of change are associated with brain atrophy as measured by magnetic resonance imaging. DESIGN, SETTING, AND PARTICIPANTS This cohort study was set in tertiary research clinics. Each participant was a member of a pedigree with a known mutation for dominantly inherited Alzheimer disease. Participants were divided into 3 groups on the basis of the presence of a mutation and their Clinical Dementia Rating score. Data analysis was performed in June 2019. MAIN OUTCOMES AND MEASURES Rates of change of CSF tTau and pTau181 levels and their association with the rate of change of brain volume. RESULTS Data from 465 participants (283 mutation carriers and 182 noncarriers) were analyzed. The mean (SD) age of the cohort was 37.8 (11.3) years, and 262 (56.3%) were women. The mean (SD) follow-up duration was 2.7 (1.5) years. Two or more longitudinal CSF and magnetic resonance imaging assessments were available for 160 and 247 participants, respectively. Sixty-five percent of mutation carriers (183) did not have symptoms at baseline (Clinical Dementia Rating score, 0). For mutation carriers, the annual rates of change for CSF tTau and pTau181 became significantly different from 0 approximately 10 years before the estimated year of onset (mean [SE] rates of change, 5.5 [2.8] for tTau [P = .05] and 0.7 [0.3] for pTau 181 [P = .04]) and 15 years before onset (mean [SE] rates of change, 5.4 [3.9] for tTau [P = .17] and 1.1 [0.5] for pTau181 [P = .03]), respectively. The rate of change of pTau181 was positive and increased at the early stages of the disease, showing a positive rate of change starting at 15 estimated years before onset until 5 estimated years before onset (mean [SE], 0.4 [0.3]), followed by a positive but decreasing rate of change at year 0 (mean [SE], 0.1 [0.3]) and then negative rates of change at 5 years (mean [SE], −0.3 [0.4]) and 10 years (mean [SE], −0.6 [0.6]) after symptom onset. In individuals without symptoms (Clinical Dementia Rating score, 0), the rates of change of CSF tTau and pTau181 were negatively associated with brain atrophy (high rates of change in CSF measures were associated with low rates of change in brain volume in asymptomatic stages). After symptom onset (Clinical Dementia Rating score, >0), an increased rate of brain atrophy was not associated with rates of change of levels of both CSF tTau and pTau181. (continued) Key Points Question How do different proposed measurements of tau brain pathologic abnormalities (ie, levels of phosphorylated tau 181 in the cerebrospinal fluid [CSF]) and neurodegenera...

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Tau PET in autosomal dominant Alzheimer’s disease: relationship with cognition, dementia and other biomarkers

Cited by 143 publications

References 70 publications

Time between milestone events in the Alzheimer’s disease amyloid cascade

Time between milestone events in the Alzheimer’s disease amyloid cascade

Predicting future rates of tau accumulation on PET

Association of Longitudinal Changes in Cerebrospinal Fluid Total Tau and Phosphorylated Tau 181 and Brain Atrophy With Disease Progression in Patients With Alzheimer Disease

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