JAMA network open · 2025
Abnormal Amyloid-β Duration, Tau, and Neurodegeneration in Cranial Images.
СтатьяПоддержка NIH: внешняя программаНазвание и аннотация: Перевод в очереди
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Stephenson Henry Gilreath, Langhough Rebecca, Jonaitis Erin, Du Lianlian, Van Hulle Carol, Chin Nathaniel A, Okonkwo Ozioma C, Carlsson Cynthia M, Asthana Sanjay, Christian Bradley T, Johnson Sterling C, Bendlin Barbara B, Betthauser Tobey J
Аннотация
IMPORTANCE: It is unclear whether the duration of amyloid-β (Aβ) pathology is associated with neurodegeneration and whether this depends on the presence of tau.
OBJECTIVE: To examine the association of longitudinal atrophy with Aβ positron emission tomography (PET)-positivity (Aβ+) and the estimated duration of Aβ+ (Aβ+ duration), controlling for tau-positivity.
DESIGN, SETTING, AND PARTICIPANTS: Data for this longitudinal cohort study were drawn from the Wisconsin Registry for Alzheimer Prevention and the Wisconsin Alzheimer Disease Research Center Clinical Core Study. Participants who had 2 or more magnetic resonance imaging (MRI) visits, 1 Pittsburgh compound B (PiB) PET visit, and 1 MK-6240 PET visit with other covariates available were included. A replication analysis was conducted using data from the OASIS-3 dataset. All data were collected between June 1, 2009, and January 22, 2025. Follow-up times ranged from 1.0 to 13.0 years (median [IQR], 8.8 [5.9-10.6] years).
EXPOSURES: Sampled iterative local approximation (SILA)-estimated PiB PET uptake at baseline MRI was used to estimate Aβ+ and its duration at baseline MRI. MK-6240 PET uptake in the entorhinal cortex was used to create tau-positive and tau-negative groups using a threshold of 1.27 standardized uptake value ratio.
MAIN OUTCOMES AND MEASURES: SILA-based modeling of PiB PET data was used to obtain estimated Aβ+ duration at baseline MRI age. Linear mixed-effects models tested differences in atrophy between Aβ+ vs Aβ- individuals and with Aβ+ duration, controlling for individuals who were tau-positive (measured via MK-6240 tau PET) at their most recent PET scan within their MRI visits. Z-scored volumes in temporo-parietal regions of interest associated with AD dementia were assessed via a robust normative approach.
RESULTS: A total of 95 Aβ+ (median [IQR] age, 66.4 [61.1-70.4] years; 59 female [62.11%]) and 275 Aβ- (median [IQR] age, 60.2 [55.7-64.6] years; 183 [66.55%] female) individuals were included. Aβ+ (partial η2, 0.015-0.043) and tau-positivity (partial η2, 0.018-0.100) were independently associated with neurodegeneration, with generally small effect sizes. Aβ+ duration was associated with atrophy in a greater number of regions of interest than Aβ+ status alone with somewhat larger effect sizes (partial η2, 0.013-0.056). Results were mostly similar in the OASIS-3 dataset.
CONCLUSIONS AND RELEVANCE: In this longitudinal cohort study, subtle neurodegeneration was observed soon after the onset of Aβ pathology. These results may be consistent with Aβ pathology as a pathological state.
OBJECTIVE: To examine the association of longitudinal atrophy with Aβ positron emission tomography (PET)-positivity (Aβ+) and the estimated duration of Aβ+ (Aβ+ duration), controlling for tau-positivity.
DESIGN, SETTING, AND PARTICIPANTS: Data for this longitudinal cohort study were drawn from the Wisconsin Registry for Alzheimer Prevention and the Wisconsin Alzheimer Disease Research Center Clinical Core Study. Participants who had 2 or more magnetic resonance imaging (MRI) visits, 1 Pittsburgh compound B (PiB) PET visit, and 1 MK-6240 PET visit with other covariates available were included. A replication analysis was conducted using data from the OASIS-3 dataset. All data were collected between June 1, 2009, and January 22, 2025. Follow-up times ranged from 1.0 to 13.0 years (median [IQR], 8.8 [5.9-10.6] years).
EXPOSURES: Sampled iterative local approximation (SILA)-estimated PiB PET uptake at baseline MRI was used to estimate Aβ+ and its duration at baseline MRI. MK-6240 PET uptake in the entorhinal cortex was used to create tau-positive and tau-negative groups using a threshold of 1.27 standardized uptake value ratio.
MAIN OUTCOMES AND MEASURES: SILA-based modeling of PiB PET data was used to obtain estimated Aβ+ duration at baseline MRI age. Linear mixed-effects models tested differences in atrophy between Aβ+ vs Aβ- individuals and with Aβ+ duration, controlling for individuals who were tau-positive (measured via MK-6240 tau PET) at their most recent PET scan within their MRI visits. Z-scored volumes in temporo-parietal regions of interest associated with AD dementia were assessed via a robust normative approach.
RESULTS: A total of 95 Aβ+ (median [IQR] age, 66.4 [61.1-70.4] years; 59 female [62.11%]) and 275 Aβ- (median [IQR] age, 60.2 [55.7-64.6] years; 183 [66.55%] female) individuals were included. Aβ+ (partial η2, 0.015-0.043) and tau-positivity (partial η2, 0.018-0.100) were independently associated with neurodegeneration, with generally small effect sizes. Aβ+ duration was associated with atrophy in a greater number of regions of interest than Aβ+ status alone with somewhat larger effect sizes (partial η2, 0.013-0.056). Results were mostly similar in the OASIS-3 dataset.
CONCLUSIONS AND RELEVANCE: In this longitudinal cohort study, subtle neurodegeneration was observed soon after the onset of Aβ pathology. These results may be consistent with Aβ pathology as a pathological state.