| 1. |
- Cullen, Nicholas C., et al.
(författare)
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Individualized prognosis of cognitive decline and dementia in mild cognitive impairment based on plasma biomarker combinations
- 2021
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Ingår i: Nature Aging. - : Springer Science and Business Media LLC. - 2662-8465. ; 1, s. 114-123
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Tidskriftsartikel (refereegranskat)abstract
- We developed models for individualized risk prediction of cognitive decline in mild cognitive impairment (MCI) using plasma biomarkers of β-amyloid (Aβ), tau and neurodegeneration. A total of 573 patients with MCI from the Swedish BioFINDER study and the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were included in the study. The primary outcomes were longitudinal cognition and conversion to Alzheimer’s disease (AD) dementia. A model combining tau phosphorylated at threonine 181 (P-tau181) and neurofilament light (NfL), but not Aβ42/Aβ40, had the best prognosis performance of all models (area under the curve = 0.88 for 4-year conversion to AD in BioFINDER, validated in ADNI), was stronger than a basic model of age, sex, education and baseline cognition, and performed similarly to cerebrospinal fluid biomarkers. A publicly available online tool for individualized prognosis in MCI based on our combined plasma biomarker models is introduced. Combination of plasma biomarkers may be of high value to identify individuals with MCI who will progress to AD dementia in clinical trials and in clinical practice.
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| 2. |
- Cullen, Nicholas C., et al.
(författare)
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Plasma biomarkers of Alzheimer’s disease improve prediction of cognitive decline in cognitively unimpaired elderly populations
- 2021
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Plasma biomarkers of amyloid, tau, and neurodegeneration (ATN) need to be characterized in cognitively unimpaired (CU) elderly individuals. We therefore tested if plasma measurements of amyloid-β (Aβ)42/40, phospho-tau217 (P-tau217), and neurofilament light (NfL) together predict clinical deterioration in 435 CU individuals followed for an average of 4.8 ± 1.7 years in the BioFINDER study. A combination of all three plasma biomarkers and basic demographics best predicted change in cognition (Pre-Alzheimer’s Clinical Composite; R2 = 0.14, 95% CI [0.12–0.17]; P < 0.0001) and subsequent AD dementia (AUC = 0.82, 95% CI [0.77–0.91], P < 0.0001). In a simulated clinical trial, a screening algorithm combining all three plasma biomarkers would reduce the required sample size by 70% (95% CI [54–81]; P < 0.001) with cognition as trial endpoint, and by 63% (95% CI [53–70], P < 0.001) with subsequent AD dementia as trial endpoint. Plasma ATN biomarkers show usefulness in cognitively unimpaired populations and could make large clinical trials more feasible and cost-effective.
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| 3. |
- Groot, Colin, et al.
(författare)
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Phospho-tau with subthreshold tau-PET predicts increased tau accumulation rates in amyloid-positive individuals
- 2023
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Ingår i: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156. ; 146:4, s. 1580-1591
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Tidskriftsartikel (refereegranskat)abstract
- Different tau biomarkers become abnormal at different stages of Alzheimer's disease, with CSF phospho-tau typically becoming elevated at subthreshold levels of tau-PET binding. To capitalize on the temporal order of tau biomarker-abnormality and capture the earliest changes of tau accumulation, we implemented an observational study design to examine longitudinal changes in Tau-PET, cortical thickness and cognitive decline in amyloid-β-positive (A+) individuals with elevated CSF P-tau levels (P+) but subthreshold Tau-PET retention (T-). To this end, individuals without dementia (i.e., cognitively unimpaired or mild cognitive impairment, N = 231) were selected from the BioFINDER-2 study. Amyloid-β-positive (A+) individuals were categorized into biomarker groups based on cut-offs for abnormal CSF P-tau217 and [18F]RO948 (Tau) PET, yielding groups of tau-concordant-negative (A + P-T-; n = 30), tau-discordant (i.e., A + P+T-; n = 48) and tau-concordant-positive (A + P+T+; n = 18) individuals. In addition, 135 amyloid-β-negative, tau-negative, cognitively unimpaired individuals served as controls. Differences in annual change in regional Tau-PET, cortical thickness and cognition between the groups were assessed using general linear models, adjusted for age, sex, clinical diagnosis and (for cognitive measures only) education. Mean follow-up time was ∼2 years. Longitudinal increase in Tau-PET was faster in the A + P+T- group than in the control and A + P-T- groups across medial temporal and neocortical regions, with the highest accumulation rates in the medial temporal lobe. The A + P+T- group showed a slower rate of increases in tau-PET compared to the A + P+T+ group, primarily in neocortical regions. We did not detect differences in yearly change in cortical thickness or in cognitive decline between the A + P+T- and A + P-T- groups. The A + P+T+ group, however, showed faster cognitive decline compared to all other groups. Altogether, these findings suggest that the A + P+T- biomarker profile in persons without dementia is associated with an isolated effect on increased Tau-PET accumulation rates but not on cortical thinning and cognitive decline. While this suggests that the tau-discordant biomarker profile is not strongly associated with short-term clinical decline, this group does represent an interesting population for monitoring effects of interventions with disease modifying agents on tau accumulation in early Alzheimer's disease, and for examining the emergence of tau aggregates in Alzheimer's disease. Further, we suggest to update the AT(N) criteria for Alzheimer's disease biomarker classification to APT(N).
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| 4. |
- Janelidze, Shorena, et al.
(författare)
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Detecting amyloid positivity in early Alzheimer's disease using combinations of plasma A beta 42/A beta 40 and p-tau
- 2022
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Ingår i: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 18:2, s. 283-293
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: We studied usefulness of combining blood amyloid beta A(beta)42/A beta 40, phosphorylated tau (p-tau)217, and neurofilament light (NfL) to detect abnormal brain A beta deposition in different stages of early Alzheimer's disease (AD). Methods: Plasma biomarkers were measured using mass spectrometry (A beta 42/A beta 40) and immunoassays (p-tau217 and NfL) in cognitively unimpaired individuals (CU, N = 591) and patients with mild cognitive impairment (MCI, N = 304) from two independent cohorts (BioFINDER-1, BioFINDER-2). Results: In CU, a combination of plasma A beta 42/A beta 40 and p-tau217 detected abnormal brain A beta status with area under the curve (AUC) of 0.83 to 0.86. In MCI, the models including p-tau217 alone or A beta 42/A beta 40 and p-tau217 had similar AUCs (0.86-0.88); however, the latter showed improved model fit. The models were implemented in an online application providing individualized risk assessments (https://brainapps.shinyappas.io/PredictAAbplasma/). Discussion:A combination of plasma A beta 42/A beta 40 and p-tau217 discriminated A beta status with relatively high accuracy, whereas p-tau217 showed strongest associations with A beta pathology in MCI but not in CU.
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| 5. |
- Johansson, Maurits, et al.
(författare)
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Mild behavioral impairment and its relation to tau pathology in preclinical Alzheimer's disease
- 2021
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Ingår i: Translational Psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Mild behavioral impairment (MBI) is suggested as risk marker for neurodegenerative diseases, such as Alzheimer's disease (AD). Recently, pathologic tau deposition in the brain has been shown closely related to clinical manifestations, such as cognitive deficits. Yet, associations between tau pathology and MBI have rarely been investigated. It is further debated if MBI precedes cognitive deficits in AD. Here, we explored potential mechanisms by which MBI is related to AD, this by studying associations between MBI and tau in preclinical AD. In all, 50 amyloid-beta -positive cognitively unimpaired subjects (part of the BioFINDER-2 study) underwent MBI-checklist (MBI-C) to assess MBI, and the Alzheimer's Disease Assessment Scale - Cognitive subscale (ADAS-Cog) delayed word recall (ADAS-DR) to assess episodic memory. Early tau pathology was determined using tau-PET ([F-18]RO948 retention in entorhinal cortex/hippocampus) and cerebrospinal fluid (CSF) P-tau(181). Regression models were used to test for associations. We found that higher tau-PET signal in the entorhinal cortex/hippocampus and CSF P-tau(181) levels were associated with higher MBI-C scores (beta =0.010, SE=0.003, p=0.003 and beta =1.263, SE=0.446, p=0.007, respectively). When MBI-C and ADAS-DR were entered together in the regression models, tau-PET (beta =0.009, p=0.009) and CSF P-tau(181) (beta =0.408, p=0.006) were predicted by MBI-C, but not ADAS-DR. We conclude that in preclinical AD, MBI is associated with tau independently from memory deficits. This denotes MBI as an important early clinical manifestation related to tau pathology in AD.
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| 6. |
- Leuzy, Antoine, et al.
(författare)
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A multicenter comparison of [18F]flortaucipir, [18F]RO948, and [18F]MK6240 tau PET tracers to detect a common target ROI for differential diagnosis
- 2021
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Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 48:7, s. 2295-2305
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: This study aims to determine whether comparable target regions of interest (ROIs) and cut-offs can be used across [18F]flortaucipir, [18F]RO948, and [18F]MK6240 tau positron emission tomography (PET) tracers for differential diagnosis of Alzheimer’s disease (AD) dementia vs either cognitively unimpaired (CU) individuals or non-AD neurodegenerative diseases. Methods: A total of 1755 participants underwent tau PET using either [18F]flortaucipir (n = 975), [18F]RO948 (n = 493), or [18F]MK6240 (n = 287). SUVR values were calculated across four theory-driven ROIs and several tracer-specific data-driven (hierarchical clustering) regions of interest (ROIs). Diagnostic performance and cut-offs for ROIs were determined using receiver operating characteristic analyses and the Youden index, respectively. Results: Comparable diagnostic performance (area under the receiver operating characteristic curve [AUC]) was observed between theory- and data-driven ROIs. The theory-defined temporal meta-ROI generally performed very well for all three tracers (AUCs: 0.926–0.996). An SUVR value of approximately 1.35 was a common threshold when using this ROI. Conclusion: The temporal meta-ROI can be used for differential diagnosis of dementia patients with [18F]flortaucipir, [18F]RO948, and [18F]MK6240 tau PET with high accuracy, and that using very similar cut-offs of around 1.35 SUVR. This ROI/SUVR cut-off can also be applied across tracers to define tau positivity.
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| 7. |
- Leuzy, Antoine, et al.
(författare)
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Biomarker-Based Prediction of Longitudinal Tau Positron Emission Tomography in Alzheimer Disease
- 2022
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Ingår i: JAMA Neurology. - : American Medical Association (AMA). - 2168-6149. ; 79:2, s. 149-158
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Tidskriftsartikel (refereegranskat)abstract
- Importance: There is currently no consensus as to which biomarkers best predict longitudinal tau accumulation at different clinical stages of Alzheimer disease (AD). Objective: To describe longitudinal [18F]RO948 tau positron emission tomography (PET) findings across the clinical continuum of AD and determine which biomarker combinations showed the strongest associations with longitudinal tau PET and best optimized clinical trial enrichment. Design, Setting, and Participants: This longitudinal cohort study consecutively enrolled amyloid-β (Aβ)-negative cognitively unimpaired (CU) participants, Aβ-positive CU individuals, Aβ-positive individuals with mild cognitive impairment (MCI), and individuals with AD dementia between September 2017 and November 2020 from the Swedish BioFINDER-2 (discovery cohort) and BioFINDER-1 (validation cohort) studies. Exposures: Baseline plasma and cerebrospinal fluid Aβ42/Aβ40, tau phosphorylated at threonine-217 (p-tau217), p-tau181 and neurofilament light, magnetic resonance imaging, amyloid PET ([18F]flutemetamol), and tau PET ([18F]RO948 in the BioFINDER-2 study; [18F]flortaucipir in the BioFINDER-1 study). Main Outcomes and Measures: Baseline tau PET standardized uptake value ratio (SUVR) and annual percent change in tau PET SUVR across regions of interest derived using a data-driven approach combining clustering and event-based modeling. Regression models were used to examine associations between individual biomarkers and longitudinal tau PET and to identify which combinations best predicted longitudinal tau PET. These combinations were then entered in a power analysis to examine how their use as an enrichment strategy would affect sample size in a simulated clinical trial. Results: Of 343 participants, the mean (SD) age was 72.56 (7.24) years, and 157 (51.1%) were female. The clustering/event-based modeling-based approach identified 5 regions of interest (stages). In Aβ-positive CU individuals, the largest annual increase in tau PET SUVR was seen in stage I (entorhinal cortex, hippocampus, and amygdala; 4.04% [95% CI, 2.67%-5.32%]). In Aβ-positive individuals with MCI and with AD dementia, the greatest increases were seen in stages II (temporal cortical regions; 4.45% [95% CI, 3.41%-5.49%]) and IV (certain frontal regions; 5.22% [95% CI, 3.95%-6.49%]), respectively. In Aβ-negative CU individuals and those with MCI, modest change was seen in stage I (1.38% [95% CI, 0.78%-1.99%] and 1.80% [95% CI, 0.76%-2.84%], respectively). When looking at individual predictors and longitudinal tau PET in the stages that showed most change, plasma p-tau217 (R2= 0.27, P <.005), tau PET (stage I baseline SUVR; R2= 0.13, P <.05) and amyloid PET (R2= 0.10, P <.05) were significantly associated with longitudinal tau PET in stage I in Aβ-positive CU individuals. In Aβ-positive individuals with MCI, plasma p-tau217 (R2= 0.24, P <.005) and tau PET (stage II baseline SUVR; R2= 0.44, P <.001) were significantly associated with longitudinal tau PET in stage II. Findings were replicated in BioFINDER-1 using longitudinal [18F]flortaucipir. For the power analysis component, plasma p-tau217 with tau PET resulted in sample size reductions of 43% (95% CI, 34%-46%; P <.005) in Aβ-positive CU individuals and of 68% (95% CI, 61%-73%; P <.001) in Aβ-positive individuals with MCI. Conclusions and Relevance: In trials using tau PET as the outcome, plasma p-tau217 with tau PET may prove optimal for enrichment in preclinical and prodromal AD. However, plasma p-tau217 was most important in preclinical AD, while tau PET was more important in prodromal AD..
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| 8. |
- Leuzy, Antoine, et al.
(författare)
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Blood-based biomarkers for Alzheimer's disease
- 2022
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Ingår i: EMBO Molecular Medicine. - : EMBO. - 1757-4676 .- 1757-4684. ; 14:1
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Forskningsöversikt (refereegranskat)abstract
- Neurodegenerative disorders such as Alzheimer's disease (AD) represent a mounting public health challenge. As these diseases are difficult to diagnose clinically, biomarkers of underlying pathophysiology are playing an ever-increasing role in research, clinical trials, and in the clinical work-up of patients. Though cerebrospinal fluid (CSF) and positron emission tomography (PET)-based measures are available, their use is not widespread due to limitations, including high costs and perceived invasiveness. As a result of rapid advances in the development of ultra-sensitive assays, the levels of pathological brain- and AD-related proteins can now be measured in blood, with recent work showing promising results. Plasma P-tau appears to be the best candidate marker during symptomatic AD (i.e., prodromal AD and AD dementia) and preclinical AD when combined with Aβ42/Aβ40. Though not AD-specific, blood NfL appears promising for the detection of neurodegeneration and could potentially be used to detect the effects of disease-modifying therapies. This review provides an overview of the progress achieved thus far using AD blood-based biomarkers, highlighting key areas of application and unmet challenges.
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| 9. |
- Leuzy, Antoine, et al.
(författare)
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Comparing the Clinical Utility and Diagnostic Performance of Cerebrospinal Fluid P-Tau181, P-Tau217 and P-Tau231 Assays
- 2021
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Ingår i: Neurology. - 1526-632X. ; 97:17, s. 1681-1694
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND OBJECTIVES: Phosphorylated tau (P-tau) in cerebrospinal fluid (CSF) is considered an important biomarker in Alzheimer's disease (AD) and has been incorporated in recent diagnostic criteria. Several variants exist, including P-tau at threonines 181 (P-tau181), 217 (P-tau217) and 231 (P-tau231). However, no studies have compared their diagnostic performance or association to amyloid-β (Aβ) and Tau positron emission tomography (PET). Understanding which P-tau variant to use remains an important yet answered question. We aimed to compare the diagnostic accuracy of P-tau181, P-tau217 and P-tau231 in CSF for AD and their association with Aβ and Tau-PET.METHODS: 629 subjects from the Swedish BioFINDER-2 study were included (cognitively unimpaired, n=334; Aβ-positive mild cognitive impairment, n=84; AD dementia, n=119; and non-AD disorders, n=92). In addition to P-tau181 and P-tau217 measured using assays with the same detector antibodies from Eli Lilly (P-tau181Lilly, P-tau217Lilly) and P-tau231, we also included P-tau181 measurements from two commonly used assays (Innotest and Elecsys).RESULTS: Though all P-tau variants increased across the AD continuum, P-tau217Lilly showed the greatest dynamic range (13-fold-increase vs 1.9-5.4-fold-increase for other P-tau variants for AD dementia vs non-AD). P-tau217Lilly showed stronger correlations with Aβ- and Tau-PET (P<0.0001). P-tau217Lilly exhibited higher accuracy than other P-tau variants for separating AD dementia from non-AD (AUC, 0.991vs 0.906-0.982, P<0.0001) and for identifying Aβ- (AUC, 0.951 vs 0.816-0.924, P<0.0001) and Tau-PET positivity (AUC, 0.957 vs 0.836-0.938, P<0.0001). Finally, P-tau181Lilly generally performed better than the other P-tau181 assays, (e.g., AD dementia vs non-AD, AUC, 0.976 vs 0.923, P<0.0001).DISCUSSION: CSF P-tau217Lilly seem to be more useful than other included P-tau assays in the work-up of AD. Varied results across P-tau181 assays also highlights the importance of anti-tau antibodies for biomarker performance.CLASSIFICATION OF EVIDENCE: This study provides class II evidence that phosphorylated tau at threonine 217 provides higher diagnostic accuracy for diagnosis of AD dementia than P-tau at threonine 181 or 231.
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| 10. |
- Leuzy, Antoine, et al.
(författare)
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Comparison of Group-Level and Individualized Brain Regions for Measuring Change in Longitudinal Tau Positron Emission Tomography in Alzheimer Disease
- 2023
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Ingår i: JAMA Neurology. - 2168-6149. ; 80:6, s. 614-623
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Tidskriftsartikel (refereegranskat)abstract
- Importance: Longitudinal tau positron emission tomography (PET) is a relevant outcome in clinical trials evaluating disease-modifying therapies in Alzheimer disease (AD). A key unanswered question is whether the use of participant-specific (individualized) regions of interest (ROIs) is superior to conventional approaches where the same ROI (group-level) is used for each participant. Objective: To compare group- and participant-level ROIs in participants at different stages of the AD clinical continuum in terms of annual percentage change in tau-PET standardized uptake value ratio (SUVR) and sample size requirements. Design, Setting, and Participants: This was a longitudinal cohort study with consecutive participant enrollment between September 18, 2017, and November 15, 2021. Included in the analysis were participants with mild cognitive impairment and AD dementia from the prospective and longitudinal Swedish Biomarkers For Identifying Neurodegenerative Disorders Early and Reliably 2 (BioFINDER-2) study; in addition, a validation sample (the AVID 05e, Expedition-3, Alzheimer's Disease Neuroimaging Initiative [ADNI], and BioFINDER-1 study cohorts) was also included. Exposures: Tau PET (BioFINDER-2, [18F]RO948; validation sample, [18F]flortaucipir), 7 group-level (5 data-driven stages, meta-temporal, whole brain), and 5 individualized ROIs. Main Outcomes and Measures: Annual percentage change in tau-PET SUVR across ROIs. Sample size requirements in simulated clinical trials using tau PET as an outcome were also calculated. Results: A total of 215 participants (mean [SD] age, 71.4 (7.5) years; 111 male [51.6%]) from the BioFINDER-2 study were included in this analysis: 97 amyloid-β (Aβ)-positive cognitively unimpaired (CU) individuals, 77 with Aβ-positive mild cognitive impairment (MCI), and 41 with AD dementia. In the validation sample were 137 Aβ-positive CU participants, 144 with Aβ-positive MCI, and 125 with AD dementia. Mean (SD) follow-up time was 1.8 (0.3) years. Using group-level ROIs, the largest annual percentage increase in tau-PET SUVR in Aβ-positive CU individuals was seen in a composite ROI combining the entorhinal cortex, hippocampus, and amygdala (4.29%; 95% CI, 3.42%-5.16%). In individuals with Aβ-positive MCI, the greatest change was seen in the temporal cortical regions (5.82%; 95% CI, 4.67%-6.97%), whereas in those with AD dementia, the greatest change was seen in the parietal regions (5.22%; 95% CI, 3.95%-6.49%). Significantly higher estimates of annual percentage change were found using several of the participant-specific ROIs. Importantly, the simplest participant-specific approach, where change in tau PET was calculated in an ROI that best matched the participant's data-driven disease stage, performed best in all 3 subgroups. For the power analysis, sample size reductions for the participant-specific ROIs ranged from 15.94% (95% CI, 8.14%-23.74%) to 72.10% (95% CI, 67.10%-77.20%) compared with the best-performing group-level ROIs. Findings were replicated using [18F]flortaucipir. Conclusions and Relevance: Finding suggest that certain individualized ROIs carry an advantage over group-level ROIs for assessing longitudinal tau changes and increase the power to detect treatment effects in AD clinical trials using longitudinal tau PET as an outcome.
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