| 1. |
- Boccardi, M., et al.
(author)
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The strategic biomarker roadmap for the validation of Alzheimer's diagnostic biomarkers: methodological update
- 2021
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In: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 48
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Journal article (peer-reviewed)abstract
- Background The 2017 Alzheimer's disease (AD) Strategic Biomarker Roadmap (SBR) structured the validation of AD diagnostic biomarkers into 5 phases, systematically assessing analytical validity (Phases 1-2), clinical validity (Phases 3-4), and clinical utility (Phase 5) through primary and secondary Aims. This framework allows to map knowledge gaps and research priorities, accelerating the route towards clinical implementation. Within an initiative aimed to assess the development of biomarkers of tau pathology, we revised this methodology consistently with progress in AD research. Methods We critically appraised the adequacy of the 2017 Biomarker Roadmap within current diagnostic frameworks, discussed updates at a workshop convening the Alzheimer's Association and 8 leading AD biomarker research groups, and detailed the methods to allow consistent assessment of aims achievement for tau and other AD diagnostic biomarkers. Results The 2020 update applies to all AD diagnostic biomarkers. In Phases 2-3, we admitted a greater variety of study designs (e.g., cross-sectional in addition to longitudinal) and reference standards (e.g., biomarker confirmation in addition to clinical progression) based on construct (in addition to criterion) validity. We structured a systematic data extraction to enable transparent and formal evidence assessment procedures. Finally, we have clarified issues that need to be addressed to generate data eligible to evidence-to-decision procedures. Discussion This revision allows for more versatile and precise assessment of existing evidence, keeps up with theoretical developments, and helps clinical researchers in producing evidence suitable for evidence-to-decision procedures. Compliance with this methodology is essential to implement AD biomarkers efficiently in clinical research and diagnostics.
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| 2. |
- Groot, Colin, et al.
(author)
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A biomarker profile of elevated CSF p-tau with normal tau PET is associated with increased tau accumulation rates on PET in early Alzheimer’s disease
- 2022
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In: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 18:S1
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Journal article (peer-reviewed)abstract
- Background: Different tau biomarkers become abnormal at different stages of Alzheimer’s disease (AD), with CSF p-tau typically being 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 selected a group of amyloid-β-positive (A+) individuals with elevated CSF p-tau levels but negative tau-PET scans and assessed longitudinal changes in tau-PET, cortical thickness and cognitive decline. Method: Individuals without dementia (i.e., cognitively unimpaired (CU) or mild cognitive impairment, n=231) were selected from the BioFINDER-2 study. These subjects were categorized into biomarker groups based on Gaussian mixture modelling to determine cut-offs for abnormal CSF Aβ42/40 (A; <0.078), CSF p-tau217 (P; >110 pg/ml) and [18F]RO948 tau-PET SUVR within a temporal meta-ROI (T; SUVR >1.40). Resulting groups were: A+P-T- (concordant, n=30), A+P+T- (discordant, n=48) and A+P+T+ (concordant, n=18). We additionally used 135 A- CU individuals (A- CU) as a reference group (Tables 1 and 2). Differences in annual change in regional tau-PET SUVR, cortical thickness and cognition between the A+P+T- group and the other groups were assessed using general linear models, adjusted for age, sex, clinical diagnosis and (for cognitive measures) education. Result: Longitudinal change in tau-PET was faster in the A+P+T- group than in the A- CU and A+P-T- groups across medial temporal and neocortical regions, with the medial temporal increases being more pronounced. The A+P+T- group showed slower rate of increases in tau-PET compared to the A+P+T+ group, primarily in neocortical regions (Figures 1 and 2). We did not detect differences in yearly change in cortical thickness (Figure 3) or in cognitive decline (Figure 3) 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. Conclusion: These findings suggest that the A+P+T- biomarker profile is associated with early tau accumulation, and with relative sparing of cortical thinning and cognitive decline compared to A+P+T+ individuals. Therefore, the A+P+T- group represents an interesting target-group for early anti-tau interventions and for examining the emergence of tau aggregates in early AD.
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| 3. |
- Groot, Colin, et al.
(author)
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Phospho-tau with subthreshold tau-PET predicts increased tau accumulation rates in amyloid-positive individuals
- 2023
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In: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156. ; 146:4, s. 1580-1591
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Journal article (peer-reviewed)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. |
- Leuzy, Antoine, et al.
(author)
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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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In: 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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Journal article (peer-reviewed)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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| 5. |
- Leuzy, Antoine, et al.
(author)
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Biomarker-Based Prediction of Longitudinal Tau Positron Emission Tomography in Alzheimer Disease
- 2022
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In: JAMA Neurology. - : American Medical Association (AMA). - 2168-6149. ; 79:2, s. 149-158
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Journal article (peer-reviewed)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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| 6. |
- Leuzy, Antoine, et al.
(author)
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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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In: JAMA Neurology. - 2168-6149. ; 80:6, s. 614-623
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Journal article (peer-reviewed)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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| 7. |
- Leuzy, Antoine, et al.
(author)
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Derivation and utility of an A beta-PET pathology accumulation index to estimate A beta load
- 2020
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In: Neurology. - : LIPPINCOTT WILLIAMS & WILKINS. - 0028-3878 .- 1526-632X. ; 95:21, s. E2834-E2844
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Journal article (peer-reviewed)abstract
- Objective To evaluate a novel beta-amyloid (A beta)-PET-based quantitative measure (A beta accumulation index [A beta index]), including the assessment of its ability to discriminate between participants based on A beta status using visual read, CSF A beta(42)/A beta(40), and post-mortem neuritic plaque burden as standards of truth. Methods One thousand one hundred twenty-one participants (with and without cognitive impairment) were scanned with A beta-PET: Swedish BioFINDER, n = 392, [F-18]flutemetamol; Alzheimer's Disease Neuroimaging Initiative (ADNI), n = 692, [F-18]florbetapir; and a phase 3 end-of-life study, n = 100, [F-18] flutemetamol. The relationships between A beta index and standardized uptake values ratios (SUVR) from A beta-PET were assessed. The diagnostic performances of A beta index and SUVR were compared with visual reads, CSF A beta(42)/A beta(40), and A beta histopathology used as reference standards. Results Strong associations were observed between A beta index and SUVR (R-2: BioFINDER 0.951, ADNI 0.943, end-of-life, 0.916). Both measures performed equally well in differentiating A beta-positive from A beta-negative participants, with areas under the curve (AUCs) of 0.979 to 0.991 to detect abnormal visual reads, AUCs of 0.961 to 0.966 to detect abnormal CSF A beta(42)/A beta(40), and AUCs of 0.820 to 0.823 to detect abnormal A beta histopathology. Both measures also showed a similar distribution across postmortem-based A beta phases (based on anti-A beta 4G8 antibodies). Compared to models using visual read alone, the addition of the A beta index resulted in a significant increase in AUC and a decrease in Akaike information criterion to detect abnormal A beta histopathology. Conclusion The proposed A beta index showed a tight association to SUVR and carries an advantage over the latter in that it does not require the definition of regions of interest or the use of MRI. A beta index may thus prove simpler to implement in clinical settings and may also facilitate the comparison of findings using different A beta-PET tracers. Classification of evidence This study provides Class III evidence that the A beta accumulation index accurately differentiates A beta-positive from A beta-negative participants compared to A beta-PET visual reads, CSF A beta(42)/A beta(40), and A beta histopathology.
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| 8. |
- Leuzy, Antoine, et al.
(author)
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Derivation and utility of an Aβ-PET pathology accumulation index to estimate Aβ load
- 2020
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In: Neurology. - 1526-632X. ; 95:21, s. 2834-2844
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Journal article (peer-reviewed)abstract
- OBJECTIVE: To evaluate a novel β-amyloid (Aβ)-PET-based quantitative measure (Aβ accumulation index [Aβ index]), including the assessment of its ability to discriminate between participants based on Aβ status using visual read, CSF Aβ42/Aβ40, and post-mortem neuritic plaque burden as standards of truth. METHODS: One thousand one hundred twenty-one participants (with and without cognitive impairment) were scanned with Aβ-PET: Swedish BioFINDER, n = 392, [18F]flutemetamol; Alzheimer's Disease Neuroimaging Initiative (ADNI), n = 692, [18F]florbetapir; and a phase 3 end-of-life study, n = 100, [18F]flutemetamol. The relationships between Aβ index and standardized uptake values ratios (SUVR) from Aβ-PET were assessed. The diagnostic performances of Aβ index and SUVR were compared with visual reads, CSF Aβ42/Aβ40, and Aβ histopathology used as reference standards. RESULTS: Strong associations were observed between Aβ index and SUVR (R2: BioFINDER 0.951, ADNI 0.943, end-of-life, 0.916). Both measures performed equally well in differentiating Aβ-positive from Aβ-negative participants, with areas under the curve (AUCs) of 0.979 to 0.991 to detect abnormal visual reads, AUCs of 0.961 to 0.966 to detect abnormal CSF Aβ42/Aβ40, and AUCs of 0.820 to 0.823 to detect abnormal Aβ histopathology. Both measures also showed a similar distribution across postmortem-based Aβ phases (based on anti-Aβ 4G8 antibodies). Compared to models using visual read alone, the addition of the Aβ index resulted in a significant increase in AUC and a decrease in Akaike information criterion to detect abnormal Aβ histopathology. CONCLUSION: The proposed Aβ index showed a tight association to SUVR and carries an advantage over the latter in that it does not require the definition of regions of interest or the use of MRI. Aβ index may thus prove simpler to implement in clinical settings and may also facilitate the comparison of findings using different Aβ-PET tracers. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that the Aβ accumulation index accurately differentiates Aβ-positive from Aβ-negative participants compared to Aβ-PET visual reads, CSF Aβ42/Aβ40, and Aβ histopathology.
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| 9. |
- Leuzy, Antoine, et al.
(author)
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Diagnostic Performance of RO948 F 18 Tau Positron Emission Tomography in the Differentiation of Alzheimer Disease from Other Neurodegenerative Disorders
- 2020
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In: JAMA Neurology. - : American Medical Association (AMA). - 2168-6149. ; 77:8, s. 955-965
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Journal article (peer-reviewed)abstract
- Importance: The diagnostic performance of second-generation tau positron emission tomographic (PET) tracers is not yet known. Objective: To examine the novel tau PET tracer RO948 F 18 ([18F]RO948) performance in discriminating Alzheimer disease (AD) from non-AD neurodegenerative disorders. Design, Setting, and Participants: In this diagnostic study, 613 participants in the Swedish BioFINDER-2 study were consecutively enrolled in a prospective cross-sectional study from September 4, 2017, to August 28, 2019. Participants included 257 cognitively unimpaired controls, 154 patients with mild cognitive impairment, 100 patients with AD dementia, and 102 with non-AD neurodegenerative disorders. Evaluation included a comparison of tau PET tracer [18F]RO948 with magnetic resonance imaging (MRI) and cerebrospinal fluid and a head-to-head comparison between [18F]RO948 and flortaucipir F 18 ([18F]flortaucipir) in patients with semantic variant primary progressive aphasia (svPPA). Exposures: [18F]RO948 (all patients) and [18F]flortaucipir (3 patients with svPPA) tau PET; MRI (hippocampal volume, composite temporal lobe cortical thickness, whole-brain cortical thickness) and cerebrospinal fluid measures (p-tau181 and amyloid Aβ42 and Aβ40 ratio[Aβ42/Aβ40], and Aβ42/p-tau181 ratio). Main Outcomes and Measures: Standard uptake value ratios (SUVRs) in 4 predefined regions of interest (ROIs) reflecting Braak staging scheme for tau pathology and encompass I-II (entorhinal cortex), III-IV (inferior/middle temporal, fusiform gyrus, parahippocampal cortex, and amygdala), I-IV, and V-VI (widespread neocortical areas), area under the receiver operating characteristic curve (AUC) values, and subtraction images between [18F]RO948 and [18F]flortaucipir. Results: Diagnostic groups among the 613 participants included cognitively unimpaired (mean [SD] age, 65.8 [12.1] years; 117 men [46%]), mild cognitive impairment (age, 70.8 [8.3] years; 82 men [53%]), AD dementia (age, 73.5 [6.7] years; 57 men [57%]), and non-AD disorders (age, 70.5 [8.6] years; 41 men [40%]). Retention of [18F]RO948 was higher in AD dementia compared with all other diagnostic groups. [18F]RO948 could distinguish patients with AD dementia from individuals without cognitive impairment and those with non-AD disorders, and the highest AUC was obtained using the I-IV ROI (AUC = 0.98; 95% CI, 0.96-0.99 for AD vs no cognitive impairment and AUC = 0.97; 95% CI, 0.95-0.99 for AD vs non-AD disorders), which outperformed MRI (highest AUC = 0.91 for AD vs no cognitive impairment using whole-brain thickness, and AUC = 0.80 for AD vs non-AD disorders using temporal lobe thickness) and cerebrospinal fluid measures (highest AUC = 0.94 for AD vs no cognitive impairment using Aβ42/p-tau181, and AUC = 0.93 for AD vs non-AD disorders using Aβ42/Aβ40). Generally, tau PET positivity using [18F]RO948 was observed only in Aβ-positive cases or in MAPT R406W mutation carriers. Retention of [18F]RO948 was not pronounced in patients with svPPA, and head-to-head comparison revealed lower temporal lobe uptake than with [18F]flortaucipir. Conclusions and Relevance: In this study, elevated [18F]RO948 SUVRs were most often seen among Aβ-positive cases, which suggests that [18F]RO948 has high specificity for AD-type tau and highlights its potential as a diagnostic marker in the differential diagnosis of AD.
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| 10. |
- Ossenkoppele, Rik, et al.
(author)
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Accuracy of Tau Positron Emission Tomography as a Prognostic Marker in Preclinical and Prodromal Alzheimer Disease : A Head-to-Head Comparison against Amyloid Positron Emission Tomography and Magnetic Resonance Imaging
- 2021
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In: JAMA Neurology. - : American Medical Association (AMA). - 2168-6149. ; 78:8, s. 961-971
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Journal article (peer-reviewed)abstract
- Importance: Tau positron emission tomography (PET) tracers have proven useful for the differential diagnosis of dementia, but their utility for predicting cognitive change is unclear. Objective: To examine the prognostic accuracy of baseline fluorine 18 (18F)-flortaucipir and [18F]RO948 (tau) PET in individuals across the Alzheimer disease (AD) clinical spectrum and to perform a head-to-head comparison against established magnetic resonance imaging (MRI) and amyloid PET markers. Design, Setting, and Participants: This prognostic study collected data from 8 cohorts in South Korea, Sweden, and the US from June 1, 2014, to February 28, 2021, with a mean (SD) follow-up of 1.9 (0.8) years. A total of 1431 participants were recruited from memory clinics, clinical trials, or cohort studies; 673 were cognitively unimpaired (CU group; 253 [37.6%] positive for amyloid-β [Aβ]), 443 had mild cognitive impairment (MCI group; 271 [61.2%] positive for Aβ), and 315 had a clinical diagnosis of AD dementia (315 [100%] positive for Aβ). Exposures: [18F]Flortaucipir PET in the discovery cohort (n = 1135) or [18F]RO948 PET in the replication cohort (n = 296), T1-weighted MRI (n = 1431), and amyloid PET (n = 1329) at baseline and repeated Mini-Mental State Examination (MMSE) evaluation. Main Outcomes and Measures: Baseline [18F]flortaucipir/[18F]RO948 PET retention within a temporal region of interest, MRI-based AD-signature cortical thickness, and amyloid PET Centiloids were used to predict changes in MMSE using linear mixed-effects models adjusted for age, sex, education, and cohort. Mediation/interaction analyses tested whether associations between baseline tau PET and cognitive change were mediated by baseline MRI measures and whether age, sex, and APOE genotype modified these associations. Results: Among 1431 participants, the mean (SD) age was 71.2 (8.8) years; 751 (52.5%) were male. Findings for [18F]flortaucipir PET predicted longitudinal changes in MMSE, and effect sizes were stronger than for AD-signature cortical thickness and amyloid PET across all participants (R2, 0.35 [tau PET] vs 0.24 [MRI] vs 0.17 [amyloid PET]; P <.001, bootstrapped for difference) in the Aβ-positive MCI group (R2, 0.25 [tau PET] vs 0.15 [MRI] vs 0.07 [amyloid PET]; P <.001, bootstrapped for difference) and in the Aβ-positive CU group (R2, 0.16 [tau PET] vs 0.08 [MRI] vs 0.08 [amyloid PET]; P <.001, bootstrapped for difference). These findings were replicated in the [18F]RO948 PET cohort. MRI mediated the association between [18F]flortaucipir PET and MMSE in the groups with AD dementia (33.4% [95% CI, 15.5%-60.0%] of the total effect) and Aβ-positive MCI (13.6% [95% CI, 0.0%-28.0%] of the total effect), but not the Aβ-positive CU group (3.7% [95% CI, -17.5% to 39.0%]; P =.71). Age (t = -2.28; P =.02), but not sex (t = 0.92; P =.36) or APOE genotype (t = 1.06; P =.29) modified the association between baseline [18F]flortaucipir PET and cognitive change, such that older individuals showed faster cognitive decline at similar tau PET levels. Conclusions and Relevance: The findings of this prognostic study suggest that tau PET is a promising tool for predicting cognitive change that is superior to amyloid PET and MRI and may support the prognostic process in preclinical and prodromal stages of AD.
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