Comparison of Group-Level and Individualized Brain Regions for Measuring Change in Longitudinal Tau Positron Emission Tomography in Alzheimer Disease
Authors: Leuzy Antoine , Binette Alexa Pichet , Vogel Jacob W. , Klein Gregory , Borroni Edilio , Tonietto Matteo , Strandberg Olof , Mattsson-Carlgren Niklas , Palmqvist Sebastian , Pontecorvo Michael J. , Iaccarino Leonardo , Stomrud Erik , Ossenkoppele Rik , Smith Ruben , Hansson Oskar ,   Alzheimer’s Disease Neuroimaging Initiative, Weiner Michael W. , Aisen Paul , Petersen Ronald , Jack, Jr. Clifford R. , Jagust William , Trojanowki John Q. , Toga Arthur W. , Beckett Laurel , Green Robert C. , Saykin Andrew J. , Morris John , Shaw Leslie M. , Khachaturian Zaven , Sorensen Greg , Carrillo Maria , Kuller Lew , Raichle Marc , Paul Steven , Davies Peter , Fillit Howard , Hefti Franz , Holtzman David , Mesulam M. Marcel , Potter William , Snyder Peter , Logovinsky Veronika , Montine Tom , Jimenez Gustavo , Donohue Michael , Gessert Devon , Harless Kelly , Salazar Jennifer , Cabrera Yuliana , Walter Sarah , Hergesheimer Lindsey , Harvey Danielle , Bernstein Matthew , Fox Nick , Thompson Paul , Schuff Norbert , DeCarli Charles , Borowski Bret , Gunter Jeff , Senjem Matt , Vemuri Prashanthi , Jones David , Kantarci Kejal , Ward Chad , Koeppe Robert A. , Foster Norm , Reiman, Eric M. , Chen Kewei , Mathis Chet , Landau Susan , Morris John C. , Cairns Nigel J. , Franklin Erin , Taylor‐Reinwald Lisa , Lee Virginia , Korecka Magdalena , Figurski Michal , Crawford Karen , Neu Scott , Foroud Tatiana M. , Potkin Steven , Shen Li , Faber Kelley , Kim Sungeun , Nho Kwangsik , Thal Lean , Buckholtz Neil , Albert Marilyn , Frank Richard , Hsiao John 
Published: May 2023

ImportanceLongitudinal 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.ObjectiveTo 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 ParticipantsThis 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.ExposuresTau 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 MeasuresAnnual percentage change in tau-PET SUVR across ROIs. Sample size requirements in simulated clinical trials using tau PET as an outcome were also calculated.ResultsA 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 RelevanceFinding 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.