Connectivity as a universal predictor of tau progression in atypical Alzheimer's disease.
СтатьяМногоцентровое исследованиеНазвание и аннотация: Перевод в очереди
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de Bruin Hannah, Groot Colin, Barthel Henryk, Bischof Gérard N, Blazhenets Ganna, Boellaard Ronald, Boon Baayla D C, Brendel Matthias, Cash David M, Coath William, Day Gregory S, Dickerson Bradford C, Doering Elena, Drzezga Alexander, van Dyck Christopher H, van Eimeren Thilo, van der Flier Wiesje M, Fredericks Carolyn A, Fryer Tim D, van de Giessen Elsmarieke, Gordon Brian A, Graff-Radford Jonathan, Grinberg Lea T, Hansson Oskar, Hobbs Diana A, Hoenig Merle C, Höglinger Günter, Irwin David J, Jones P Simon, Josephs Keith A, Katsumi Yuta, La Joie Renaud, Lee Edward B, Levin Johannes, Malpetti Maura, McGinnis Scott M, Mecca Adam P, Mohanty Rosaleena, Nasrallah Ilya M, O'Brien John T, O'Dell Ryan S, Palleis Carla, Perneczky Robert, Phillips Jeffrey S, Putcha Deepti, Rabinovici Gil D, Rahmouni Nesrine, Rosa-Neto Pedro, Rowe James B, Rullmann Michael, Sabri Osama, Saur Dorothee, Schildan Andreas, Schott Jonathan M, Schroeter Matthias L, Seeley William W, Servaes Stijn, Sintini Irene, Smith Ruben, Spina Salvatore, Stevenson Jenna, Stomrud Erik, Strandberg Olof, Therriault Joseph, Tideman Pontus, Touroutoglou Alexandra, Trainer Anne E, Visser Denise, Wekselman Fattin, Weston Philip S J, Whitwell Jennifer L, Wolk David A, Yong Keir, Pijnenburg Yolande A L, Franzmeier Nicolai, Ossenkoppele Rik
Аннотация
The link between regional tau load and clinical manifestation of Alzheimer's disease (AD) highlights the importance of characterizing spatial tau distribution across disease variants. In typical (memory-predominant) AD, the spatial progression of tau pathology mirrors the functional connections from temporal lobe epicentres. However, given the limited spatial heterogeneity of tau in typical AD, atypical (non-amnestic-predominant) AD variants with distinct tau patterns provide a key opportunity to investigate the universality of connectivity as a scaffold for tau progression. In this large-scale, multicentre study across 14 international sites, we included cross-sectional tau-PET data from 320 individuals with atypical AD (n = 139 posterior cortical atrophy/PCA-AD; n = 103 logopenic variant primary progressive aphasia/lvPPA-AD; n = 35 behavioural variant AD/bvAD; n = 43 corticobasal syndrome/CBS-AD), with a subset of individuals (n = 78) having longitudinal tau-PET data. Additionally, as an independent sample, we included regional post-mortem tau stainings from 93 atypical AD patients from two sites (n = 19 PCA-AD, n = 32 lvPPA-AD, n = 23 bvAD, n = 19 CBS-AD). Gaussian mixture modelling was used to harmonize different tau-PET tracers by transforming tau-PET standardized uptake value ratios to tau positivity probabilities (a uniform scale ranging from 0% to 100%). Using linear regression, we assessed whether brain regions with stronger resting-state functional MRI-based functional connectivity, derived from healthy elderly controls in the Alzheimer's Disease Neuroimaging Initiative (ADNI), showed greater covariance in cross-sectional and longitudinal tau-PET and post-mortem tau pathology. Furthermore, we examined whether functional connectivity of tau-PET epicentres (i.e. the top 5% of regions with the highest baseline tau load) and tau-PET accumulation epicentres (i.e. the top 5% of regions with the highest tau accumulation rates) was associated with cross-sectional and longitudinal tau patterns. Our findings show that tau-PET epicentres aligned with clinical variants, e.g. a visual network predominant pattern in PCA-AD ('visual AD') and left-hemispheric temporal predominance, particularly within the language network, in lvPPA-AD ('language AD'). Moreover, more strongly functionally connected regions showed correlated concurrent tau-PET levels (confirmed with post-mortem data) and tau-PET accumulation rates. The functional connectivity profile of tau-PET epicentres and accumulation epicentres corresponded to tau-PET progression patterns, with higher tau-PET levels and accumulation rates in functionally close regions, and lower tau-PET levels and accumulation rates in functionally distant regions. Our data are consistent with the hypothesis that tau propagation occurs along functional connections originating from local epicentres, across all AD clinical variants. Since tau proteinopathy is a major driver of neurodegeneration and cognitive decline, this finding may advance personalized medicine and participant-specific end points in clinical trials.