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000281875 037__ $$aDZNE-2025-01246
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000281875 1001_ $$00000-0002-9011-1120$$ade Bruin, Hannah$$b0
000281875 245__ $$aConnectivity as a universal predictor of tau progression in atypical Alzheimer's disease.
000281875 260__ $$aOxford$$bOxford Univ. Press$$c2025
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000281875 520__ $$aThe 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.
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000281875 650_7 $$2Other$$aPET
000281875 650_7 $$2Other$$aatypical Alzheimer's disease
000281875 650_7 $$2Other$$aconnectivity
000281875 650_7 $$2Other$$afMRI
000281875 650_7 $$2Other$$aheterogeneity
000281875 650_7 $$2Other$$atau
000281875 650_7 $$2NLM Chemicals$$atau Proteins
000281875 650_2 $$2MeSH$$aHumans
000281875 650_2 $$2MeSH$$aAlzheimer Disease: diagnostic imaging
000281875 650_2 $$2MeSH$$aAlzheimer Disease: metabolism
000281875 650_2 $$2MeSH$$aAlzheimer Disease: pathology
000281875 650_2 $$2MeSH$$aFemale
000281875 650_2 $$2MeSH$$aMale
000281875 650_2 $$2MeSH$$aDisease Progression
000281875 650_2 $$2MeSH$$aAged
000281875 650_2 $$2MeSH$$atau Proteins: metabolism
000281875 650_2 $$2MeSH$$aPositron-Emission Tomography
000281875 650_2 $$2MeSH$$aCross-Sectional Studies
000281875 650_2 $$2MeSH$$aMiddle Aged
000281875 650_2 $$2MeSH$$aAged, 80 and over
000281875 650_2 $$2MeSH$$aBrain: diagnostic imaging
000281875 650_2 $$2MeSH$$aBrain: metabolism
000281875 650_2 $$2MeSH$$aBrain: pathology
000281875 650_2 $$2MeSH$$aMagnetic Resonance Imaging
000281875 650_2 $$2MeSH$$aLongitudinal Studies
000281875 7001_ $$aGroot, Colin$$b1
000281875 7001_ $$aBarthel, Henryk$$b2
000281875 7001_ $$0P:(DE-2719)9002485$$aBischof, Gérard N$$b3
000281875 7001_ $$aBlazhenets, Ganna$$b4
000281875 7001_ $$aBoellaard, Ronald$$b5
000281875 7001_ $$aBoon, Baayla D C$$b6
000281875 7001_ $$0P:(DE-2719)9001539$$aBrendel, Matthias$$b7
000281875 7001_ $$00000-0001-7833-616X$$aCash, David M$$b8
000281875 7001_ $$00000-0002-3976-9461$$aCoath, William$$b9
000281875 7001_ $$aDay, Gregory S$$b10
000281875 7001_ $$00000-0002-5958-3445$$aDickerson, Bradford C$$b11
000281875 7001_ $$0P:(DE-2719)9000532$$aDoering, Elena$$b12$$udzne
000281875 7001_ $$0P:(DE-2719)2811239$$aDrzezga, Alexander$$b13$$udzne
000281875 7001_ $$avan Dyck, Christopher H$$b14
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000281875 7001_ $$00000-0001-8766-6224$$avan der Flier, Wiesje M$$b16
000281875 7001_ $$00000-0002-7051-6382$$aFredericks, Carolyn A$$b17
000281875 7001_ $$aFryer, Tim D$$b18
000281875 7001_ $$avan de Giessen, Elsmarieke$$b19
000281875 7001_ $$00000-0003-2109-2955$$aGordon, Brian A$$b20
000281875 7001_ $$00000-0003-2770-0691$$aGraff-Radford, Jonathan$$b21
000281875 7001_ $$00000-0002-6809-0618$$aGrinberg, Lea T$$b22
000281875 7001_ $$00000-0001-8467-7286$$aHansson, Oskar$$b23
000281875 7001_ $$aHobbs, Diana A$$b24
000281875 7001_ $$aHoenig, Merle C$$b25
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000281875 7001_ $$00000-0002-5599-5098$$aIrwin, David J$$b27
000281875 7001_ $$aJones, P Simon$$b28
000281875 7001_ $$00000-0003-2930-8634$$aJosephs, Keith A$$b29
000281875 7001_ $$00000-0003-0413-747X$$aKatsumi, Yuta$$b30
000281875 7001_ $$00000-0003-2581-8100$$aLa Joie, Renaud$$b31
000281875 7001_ $$00000-0002-4589-1180$$aLee, Edward B$$b32
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000281875 7001_ $$00000-0001-8923-9656$$aMalpetti, Maura$$b34
000281875 7001_ $$aMcGinnis, Scott M$$b35
000281875 7001_ $$aMecca, Adam P$$b36
000281875 7001_ $$00000-0001-6499-1251$$aMohanty, Rosaleena$$b37
000281875 7001_ $$aNasrallah, Ilya M$$b38
000281875 7001_ $$00000-0002-0837-5080$$aO'Brien, John T$$b39
000281875 7001_ $$aO'Dell, Ryan S$$b40
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000281875 7001_ $$0P:(DE-2719)2812234$$aPerneczky, Robert$$b42$$udzne
000281875 7001_ $$00000-0003-0079-9441$$aPhillips, Jeffrey S$$b43
000281875 7001_ $$00000-0001-5575-5572$$aPutcha, Deepti$$b44
000281875 7001_ $$aRabinovici, Gil D$$b45
000281875 7001_ $$aRahmouni, Nesrine$$b46
000281875 7001_ $$00000-0001-9116-1376$$aRosa-Neto, Pedro$$b47
000281875 7001_ $$aRowe, James B$$b48
000281875 7001_ $$aRullmann, Michael$$b49
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000281875 7001_ $$aSaur, Dorothee$$b51
000281875 7001_ $$aSchildan, Andreas$$b52
000281875 7001_ $$00000-0003-2059-024X$$aSchott, Jonathan M$$b53
000281875 7001_ $$00000-0001-7977-1083$$aSchroeter, Matthias L$$b54
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