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000283069 037__ $$aDZNE-2025-01476
000283069 041__ $$aEnglish
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000283069 1001_ $$aTsvetanov, Kamen A$$b0
000283069 1112_ $$aAlzheimer’s Association International Conference$$cToronto$$d2025-07-27 - 2025-07-31$$gAAIC 25$$wCanada
000283069 245__ $$aStructure‐function decoupling in genetic frontotemporal dementia
000283069 260__ $$c2025
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000283069 520__ $$aFunctional network integrity is important for maintaining cognitive performance during the 10-20 year presymptomatic period of frontotemporal dementia (FTD), conferring resilience to advancing neuropathology and atrophy. The extent to which functional integrity relies on preserved structural connectivity is unclear. Here, we test the relationship between functional connectivity and structural connectivity, termed structure-function coupling, against genetic risk for FTD and disease progression.We studied 56 symptomatic and 165 pre-symptomatic FTD-mutation carriers, and 141 family members without mutations, from the GENFI cohort. Diffusion weighted imaging and functional magnetic resonance imaging (Siemens MR platforms) were acquired and analysed using established approaches to quantify participant-level structural and functional connectomes (Figure 1-(1)). Connectomes were defined in the Brainnetome Atlas and re-mapped onto a subcortical network and seven resting-state networks based on the Yeo Networks (Figure 1-(2)). An inter-subject regularized canonical correlation analysis (CCA) with permutation-based cross-validation was used to jointly analyse the structural and functional connectomes (Figure 1-(3-4)). Second-level analysis with robust multiple linear regression models tested for differences between non-carriers, pre-symptomatic carriers and symptomatic carriers in the strength of association between structural and functional CCA subject scores. Age, sex, head motion and scanner site were included as covariates.Canonical correlation analysis identified significant components linking structural and functional connectivity. The first component (r=0.656, p <0.001) reflected a structural connectivity pattern with high within- and between-networks loadings (Figure 1-(5)) with strong within-networks functional connectivity and weak-to-negative between-network functional connectivity (Figure 1-(6)). This component associated structural integrity with function segregation, whereby individuals with high structural connectivity within and between networks exhibit greater functional network segregation as shown by strong within-network functional connectivity and weak between network connectivity. The strength of this structure-function coupling was greater for non-carriers compared to pre-symptomatic carriers (Figure 1-(7)). Symptomatic carriers showed minimal relationship between structural and functional scores, indicating structure-function decoupling, consistent with the hypothesis that cognitive decline is triggered by critical decoupling of previously synergistic neural systems.Our findings demonstrate progressive de-coupling between structural connectivity and functional segregation over the course of genetic frontotemporal dementia. These results have implications for designing pre-symptomatic disease-modifying 'preventative' trials, supported by imaging-based surrogate markers of neural system dynamics.
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000283069 650_7 $$2NLM Chemicals$$aBiomarkers
000283069 650_2 $$2MeSH$$aHumans
000283069 650_2 $$2MeSH$$aMale
000283069 650_2 $$2MeSH$$aFemale
000283069 650_2 $$2MeSH$$aFrontotemporal Dementia: genetics
000283069 650_2 $$2MeSH$$aFrontotemporal Dementia: diagnostic imaging
000283069 650_2 $$2MeSH$$aFrontotemporal Dementia: physiopathology
000283069 650_2 $$2MeSH$$aFrontotemporal Dementia: pathology
000283069 650_2 $$2MeSH$$aMiddle Aged
000283069 650_2 $$2MeSH$$aMagnetic Resonance Imaging
000283069 650_2 $$2MeSH$$aConnectome
000283069 650_2 $$2MeSH$$aBiomarkers
000283069 650_2 $$2MeSH$$aBrain: physiopathology
000283069 650_2 $$2MeSH$$aBrain: diagnostic imaging
000283069 650_2 $$2MeSH$$aBrain: pathology
000283069 650_2 $$2MeSH$$aAged
000283069 650_2 $$2MeSH$$aDisease Progression
000283069 650_2 $$2MeSH$$aMutation: genetics
000283069 650_2 $$2MeSH$$aAdult
000283069 650_2 $$2MeSH$$aCohort Studies
000283069 650_2 $$2MeSH$$aNeural Pathways: physiopathology
000283069 650_2 $$2MeSH$$aNeural Pathways: diagnostic imaging
000283069 650_2 $$2MeSH$$aDiffusion Magnetic Resonance Imaging
000283069 7001_ $$aJones, P Simon$$b1
000283069 7001_ $$aMalpetti, Maura$$b2
000283069 7001_ $$aRittman, Timothy$$b3
000283069 7001_ $$aBouzigues, Arabella$$b4
000283069 7001_ $$avan Swieten, John$$b5
000283069 7001_ $$aJiskoot, Lize$$b6
000283069 7001_ $$aSeelaar, Harro$$b7
000283069 7001_ $$aBorroni, Barbara$$b8
000283069 7001_ $$aPremi, Enrico$$b9
000283069 7001_ $$aSanchez-Valle, Raquel$$b10
000283069 7001_ $$aMoreno, Fermin$$b11
000283069 7001_ $$aLaforce, Robert$$b12
000283069 7001_ $$aGraff, Caroline$$b13
000283069 7001_ $$0P:(DE-2719)2811275$$aSynofzik, Matthis$$b14$$udzne
000283069 7001_ $$aGalimberti, Daniela$$b15
000283069 7001_ $$aMasellis, Mario$$b16
000283069 7001_ $$aTartaglia, Carmela$$b17
000283069 7001_ $$aFinger, Elizabeth$$b18
000283069 7001_ $$aVandenberghe, Rik$$b19
000283069 7001_ $$ade Mendonça, Alexandre$$b20
000283069 7001_ $$aTagliavini, Fabrizio$$b21
000283069 7001_ $$aSantana, Isabel$$b22
000283069 7001_ $$aDucharme, Simon$$b23
000283069 7001_ $$aButler, Christopher$$b24
000283069 7001_ $$aGerhard, Alexander$$b25
000283069 7001_ $$0P:(DE-2719)2811659$$aLevin, Johannes$$b26$$udzne
000283069 7001_ $$aOtto, Markus$$b27
000283069 7001_ $$aSorbi, Sandro$$b28
000283069 7001_ $$aRussell, Lucy L$$b29
000283069 7001_ $$aRohrer, Jonathan D$$b30
000283069 7001_ $$aRowe, James B$$b31
000283069 7001_ $$aGenetic FTD Initiative, GENFI$$b32$$eCollaboration Author
000283069 773__ $$0PERI:(DE-600)2201940-6$$a10.1002/alz70856_100438$$gVol. 21 Suppl 2, no. Suppl 2, p. e100438$$nSuppl 2$$pe100438$$tAlzheimer's and dementia$$v21$$x1552-5260$$y2025
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