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000280021 1001_ $$00000-0002-0267-8590$$aBouzigues, Arabella$$b0
000280021 245__ $$aStructural and functional connectivity in tau mutation carriers: from presymptomatic to symptomatic frontotemporal dementia.
000280021 260__ $$aHoboken, NJ$$bWiley$$c2025
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000280021 520__ $$aMicrotubule-associated protein tau (MAPT) mutations cause frontotemporal dementia (FTD), characterised by behavioural, language, and motor impairments due to brain connectivity disruptions. We investigated structural and functional connectivity in 86 mutation carriers and 272 controls to map connectivity changes at different disease stages.The CDR Dementia Staging Instrument plus National Alzheimer's Coordinating Center (NACC) Behaviour and Language domains (CDR plus NACC FTLD) stratified carriers into three groups: asymptomatic, prodromal, and symptomatic. We extracted measures of cortical thickness, white matter integrity, and functional connectivity, which were compared between each carrier group and controls using linear mixed models.Early isolated functional disruptions in salience/visual networks were present in asymptomatic carriers, along with anterior cingulate gray matter reductions. In prodromal carriers, functional changes extended to other networks, with additional structural damage in temporal poles/cingulate.This study shows that functional networks likely drive lifelong compensation for a genetically determined disease, manifesting clinically when structural damage reaches a critical threshold. This supports connectivity measures as potential biomarkers for MAPT-related neurodegeneration.Our findings reveal the progressive and staged nature of structural and functional connectivity alterations in MAPT mutation carriers, with distinct patterns at each disease stage. In asymptomatic carriers, we identified early functional connectivity alterations in salience and visual networks, despite preserved white matter and only subtle gray matter atrophy. These appear to represent both response to pathology and possible compensatory mechanisms. In prodromal carriers, functional connectivity alterations were accompanied by structural damage, including cortical atrophy and white matter tract disruptions, in regions directly connected to early-affected networks. The sequential progression, from functional connectivity changes to structural degeneration, aligns with the hypothesis that tau propagates along axonal connections, disrupting neural network integrity before measurable atrophy occurs. We propose a theoretical data-driven model of biomarker evolution in MAPT mutation carriers, highlighting functional disruptions as early indicators and structural damage as a later-stage hallmark. These connectivity biomarkers have the potential to inform therapeutic strategies and clinical trial design.
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000280021 650_7 $$2Other$$aMAPT
000280021 650_7 $$2Other$$afunctional connectivity
000280021 650_7 $$2Other$$agenetic frontotemporal dementia
000280021 650_7 $$2Other$$agraph analysis
000280021 650_7 $$2Other$$agray matter
000280021 650_7 $$2Other$$amacroscale organization
000280021 650_7 $$2Other$$amutation
000280021 650_7 $$2Other$$aneurodegeneration
000280021 650_7 $$2Other$$atau
000280021 650_7 $$2Other$$atau pathology
000280021 650_7 $$2Other$$awhite matter
000280021 650_7 $$2NLM Chemicals$$atau Proteins
000280021 650_7 $$2NLM Chemicals$$aMAPT protein, human
000280021 650_2 $$2MeSH$$aHumans
000280021 650_2 $$2MeSH$$aFrontotemporal Dementia: genetics
000280021 650_2 $$2MeSH$$aFrontotemporal Dementia: pathology
000280021 650_2 $$2MeSH$$aFrontotemporal Dementia: physiopathology
000280021 650_2 $$2MeSH$$aFrontotemporal Dementia: diagnostic imaging
000280021 650_2 $$2MeSH$$atau Proteins: genetics
000280021 650_2 $$2MeSH$$aMale
000280021 650_2 $$2MeSH$$aFemale
000280021 650_2 $$2MeSH$$aMiddle Aged
000280021 650_2 $$2MeSH$$aMutation: genetics
000280021 650_2 $$2MeSH$$aMagnetic Resonance Imaging
000280021 650_2 $$2MeSH$$aAged
000280021 650_2 $$2MeSH$$aWhite Matter: pathology
000280021 650_2 $$2MeSH$$aWhite Matter: diagnostic imaging
000280021 650_2 $$2MeSH$$aHeterozygote
000280021 650_2 $$2MeSH$$aBrain: pathology
000280021 650_2 $$2MeSH$$aBrain: physiopathology
000280021 650_2 $$2MeSH$$aBrain: diagnostic imaging
000280021 650_2 $$2MeSH$$aProdromal Symptoms
000280021 7001_ $$aDu, Vincent Le$$b1
000280021 7001_ $$aJoulot, Matthieu$$b2
000280021 7001_ $$aPeysson, Ninon$$b3
000280021 7001_ $$aHouot, Marion$$b4
000280021 7001_ $$aBéranger, Benoît$$b5
000280021 7001_ $$aRussell, Lucy L$$b6
000280021 7001_ $$aFoster, Phoebe H$$b7
000280021 7001_ $$aFerry-Bolder, Eve$$b8
000280021 7001_ $$avan Swieten, John C$$b9
000280021 7001_ $$aJiskoot, Lize$$b10
000280021 7001_ $$aSeelaar, Harro$$b11
000280021 7001_ $$aSanchez-Valle, Raquel$$b12
000280021 7001_ $$aLaforce, Robert$$b13
000280021 7001_ $$aGraff, Caroline$$b14
000280021 7001_ $$aGalimberti, Daniela$$b15
000280021 7001_ $$aVandenberghe, Rik$$b16
000280021 7001_ $$ade Mendonça, Alexandre$$b17
000280021 7001_ $$aTiraboschi, Pietro$$b18
000280021 7001_ $$aSantana, Isabel$$b19
000280021 7001_ $$aGerhard, Alexander$$b20
000280021 7001_ $$0P:(DE-2719)2811659$$aLevin, Johannes$$b21$$udzne
000280021 7001_ $$aSorbi, Sandro$$b22
000280021 7001_ $$aOtto, Markus$$b23
000280021 7001_ $$aBertoux, Maxime$$b24
000280021 7001_ $$aLebouvier, Thibaud$$b25
000280021 7001_ $$aDucharme, Simon$$b26
000280021 7001_ $$aButler, Chris R$$b27
000280021 7001_ $$aBer, Isabelle Le$$b28
000280021 7001_ $$aFinger, Elizabeth$$b29
000280021 7001_ $$aTartaglia, Maria Carmela$$b30
000280021 7001_ $$aMasellis, Mario$$b31
000280021 7001_ $$aRowe, James B$$b32
000280021 7001_ $$0P:(DE-2719)2811275$$aSynofzik, Matthis$$b33$$udzne
000280021 7001_ $$aMoreno, Fermin$$b34
000280021 7001_ $$aBorroni, Barbara$$b35
000280021 7001_ $$aRohrer, Jonathan D$$b36
000280021 7001_ $$aMigliaccio, Raffaella$$b37
000280021 7001_ $$aInitiative, GENetic Frontotemporal dementia$$b38$$eCollaboration Author
000280021 773__ $$0PERI:(DE-600)2201940-6$$a10.1002/alz.70367$$gVol. 21, no. 7, p. e70367$$n7$$pe70367$$tAlzheimer's and dementia$$v21$$x1552-5260$$y2025
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