TY  - JOUR
AU  - Bouzigues, Arabella
AU  - Du, Vincent Le
AU  - Joulot, Matthieu
AU  - Peysson, Ninon
AU  - Houot, Marion
AU  - Béranger, Benoît
AU  - Russell, Lucy L
AU  - Foster, Phoebe H
AU  - Ferry-Bolder, Eve
AU  - van Swieten, John C
AU  - Jiskoot, Lize
AU  - Seelaar, Harro
AU  - Sanchez-Valle, Raquel
AU  - Laforce, Robert
AU  - Graff, Caroline
AU  - Galimberti, Daniela
AU  - Vandenberghe, Rik
AU  - de Mendonça, Alexandre
AU  - Tiraboschi, Pietro
AU  - Santana, Isabel
AU  - Gerhard, Alexander
AU  - Levin, Johannes
AU  - Sorbi, Sandro
AU  - Otto, Markus
AU  - Bertoux, Maxime
AU  - Lebouvier, Thibaud
AU  - Ducharme, Simon
AU  - Butler, Chris R
AU  - Ber, Isabelle Le
AU  - Finger, Elizabeth
AU  - Tartaglia, Maria Carmela
AU  - Masellis, Mario
AU  - Rowe, James B
AU  - Synofzik, Matthis
AU  - Moreno, Fermin
AU  - Borroni, Barbara
AU  - Rohrer, Jonathan D
AU  - Migliaccio, Raffaella
TI  - Structural and functional connectivity in tau mutation carriers: from presymptomatic to symptomatic frontotemporal dementia.
JO  - Alzheimer's and dementia
VL  - 21
IS  - 7
SN  - 1552-5260
CY  - Hoboken, NJ
PB  - Wiley
M1  - DZNE-2025-00865
SP  - e70367
PY  - 2025
AB  - Microtubule-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.
KW  - Humans
KW  - Frontotemporal Dementia: genetics
KW  - Frontotemporal Dementia: pathology
KW  - Frontotemporal Dementia: physiopathology
KW  - Frontotemporal Dementia: diagnostic imaging
KW  - tau Proteins: genetics
KW  - Male
KW  - Female
KW  - Middle Aged
KW  - Mutation: genetics
KW  - Magnetic Resonance Imaging
KW  - Aged
KW  - White Matter: pathology
KW  - White Matter: diagnostic imaging
KW  - Heterozygote
KW  - Brain: pathology
KW  - Brain: physiopathology
KW  - Brain: diagnostic imaging
KW  - Prodromal Symptoms
KW  - MAPT (Other)
KW  - functional connectivity (Other)
KW  - genetic frontotemporal dementia (Other)
KW  - graph analysis (Other)
KW  - gray matter (Other)
KW  - macroscale organization (Other)
KW  - mutation (Other)
KW  - neurodegeneration (Other)
KW  - tau (Other)
KW  - tau pathology (Other)
KW  - white matter (Other)
KW  - tau Proteins (NLM Chemicals)
KW  - MAPT protein, human (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40673371
DO  - DOI:10.1002/alz.70367
UR  - https://pub.dzne.de/record/280021
ER  -