Network Connectivity Alterations across the MAPT Mutation Clinical Spectrum

Liwen Zhang, Taru M. Flagan, Suvi Häkkinen, Stephanie A. Chu, Jesse A. Brown, Alex J. Lee, Lorenzo Pasquini, Maria Luisa Mandelli, Maria Luisa Gorno-Tempini, Virginia E. Sturm, Jennifer S. Yokoyama, Brian S. Appleby, Yann Cobigo, Bradford C. Dickerson, Kimiko Domoto-Reilly, Daniel H. Geschwind, Nupur Ghoshal, Neill R. Graff-Radford, Murray Grossman, Ging Yuek Robin HsiungEdward D. Huey, Kejal Kantarci, Argentina Lario Lago, Irene Litvan, Ian R. Mackenzie, Mario F. Mendez, Chiadi U. Onyike, Eliana Marisa Ramos, Erik D. Roberson, Maria Carmela Tartaglia, Arthur W. Toga, Sandra Weintraub, Zbigniew K. Wszolek, Leah K. Forsberg, Hilary W. Heuer, Bradley F. Boeve, Adam L. Boxer, Howard J. Rosen, Bruce L. Miller, William W. Seeley, Suzee E. Lee

Research output: Contribution to journalArticlepeer-review


Objective: Microtubule-associated protein tau (MAPT) mutations cause frontotemporal lobar degeneration, and novel biomarkers are urgently needed for early disease detection. We used task-free functional magnetic resonance imaging (fMRI) mapping, a promising biomarker, to analyze network connectivity in symptomatic and presymptomatic MAPT mutation carriers. Methods: We compared cross-sectional fMRI data between 17 symptomatic and 39 presymptomatic carriers and 81 controls with (1) seed-based analyses to examine connectivity within networks associated with the 4 most common MAPT-associated clinical syndromes (ie, salience, corticobasal syndrome, progressive supranuclear palsy syndrome, and default mode networks) and (2) whole-brain connectivity analyses. We applied K-means clustering to explore connectivity heterogeneity in presymptomatic carriers at baseline. Neuropsychological measures, plasma neurofilament light chain, and gray matter volume were compared at baseline and longitudinally between the presymptomatic subgroups defined by their baseline whole-brain connectivity profiles. Results: Symptomatic and presymptomatic carriers had connectivity disruptions within MAPT-syndromic networks. Compared to controls, presymptomatic carriers showed regions of connectivity alterations with age. Two presymptomatic subgroups were identified by clustering analysis, exhibiting predominantly either whole-brain hypoconnectivity or hyperconnectivity at baseline. At baseline, these two presymptomatic subgroups did not differ in neuropsychological measures, although the hypoconnectivity subgroup had greater plasma neurofilament light chain levels than controls. Longitudinally, both subgroups showed visual memory decline (vs controls), yet the subgroup with baseline hypoconnectivity also had worsening verbal memory and neuropsychiatric symptoms, and extensive bilateral mesial temporal gray matter decline. Interpretation: Network connectivity alterations arise as early as the presymptomatic phase. Future studies will determine whether presymptomatic carriers' baseline connectivity profiles predict symptomatic conversion. ANN NEUROL 2023;94:632–646.

Original languageEnglish
Pages (from-to)632-646
Number of pages15
JournalAnnals of neurology
Issue number4
StatePublished - Oct 2023


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