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