Functional Connectivity Associations With Markers of Disease Progression in GRN Pathogenic Variant Carriers.
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Flagan Taru M, Chu Stephanie A, Häkkinen Suvi, Zhang Liwen, McFall David, Rohrer Jonathan D, Brown Jesse A, Lee Alex J, Fernhoff Kristen, Pasquini Lorenzo, Rankin Katherine P, Mandelli Maria Luisa, Gorno-Tempini Maria Luisa, Yokoyama Jennifer S, Sturm Virginia E, Appleby Brian, Dickerson Bradford C, Domoto-Reilly Kimiko, Foroud Tatiana, Geschwind Daniel H, Ghoshal Nupur, Graff-Radford Neill R, Hsiung Ging-Yuek Robin, Huang Eric J, Huey Edward, Kantarci Kejal, Litvan Irene, Mackenzie Ian R, Mendez Mario F, Onyike Chiadi U, Petrucelli Leonard, Ramos Eliana Marisa, Roberson Erik D, Rojas Julio C, Tartaglia Maria Carmela, Toga Arthur W, Weintraub Sandra, Forsberg Leah K, Heuer Hilary W, Boeve Brad F, Boxer Adam L, Rosen Howard J, Miller Bruce L, Moreno Fermin, Seeley William W, Lee Suzee E, ALLFTD Consortium
Аннотация
METHODS: Utilizing T1 and task-free functional magnetic resonance imaging from 49 asymptomatic and 26 symptomatic GRN variant carriers, we determined the relationships between functional connectivity, as measured by voxelwise whole-brain degree, and GRN-relevant markers of disease progression, including plasma neurofilament light chain concentrations, cerebrospinal fluid complement C1q and C3b protein levels, obsessive-compulsive disorder symptom severity, and gray matter volume.
RESULTS: Neurofilament light chain concentrations were associated with frontotemporoparietal and thalamic hyperconnectivity in asymptomatic GRN variant carriers and extensive regions of atrophy in symptomatic carriers. Complement levels were associated with regions of hyperconnectivity, but not gray matter volume, in symptomatic carriers. Obsessive-compulsive disorder symptom severity was associated with hypoconnectivity across all GRN carriers. Asymptomatic carriers with thalamic hyperconnectivity tended to have lower gray matter volume in the bilateral insula and left lateral parietal cortex, early regions of atrophy in GRN-frontotemporal dementia.
INTERPRETATION: In asymptomatic carriers, the co-occurrence of hyperconnectivity, high neurofilament light chain, and low gray matter volume suggests that functional hyperconnectivity may portend the onset of clinical decline. These findings point toward hyperconnectivity as an indicator of approaching symptomatic onset.