Structural and functional alterations in young adult presymptomatic frontotemporal lobar degeneration mutation carriers

• Published in: Alzheimer's & dementia Vol. 19; no. S16
• Main Authors: Lombardi, Jolina, Zhang, Liwen, Flagan, Taru M., Vargas, Andrea Gorham, Mandelli, Maria Luisa, Brown, Jesse A., Häkkinen, Suvi, Rosen, Howard J., Kantarci, Kejal, Ramos, Eliana Marisa, Miller, Bruce L, Tempini, Maria Luisa Gorno, Seeley, William W., Lee, Suzee E.
• Format: Journal Article
• Language: English
• Published: 01.12.2023
• ISSN: 1552-5260; 1552-5279
• DOI: 10.1002/alz.079354

Background Presymptomatic frontotemporal lobar degeneration (FTLD) mutation carriers as young as their thirties display gray matter (GM) deficits and alterations in the specific neural networks targeted during the symptomatic phase (Lee et al. NeuroImage Clin 2017; Bertrand et al. JAMA Neurol 2018). These studies raise the question of a potential neurodevelopmental role of pathogenic mutations in FTLD, yet sufficient research in young adults is lacking. Method Leveraging 3T MRI brain scans from UCSF and the ALLFTD Consortia, we studied structural and functional connectivity alterations in 31 presymptomatic mutation carriers [PreSxAll; 12 C9orf72,13 MAPT, 6 GRN, mean age: 25.2±3.9, range 18‐30 years] and 28 demographically‐matched healthy controls [HC; mean age: 26.5±3.1, range 18‐30 years]. We performed voxel‐based morphometry (VBM) to compare GM volume between HC and PreSxAll, and HC and each mutation carrier subgroup using ANCOVA (SPM12). VBM statistical results were thresholded at a height of p<0.001 uncorrected or p<0.05 familywise error corrected. We used seed‐based task‐free functional MRI (tf‐fMRI) analysis to examine salience network (SN) and default mode network (DMN) connectivity. Single‐subject connectivity maps were analyzed using ANCOVA in SPM for group comparisons and masked to the relevant network. Tf‐fMRI results were thresholded at a height of p<0.05 and extent of p<0.05. For all analyses, nuisance covariates included age, sex, education, handedness, scanner and TIV (GM only). Result We found no significant GM differences between groups. PreSxAll showed regions of SN hyperconnectivity compared with HC, specifically in the bilateral insula, right superior frontal gyrus, bilateral midcingulate cortex, and the left cerebellum. Compared to controls, each mutation carrier subgroup featured SN hyperconnectivity within key network hubs, such as the insula and anterior cingulate cortex. The DMN showed no significant alterations for PreSxAll vs. HC. Scattered small clusters of DMN alterations were noted in subcortical regions and the cerebellum in presymptomatic C9orf72 and GRN. Conclusion Despite the absence of GM deficits in young adult FTLD mutation carriers, tf‐fMRI detected SN alterations in these carriers compared with healthy controls. Future studies focused on other neuroimaging measures will further explore differences in young adult FTLD mutation carriers.