Presymptomatic and symptomatic MAPT mutation carriers feature functional connectivity alterations
Authors: Zhang Liwen , Flagan Taru M. , Chu Stephanie A. , Häkkinen Suvi , Brown Jesse A. , Lee Alex Jihun , Pasquini Lorenzo , Mandelli Maria Luisa , Tempini Maria Luisa Gorno , Appleby Brian , Dickerson Brad C. , Domoto‐Reilly Kimiko , Geschwind Daniel H. , Ghoshal Nupur , Graff‐Radford Neill R. , Grossman Murray , Hsiung Ging‐Yuek Robin , Huey Edward D. , Kantarci Kejal , Karydas Anna M. , Kaufer Daniel , Knopman David S. , Litvan Irene , Mackenzie Ian R. , Mendez Mario , Onyike Chiadi U. , Ramos Eliana Marisa , Roberson Erik D. , Trataglia Maria Carmela , Toga Arthur W. , Weintraub Sandra , 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 Consortia
Published: February 2022

Background

Clinical trials for tauopathies require novel biomarkers for disease detection and monitoring. One previous study found functional connectivity (FC) alterations in presymptomatic (preSx) MAPT mutation carriers (Whitwell et al., 2011), yet studies have not examined FC networks along the MAPT disease continuum. We hypothesized that both symptomatic (Sx) and preSx MAPT mutation carriers would show FC alterations compared to healthy controls (HC).

Method

Leveraging task‐free fMRI data from the UCSF Memory and Aging Center and the ARTFL/LEFFTDS Consortia (Boeve et al., 2019), we compared 14 Sx and 33 preSx to 80 HC to characterize their FC profiles. Using a seed‐based approach, we studied FC within networks associated with different MAPT clinical syndromes (i.e., salience network [SN] for behavioral variant frontotemporal dementia, default mode network [DMN] for Alzheimer’s‐like amnestic syndrome, corticobasal syndrome [CBS] and progressive supranuclear palsy [PSP] networks). Complementing the seed‐based approach, we next calculated whole‐brain intra‐/inter‐network FC matrices for 14 networks (Brown et al., 2019), and applied K‐means clustering to assess whether preSx displayed heterogeneous connectivity profiles. ComBat was applied to harmonize multi‐site imaging data (Fortin et al., 2017, 2018). Thresholding was set at a joint height and extent threshold of p<0.05 (uncorrected) with age, sex, education and handedness as nuisance covariates.

Result

Compared to HC, Sx featured disrupted FC within key hubs of all four networks, and regions of cerebellar and pontine hyperconnectivity within CBS and PSP networks. As seen in Sx vs. HC, preSx had similar anatomical patterns of SN/CBS network hypoconnectivity and CBS/PSP network hyperconnectivity vs. HC. In contrast to Sx, who had DMN disruption, preSx showed DMN hyperconnectivity vs. HC.

Whole‐brain analyses revealed that Sx had disrupted intra‐/inter‐network FC in networks involving the insula/anterior temporal lobe. Clustering analysis identified two preSx subgroups. Compared to HC, preSx1 principally had disrupted FC across networks including those disrupted in Sx, whereas preSx2 mainly demonstrated hyperconnectivity.

Conclusion

Sx and preSx both demonstrated robust FC alterations. Future studies will investigate whether the preSx subgroup whose whole‐brain FC was similar to Sx in that it showed principally FC disruption may be at greater risk for imminent symptom conversion and/or neurodegeneration.