Fig. 1: Summary of analysis pipeline and main results.
From: Cell-specific mechanisms drive connectivity across the time course of Huntington’s disease
Data from three cohorts (a) were used in this study: HD-YAS (57 early preHD, 60 controls), TrackOn-HD (85 late preHD, 89 controls) and Track-HD (110 manifest HD and 111 controls). Structural T1-weighted brain MRI scans (b) were parcellated using the 68 cortical region Desikan-Killiany51 atlas with FreeSurfer’s version 7 recon-all command (c). Cortical thickness, mean curvature, surface area, sulcal depth and gray matter volume were obtained (d) to compute subject-specific MIND networks. A linear mixed model was applied to each cohort obtaining z-scored effect sizes (Cohen’s d) in patient populations versus healthy controls for nodal strength and connection strengths across MIND cortical similarity matrices (e). There was hyperconnectivity in HD participants two decades before motor onset, progressing to hypoconnectivity during later stages (f), the latter being associated with neuroaxonal damage (g). Healthy structural and functional connectomes were spatially correlated with nodal strength to investigate the presence of disease epicentres (h). The distribution of neurotransmitter receptors and transporters was computed using PET data from more than 1200 healthy individuals using data from Hansen et al. (2022) (i). The relative contribution of additional structural, functional and cell-autonomous organizational principles was explored (j), finding that cell-autonomous gene expression and neurotransmitter distribution are major mechanisms contributing to nodal strength. Receptome analysis (k) showed that the first component of the distribution of neurotransmitter systems was associated with nodal strength. Finally, a neurotransmitter receptor analysis was performed disclosing a predominant association between the distribution of cholinergic and serotoninergic systems with nodal strength (l). The association with neurotransmitter systems was more prominent in granular and infragranular cortical layers. HD Huntington’s disease, MIND Morphometric Inverse Divergence, preHD premanifest HD.
