Connectome hierarchy de-differentiation relates to motor severity and to glymphatic-related imaging measures in drug-naïve Parkinson's disease

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Abstract Cortical function is organised along a principal connectome gradient spanning primary sensory to transmodal association systems, but whether this hierarchy is altered in Parkinson’s disease (PD), and whether it relates to imaging measures of the brain’s fluid environment, is unknown. In 472 participants scanned at a single site (310 drug-naïve PD, 162 healthy controls), voxel-wise connectome gradients were derived by diffusion-map embedding and hierarchy de-differentiation was indexed by alignment-independent between-network segregation and gradient dispersion. Within patients, lower sensory-to-transmodal segregation was associated with higher MDS-UPDRS-III (visual–control β=−0.21, 95% CI −0.33 to −0.09, p_FDR=0.005, n=301) and with higher Hoehn–Yahr stage, each feature explaining about 4% of the variance. De-differentiation was coupled to weaker global BOLD–CSF coupling (r=0.22, n=302, p_FDR=0.015 under the most conservative single-family correction), and at trend level to DTI-ALPS and perivascular-space morphology. These three glymphatic-related measures were near-independent of one another (|r|≤0.09), so their concordance is convergent rather than redundant. Associations persisted after adjustment for gray-matter volume, were unchanged across gradient-construction parameters and embedding alignment and replicated in an independent cohort (PD n=61). Baseline segregation was associated with subsequent MDS-UPDRS-III change (n=73, exploratory). Hierarchy de-differentiation is thus a within-disease correlate of motor severity; these cross-sectional associations identify a coherent set of relationships rather than a demonstrated pathway.

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