Neuroimaging and plasma biomarker evidence for white matter macrostructure loss in Parkinson’s disease

<h3></h3> Parkinson’s (PD) is common and debilitating with half of patients progressing to postural instability, dementia or death within 10 years. However, onset and rate of progression is variable, and biomarkers of poor outcomes limited. Here, we assessed multimodal neuroimaging and plasma markers in 98 PD patients followed-up over 3years. Poor outcomes, defined as mild cognitive impairment, dementia, frailty, or death during follow-up, occurred in 31 patients (31.6%). We compared markers of gray matter (cortical thickness), white matter (macrostructure:fibre cross-section; microstructure:fibre density), structural and functional connectivity, and plasma levels of neurofilament light chain (NFL) and phosphorylated tau181 (p-tau) between PD poor vs good outcomes. We found extensive white matter macrostructural changes in PD who progress to poor outcomes already at baseline: with 19% reduction in fibre cross-section and a subnetwork of reduced structural connectivity (105 nodes, 215 edges, p=0.017), particularly involving interhemispheric connections. Gray matter and functional connectivity were preserved. NFL but not p-tau was increased in PD poor outcomes and correlated with white matter loss. Our findings provide convergent evidence of white matter loss in PD patients progressing to poor outcomes. White matter macrostructural imaging and plasma NFL may be potential biomarkers in PD, informing the design of future clinical trials.