Neuroimaging and plasma marker evidence for white matter macrostructure loss in Parkinsons disease

Parkinsons disease (PD) is the second commonest neurodegenerative disorder and over half of patients progress to postural instability, dementia or death within 10 years of diagnosis. However, onset and rate of progression to poor outcomes is highly variable, underpinned by heterogeneity in the underlying pathological process. Improved biomarkers of poor outcomes would be helpful for targeted treatment, but most studies to-date have been limited to a single modality or the assessment of patients with established cognitive impairment. Here, we use multimodal neuroimaging and plasma biomarkers in 98 patients with PD and 28 age-matched controls followed-up over 3 years, including: gray matter (cortical thickness), white matter (macrostructure: fibre-cross section and microstructure: fibre density) at whole-brain and tract level, structural and functional connectivity and plasma levels of neurofilament light chain (NFL) and phosphorylated tau (p-tau) 181. We show extensive reductions in fibre cross-section and structural connectivity in PD with poor outcomes, with preserved gray matter and functional connectivity. NFL, but not p-tau181 levels was increased in PD with poor outcomes and correlated with white matter loss. These findings suggest that imaging sensitive to white matter macrostructure and plasma NFL may be useful biomarkers of poor outcomes in PD. As new targeted treatments are emerging, these biomarkers show important potential to aid patient selection for treatments and improve stratification to clinical trials.