Association of Cortical and Subcortical Microstructure with Clinical Progression and Fluid Biomarkers in Patients With Parkinson Disease

Abstract

Background and Objectives Mean diffusivity (MD) of diffusion magnetic resonance imaging (dMRI) has been used to measure cortical and subcortical microstructural properties. This study investigated relationships of cortical and subcortical MD, clinical progression and fluid biomarkers in Parkinson disease (PD).

Methods This longitudinal study using data from the Parkinson’s progression markers initiative (PPMI) were collected from April, 2011, to July, 2022. Clinical symptoms were assessed with MDS-UPDRS and MoCA scores. Clinical assessments were followed up to five years. Linear mixed-effects (LME) models were performed to examine associations of MD and annual rate of changes in clinical scores. Partial correlation analysis was conducted to examine the associations of MD and fluid biomarker levels.

Results A total of 174 PD patients (age 61.9 ± 9.7, 63% male) with baseline dMRI and at least two years clinical follow-up were included. Results of LME models revealed significant association between MD values, predominantly in subcortical regions, temporal lobe, occipital lobe and frontal lobe, and annual rate of changes in clinical scores (MDS-UPDRS-Part-I, standardized β > 2.35; MDS-UPDRS-Part-II, standardized β > 2.34; PIGD score, standardized β > 2.47; MoCA, standardized β < -2.42; all P < 0.05, FDR corrected). In addition, MD was associated with the levels of neurofilament light chain (NfL) in serum (r > 0.22) and α-synuclein (right putamen r = 0.31), Amyloid-β 1 to 42 (Aβ₄₂) (left hippocampus r = -0.30), phosphorylated tau at 181 threonine position (P-tau) (r > 0.26) and total tau (T-tau) (r > 0.23) in cerebrospinal fluid (CSF) at baseline (all P < 0.05, FDR corrected). Furthermore, the β coefficients derived from MD and annual rate of changes in clinical score recapitulated the spatial distribution of dopamine (DAT, D1 and D2), glutamate (mGluR5 and NMDA), serotonin (5-HT1a and 5-HT2a), cannabinoid (CB1) and GABAneurotransmitter receptors/transporters (P < 0.05, FDR corrected) derived from positron emission tomography scans in the brain of healthy volunteers.

Discussion In this cohort study, cortical and subcortical MD values at baseline were associated with clinical progression and baseline fluid biomarkers, suggesting microstructural properties could be useful for stratification of patients with fast clinical progression.