Thalamic Dorsomedial Nucleus Free Water Correlates with Cognitive Decline in Parkinson's Disease

Background: Brain diffusion tensor imaging (DTI) has been shown to reflect cognitive changes in early Parkinson's disease (PD) but the diffusion-based measure free water (FW) has not been previously assessed. Objectives: To assess if FW in the thalamic nuclei primarily involved with cognition (ie, the dorsomedial [DMN] and anterior [AN] nuclei), the nucleus basalis of Meynert (nbM), and the hippocampus correlates with and is associated with longitudinal cognitive decline and distinguishes cognitive status at baseline in early PD. Also, to explore how FW compares with conventional DTI, FW-corrected DTI, and volumetric assessments for these outcomes. Methods: Imaging data and Montreal Cognitive Assessment (MoCA) scores from the Parkinson's Progression Markers Initiative database were analyzed using partial correlations and ANCOVA. Primary outcome multiple comparisons were corrected for false discovery rate (q value). Results: Thalamic DMN FW changes over 1 year correlated with MoCA changes over both 1 and 3 years (partial correlations −0.222, q = 0.040, n = 130; and − 0.229, q = 0.040, n = 123, respectively; mean PD duration at baseline = 6.85 months). NbM FW changes over 1 year only correlated with MoCA changes over 3 years (−0.222, q = 0.040). Baseline hippocampal FW was associated with cognitive impairment at 3 years (q = 0.040) and baseline nbM FW distinguished PD-normal cognition (MoCA ≥26) from PD-cognitive impairment (MoCA ≤25), (q = 0.008). The exploratory comparisons showed FW to be the most robust assessment modality for all outcomes. Conclusions: Thalamic DMN FW is a promising cognition progression biomarker in early PD that may assist in identifying cognition protective therapies in clinical trials. FW is a robust assessment modality for these outcomes.