An International Multicenter Analysis of Brain Structure across Clinical Stages of Parkinson's Disease: The ENIGMA-Parkinson's Study

Background: Brain structure abnormalities throughout the course of Parkinson's Disease (PD) have yet to be fully elucidated. Inconsistent findings across studies may be partly due to small sample sizes and heterogeneous analysis methods. Using a multicenter approach and harmonized analysis methods, we aimed to overcome these limitations and shed light on disease stage-specific profiles of PD pathology as suggested by in vivo neuroimaging. Method: Individual brain MRI and clinical data from 2,367 PD patients and 1,183 healthy controls were collected from 19 sites, deriving from 20 countries. We analyzed regional cortical thickness, cortical surface area, and subcortical volume using mixed-effect linear models. Patients were grouped according to the Hoehn & Yahr (HY) disease stages and compared to age- and sex-matched controls. Within the PD sample, we investigated associations between Montreal Cognitive Assessment (MoCA) scores and brain morphology. Findings: The main analysis showed a thinner cortex in 38 of 68 regions in PD patients compared to controls (dmax = -0{middle dot}25, dmin = -0{middle dot}13). The bilateral putamen (left: d = -0{middle dot}16, right: d = -0{middle dot}16) and left amygdala (d = -0{middle dot}15) were smaller in patients, while the left thalamus was larger (d = 0{middle dot}17). HY staging indicated that a thinner cortex initially presents in the occipital, parietal and temporal cortex, and extends towards caudally located brain regions with increased disease severity. From HY stage 2 and onwards the bilateral putamen and amygdala were consistently smaller with larger effects denoting each increment. Finally, we found that poorer cognitive cognitive performance was associated with widespread cortical thinning as well as lower volumes of core limbic structures. Interpretation: Our findings offer robust and novel imaging signatures that are specific to the disease severity stages and in line with an ongoing neurodegenerative process, highlighting the importance of such multicenter collaborations. Funding: NIH Big Data to Knowledge program, ENIGMA World Aging Center, and ENIGMA Sex Differences Initiative, and other international agencies (listed in full in the Acknowledgments).