A worldwide study of subcortical shape as a marker for clinical staging in Parkinson's disease

Abstract

Alterations in subcortical brain regions are linked to motor and non-motor symptoms in Parkinson's disease (PD). However, associations between clinical expression and regional morphological abnormalities of the basal ganglia, thalamus, amygdala and hippocampus are not well established. We analyzed 3D T1-weighted brain MRI and clinical data from 2525 individuals with PD and 1326 controls from 22 global sources in the ENIGMA-PD consortium. We investigated disease effects using mass univariate and multivariate models on the medial thickness of 27,120 vertices of seven bilateral subcortical structures. Shape differences were observed across all Hoehn and Yahr (HY) stages, as well as correlations with motor and cognitive symptoms. Notably, we observed incrementally thinner putamen from HY1, caudate nucleus and amygdala from HY2, hippocampus, nucleus accumbens, and thalamus from HY3, and globus pallidus from HY4-5. Subregions of the thalami were thicker in HY1 and HY2. Largely congruent patterns were associated with a longer time since diagnosis and worse motor symptoms and cognitive performance. Multivariate regression revealed patterns predictive of disease stage. These cross-sectional findings provide new insights into PD subcortical degeneration by demonstrating patterns of disease stage-specific morphology, largely consistent with ongoing degeneration.

Fig. 1. Mass univariate analysis: significant vertex-wise differences in thickness between the full PD group and controls.

A Effect map projected onto the subcortical regions showing the PD versus control group comparison. Positive b-values indicate that regions are thicker and negative b-values indicate that regions are thinner in PD compared to controls. The model is corrected for age, sex, intracranial volume and cohort. B A dissection of the fourteen subcortical structures of interest in this study to guide the interpretation of panel (A). C Thalamus effect maps showing group differences and D anatomical drawing of the thalamus and its subnuclei displayed approximately in the same angle for interpretation purposes. L left hemisphere, R right hemisphere, Ant anterior nucleus, In intralaminar nuclei, LD lateral dorsal nucleus, LGN lateral geniculate nucleus, LP lateral posterior nucleus, MD mediodorsal nucleus, MGN medial geniculate nucleus, Mid midline nuclei, Pul pulvinar nucleus, VA ventral anterior nucleus, VL ventral lateral nucleus, VPL ventral posterior lateral nucleus, VPM ventral posterior medial nucleus.

Fig. 2. Mass univariate analysis: significant vertex-wise differences in thickness between HY stage and age- and sex-matched controls.

A HY1, B HY2, C HY3, and D HY45 results are shown in the dorsal and ventral view. Positive b-values indicate that regions are thicker in the PD group compared to controls and negative b-values indicate that regions are thinner. The models are corrected for intracranial volume, age, sex, and cohort. HY Hoehn and Yahr.

Fig. 3. Mass univariate analysis: significant vertex-wise correlation between clinical measures and thickness within the PD group.

A Time since diagnosis, B MoCA, and C MDS-UPDRS3 motor score while off medication are shown. Positive b-values indicate a positive correlation and negative b-values indicate a negative correlation. All regression analyses were corrected for age, sex, and intracranial volume. MoCA Montreal cognitive assessment, MDS-UPDRS3 OFF Movement Disorders Society-sponsored revision of the Unified Parkinson’s disease rating scale part 3 assessed in OFF medication state.

Fig. 4. Machine learning: binary and ordinal classification maps.

Binary and ordinal classification uses vertex-wise thickness information from all subcortical structures. The color bars represent the learned weights of the classification model, positive values (SD from the learned weights) in red, and negative values in blue. More intense colors indicate a stronger predictive power of the classification. Displayed are the results of A the binary classification of people with PD and controls, B the ordinal classification of HY1–HY2–HY345.