Progression marker of Parkinson's disease: a 4-year multi-site imaging study

Abstract

Progression markers of Parkinson's disease are crucial for successful therapeutic development. Recently, a diffusion magnetic resonance imaging analysis technique using a bitensor model was introduced allowing the estimation of the fractional volume of free water within a voxel, which is expected to increase in neurodegenerative disorders such as Parkinson's disease. Prior work demonstrated that free water in the posterior substantia nigra was elevated in Parkinson's disease compared to controls across single- and multi-site cohorts, and increased over 1 year in Parkinson's disease but not in controls at a single site. Here, the goal was to validate free water in the posterior substantia nigra as a progression marker in Parkinson's disease, and describe the pattern of progression of free water in patients with a 4-year follow-up tested in a multicentre international longitudinal study of de novo Parkinson's disease (http://www.ppmi-info.org/). The analyses examined: (i) 1-year changes in free water in 103 de novo patients with Parkinson's disease and 49 controls; (ii) 2- and 4-year changes in free water in a subset of 46 patients with Parkinson's disease imaged at baseline, 12, 24, and 48 months; (iii) whether 1- and 2-year changes in free water predict 4-year changes in the Hoehn and Yahr scale; and (iv) the relationship between 4-year changes in free water and striatal binding ratio in a subgroup of Parkinson's disease who had undergone both diffusion and dopamine transporter imaging. Results demonstrated that: (i) free water level in the posterior substantia nigra increased over 1 year in de novo Parkinson's disease but not in controls; (ii) free water kept increasing over 4 years in Parkinson's disease; (iii) sex and baseline free water predicted 4-year changes in free water; (iv) free water increases over 1 and 2 years were related to worsening on the Hoehn and Yahr scale over 4 years; and (v) the 4-year increase in free water was associated with the 4-year decrease in striatal binding ratio in the putamen. Importantly, all longitudinal results were consistent across sites. In summary, this study demonstrates an increase over 1 year in free water in the posterior substantia nigra in a large cohort of de novo patients with Parkinson's disease from a multi-site cohort study and no change in healthy controls, and further demonstrates an increase of free water in Parkinson's disease over the course of 4 years. A key finding was that results are consistent across sites and the 1-year and 2-year increase in free water in the posterior substantia nigra predicts subsequent long-term progression on the Hoehn and Yahr staging system. Collectively, these findings demonstrate that free water in the posterior substantia nigra is a valid, progression imaging marker of Parkinson's disease, which may be used in clinical trials of disease-modifying therapies.

Keywords: Parkinson’s disease; basal ganglia; biomarkers; free water; imaging.

Figure 1

Illustration of the procedure used to draw regions of interest in the ASN and PSN. Regions of interest were drawn on the b0 image in MNI space of each subject, blinded to the free water map, group status, and visit. Of note, the placement of the regions of interest was guided by anatomical landmarks and not the MNI coordinates corresponding to the substantia nigra, and was consistent across subjects and scans. First, on the b0 image we identified the slice(s) where the red nucleus was prominent and largest. Next, regions of interest were delineated inferiorly on the z-axis, starting with the slice where the red nucleus began to fade away and is only faintly visible (Slice #1), and continuing on the next, more ventral slice, where the red nucleus was no longer visible (Slice #2). In each hemisphere, the regions of interest were drawn in the area of hypointense signal (dark on b0) corresponding to the substantia nigra, while avoiding the edge of the midbrain.

Figure 2

Longitudinal changes in free water in PSN. Panels show differences (adjusted for free water at baseline) between patients with Parkinson’s disease from Cohort 1 and healthy controls (A), and free water in PSN over the course of 4 years in the patients with Parkinson’s disease from Cohort 2 (B). (C) An example of a free water map at each time point of a single Parkinson’s disease patient. Error bars represent the standard error. CON = controls; FW = free water; PD = Parkinson’s disease.

Figure 3

Relative per cent change in free water in PSN over 1 year (A) and 2 years (B) across subgroups determined based on the 4-year changes in the Hoehn and Yahr stage. In both plots, the per cent change from baseline is greater in patients with Parkinson’s disease who had a 1-point increase on the Hoehn and Yahr scale (n = 8) than in patients with Parkinson’s disease who did not progress on the scale (n = 19). Parkinson’s disease patients who had a decrease of 1 point on the scale had almost no change in free water (n = 4) compared with the other two groups. Error bars represent the standard error. FW = free water; PD = Parkinson’s disease.

Figure 4

Correlation plot illustrating the relation between 4-year relative per cent change in free water in PSN and 4-year relative per cent change in SBR in the putamen. FW = free water; PUT = putamen.