Association between neuromelanin-sensitive MRI signal and psychomotor slowing in late-life depression

Abstract

Late-life depression (LLD) is a prevalent and disabling condition in older adults that is often accompanied by slowed processing and gait speed. These symptoms are related to impaired dopamine function and sometimes remedied by levodopa (L-DOPA). In this study, we recruited 33 older adults with LLD to determine the association between a proxy measure of dopamine function-neuromelanin-sensitive magnetic resonance imaging (NM-MRI)-and baseline slowing measured by the Digit Symbol test and a gait speed paradigm. In secondary analyses, we also assessed the ability of NM-MRI to predict L-DOPA treatment response in a subset of these patients (N = 15) who received 3 weeks of L-DOPA. We scanned a further subset of these patients (N = 6) with NM-MRI at baseline and after treatment to preliminarily evaluate the effects of L-DOPA treatment on the NM-MRI signal. We found that lower baseline NM-MRI correlated with slower baseline gait speed (346 of 1807 substantia nigra-ventral tegmental area (SN-VTA) voxels, Pcorrected = 0.038), particularly in the more medial, anterior, and dorsal SN-VTA. Secondary analyses failed to show an association between baseline NM-MRI and treatment-related changes in gait speed, processing speed, or depression severity (all Pcorrected > 0.361); we however found preliminary evidence of increases in the NM-MRI signal 3 weeks post-treatment with L-DOPA compared to baseline (200 of 1807 SN-VTA voxels; Pcorrected = 0.046), although the small sample size of these preliminary analyses warrants caution in their interpretation and future replications. Overall, our findings indicate that NM-MRI is sensitive to variability in gait speed in patients with LLD, suggesting this non-invasive MRI measure may provide a promising marker for dopamine-related psychomotor slowing in geriatric neuropsychiatry.

Trial registration: ClinicalTrials.gov NCT02744391 NCT01931202.

Figures

Fig. 1. Baseline NM-MRI CNR correlates with baseline gait speed.

a Map of SN-VTA voxels where NM-MRI CNR positively correlated (thresholded at P < 0.05, voxel level) with a single-task measure of gait speed (green voxels) overlaid on the average NM-MRI CNR image from all subjects. b Scatterplot showing the average NM-MRI CNR extracted from the significant voxels in a plotted against gait speed for visualization purposes. These plotted data show a Pearson correlation coefficient of 0.49, although this effect-size estimate is likely inflated given the selection of significant voxels for this effect.

Fig. 2. Secondary analyses of baseline NM-MRI CNR do not predict changes in gait speed after 3 weeks of L-DOPA treatment in region-of-interest or voxelwise analyses.

a Scatterplot showing the average NM-MRI CNR extracted from the significant (green) voxels in Fig. 1a plotted against gait speed. These plotted data have a Pearson correlation coefficient of 0.10. b Scatterplot showing the average NM-MRI CNR extracted from the voxels where NM-MRI CNR positively correlated with the change in gait speed after 3 weeks of L-DOPA treatment (N = 64; thresholded at P < 0.05, voxel level). These plotted data have a Pearson correlation coefficient of 0.17.

Fig. 3. NM-MRI CNR significantly increases after 3 weeks of L-DOPA treatment in an exploratory analysis.

a Map of SN-VTA voxels where NM-MRI CNR was significantly increased after 3 weeks of L-DOPA (thresholded at P < 0.05, voxel level; red voxels) overlaid on the average NM-MRI CNR image from all subjects. b Histogram showing the average change across subjects in NM-MRI CNR after treatment including all SN-VTA voxels, which is generally shifted to the right of zero (denoting increased NM-MRI CNR). For visualization purposes, heights are proportional to either the number of L-DOPA voxels (N = 200; red bars corresponding to voxels in a or the number of Other SN-VTA Voxels (i.e., non-significant voxels; N = 1607); e.g., a bar with voxel proportion of 0.2 for L-DOPA voxels corresponds to 40 voxels while a bar with voxel proportion of 0.2 for Other SN-VTA Voxels corresponds to 321 voxels. c Ladder plot showing the average NM-MRI CNR extracted from the significant (red) voxels in a at baseline (Pre L-DOPA) and after 3 weeks of L-DOPA treatment (Post L-DOPA) for the 6 subjects (each shown in a different color to emphasize consistent increases across each subject).