Neuromelanin-MRI to Quantify and Track Nigral Depigmentation in Parkinson's Disease: A Multicenter Longitudinal Study Using Template-Based Standardized Analysis

Abstract

Background: Clinical diagnosis and monitoring of Parkinson's disease (PD) remain challenging because of the lack of an established biomarker. Neuromelanin-magnetic resonance imaging (NM-MRI) is an emerging biomarker of nigral depigmentation indexing the loss of melanized neurons but has unknown prospective diagnostic and tracking performance in multicenter settings.

Objectives: The aim was to investigate the diagnostic accuracy of NM-MRI in early PD in a multiprotocol setting and to determine and compare serial NM-MRI changes in PD and controls.

Methods: In this longitudinal case-control 3 T MRI study, 148 patients and 97 controls were included from six UK clinical centers, of whom 140 underwent a second scan after 1.5 to 3 years. An automated template-based analysis was applied for subregional substantia nigra NM-MRI contrast and volume assessment. A point estimate of the period of prediagnostic depigmentation was computed.

Results: All NM metrics performed well to discriminate patients from controls, with receiver operating characteristic showing 85% accuracy for ventral NM contrast and 83% for volume. Generalizability using a priori volume cutoff was good (79% accuracy). Serial MRI demonstrated accelerated NM loss in patients compared to controls. Ventral NM contrast loss was point estimated to start 5 to 6 years before clinical diagnosis. Ventral nigral depigmentation was greater in the most affected side, more severe cases, and nigral NM volume change correlated with change in motor severity.

Conclusions: We demonstrate that NM-MRI provides clinically useful diagnostic information in early PD across protocols, platforms, and sites. It provides methods and estimated depigmentation rates that highlight the potential to detect preclinical PD and track progression for biomarker-enabled clinical trials. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Keywords: neuromelanin; magnetic resonance imaging; longitudinal study; depigmentation; substantia nigra.

FIG 1

Flowchart of study progression at different stages and the demographic information of patients for baseline and follow‐up visits. All the values are presented as mean ± standard deviation (SD). *Disease duration was defined as the duration between the baseline scanning time and the time of diagnosis. **LEDD: levodopa equivalent daily dose. All the values are presented as mean ± SD.

FIG 2

Diagnostic value of neuromelanin (NM) metrics in Parkinson's disease. Upper panel: normalized contrast background ratio; ventral (_v solid) and dorsal (d dashed) NM metrics show significant reduction in people with Parkinson's disease (PD, striped bars) versus controls (HC, white bars), with ROC (receiver operating characteristic) curves on the right. For unadjusted nNMc (nigral NM contrast), see Figure S5. Middle panel: normalized volumes and ROC curves. The red open circle marks the performance of generalization using the cutoff value from an independent data set. Bottom panel: group nNMcs (right) as a function of spatial location, shifting from the ventral to the dorsal part of SN (from blue to red ROIs on the left sagittal‐view image, whose locations are also illustrated in the axial images). The error bars represent the mean ± standard deviation (SD); * indicates that the difference between groups is statistically significant, adjusted for age and sex.

FIG 3

Serial changes in substantia nigra NM‐MRI (neuromelanin‐magnetic resonance imaging) contrast. (A) Group‐level decay rates of vnNMc (ventral nigral NM contrast) and dnNMc (dorsal nigral NM contrast) in controls and patients with Parkinson's disease, with individual data presented. Error bars represent mean and SD. * indicates that the difference between groups is statistically significant. (B) Scatterplot of individual pairs of serial vnNMc versus age in controls. The black dashed line links nNMc (nigral NM contrast). The pink ascending and descending solid lines represent the best linear fits of the data, respectively, when a predefined age cutoff was applied (pink dashed lines: 95% CI [confidence interval]). (C) Linear extrapolation (red solid and dashed lines; mean and 95% CI) of the decay rate in patients, adjusted for sex and age, to the estimated mean of the controls (black solid and dashed lines; mean and 95% CI) suggests about a 5‐ to 6‐year period of ventral nigral depigmentation before clinical (motor) disease onset. The light‐red points and gray points represent baseline–follow‐up time points of vnNMc for patients and controls, respectively.

FIG 4

Association between brainstem depigmentation (nNMc and nNMv) and clinical findings: (A) UPDRS‐III (Unified Parkinson's Disease Rating Scale, Part III), (B) UPDRS‐total, and (C) laterality. Solid lines/curves: linear and exponential fittings. Dashed curves: 95% confidence interval {added}. * indicates that the difference between groups is statistically significant. The error bars represent the mean ± standard deviation (SD).