Quantitative iron-neuromelanin MRI associates with motor severity in Parkinson's disease and matches radiological disease classification

Abstract

Background: Neuromelanin- and iron-sensitive MRI studies in Parkinson's disease (PD) are limited by small sample sizes and lack detailed clinical correlation. In a large case-control PD cohort, we evaluated the diagnostic accuracy of quantitative iron-neuromelanin MRI parameters from the substantia nigra (SN), their radiological utility, and clinical association.

Methods: PD patients and age-matched controls were prospectively recruited for motor assessment and midbrain neuromelanin- and iron-sensitive [quantitative susceptibility mapping (QSM) and susceptibility map-weighted imaging (SMWI)] MRI. Quantitative neuromelanin-iron parameters from the SN were assessed for their discriminatory performance in PD classification using ROC analysis compared to those of qualitative visual classification by radiological readers of differential experience and used to predict motor severity.

Results: In total, 191 subjects (80 PD, mean age 65.0 years; 111 controls, 65.6) were included. SN masks showed (a) higher mean susceptibility (p < 0.0001) and smaller sizes after thresholding for low susceptibility (p < 0.0001) on QSM and (b) lower contrast range (p < 0.0001) and smaller sizes after thresholding for high-signal voxels (p < 0.0001) on neuromelanin-sensitive MRI in patients than in controls. Quantitative iron and neuromelanin parameters showed a moderate correlation with motor dysfunction (87.5%: 0.4< | r | <0.6, p < 0.0001), respectively. A composite quantitative neuromelanin-iron marker differentiated the groups with excellent performance (AUC 0.94), matching the diagnostic accuracy of the best-performing reader (accuracy 97%) using SMWI.

Conclusion: Quantitative neuromelanin-iron MRI is associated with PD motor severity and matched best-performing radiological PD classification using SMWI, with the potential to improve diagnostic confidence in the clinics and track disease progression and response to neuroprotective therapies.

Keywords: MRI; Parkinson's disease; classification; comparative study; correlation analysis; iron; neuromelanin; substantia nigra.

Figure 1

Anatomical landmarks for slice selection for qualitative visual evaluation and segmentation of the substantia nigra for quantitative image analysis. Corresponding consecutive (cranio-caudal—left-to-right) midbrain iron- (SMWI) and neuromelanin-sensitive MRI slices demonstrate the relations of the three slices (boxed in red) used between modalities. Loss of the normal hyperintense nigrosome-1 within the hypointense substantia nigra (yellow arrow) was assessed on SMWI slices just below the inferior pole of the red nucleus (asterisk). Loss of normal hyperintensity in the substantia nigra was assessed on neuromelanin-sensitive slices from the last slice through the interpeduncular fossa (star). Permission had been granted by the participating control subject for the publishing of these images.

Figure 2

Comparison of receiver operating characteristics (ROC) curves from best performing quantitative MRI parameters of: neuromelanin signal contrast range within segmented substantia nigral mask, substantia nigra mask size after thresholding for high neuromelanin signal voxels, and low susceptibility (<70 ppb) voxels on QSM, and composite marker (product of three aforesaid parameters) in PD classification.