Magnetic Resonance Imaging Features of the Nigrostriatal System: Biomarkers of Parkinson’s Disease Stages?

Abstract

IntroductionMagnetic resonance imaging (MRI) can be used to identify biomarkers in Parkinson’s disease (PD); R2* values reflect iron content related to high levels of oxidative stress, whereas volume and/or shape changes reflect neuronal death. We sought to assess iron overload in the nigrostriatal system and characterize its relationship with focal and overall atrophy of the striatum in the pivotal stages of PD.MethodsTwenty controls and 70 PD patients at different disease stages (untreated de novo patients, treated early-stage patients and advanced-stage patients with L-dopa-related motor complications) were included in the study. We determined the R2* values in the substantia nigra, putamen and caudate nucleus, together with striatal volume and shape analysis. We also measured R2* in an acute MPTP mouse model and in a longitudinal follow-up two years later in the early-stage PD patients.ResultsThe R2* values in the substantia nigra, putamen and caudate nucleus were significantly higher in de novo PD patients than in controls. Early-stage patients displayed significantly higher R2* values in the substantia nigra (with changes in striatal shape), relative to de novo patients. Measurements after a two-year follow-up in early-stage patients and characterization of the acute MPTP mouse model confirmed that R2* changed rapidly with disease progression. Advanced-stage patients displayed significant atrophy of striatum, relative to earlier disease stages.ConclusionEach pivotal stage in PD appears to be characterized by putative nigrostriatal MRI biomarkers: iron overload at the de novo stage, striatal shape changes at early-stage disease and generalized striatal atrophy at advanced disease.

Distinct progression pattern of susceptibility MRI in the substantia nigra of Parkinson's patients

“…Our findings of greater rates of increases in SNc R2* in PD patients overall are in agreement with those reported by Ulla and Hopes et al In a study of PD patients (n = 19) early in their disease course (untreated at the beginning of the study), Wieler et al did not observe longitudinal effects. Consistent with their finding, our subgroup analysis in early‐ to mid‐stage PD patients also did not reach statistical significance.…”

“…Together, these results suggest that susceptibility MRI can mark Parkinson's progression, and that R2* and QSM in the SNc and SNr may reflect different aspects of PD‐related pathology and follow different patterns of progression. The findings also may resolve discrepant results from some prior longitudinal studies and suggest that the pathophysiological processes of PD progression can be region specific and non‐monotonic.…”

“…Several cross‐sectional studies have demonstrated higher R2* and QSM in the SN of PD patients and fueled enthusiasm for using these susceptibility MRI metrics to gauge PD progression. The results of limited longitudinal studies, however, have been inconsistent, with some reporting increased nigral signals, whereas others failed to detect a change or showed lower R2* in later stages of PD . These inconsistencies have shed doubt on the validity of using susceptibility MRI as a PD biomarker …”

Post translational changes to α-synuclein control iron and dopamine trafficking; a concept for neuron vulnerability in Parkinson’s disease

“…To a lesser extent, iron overload also seems to precede atrophy in the striatum [45]. Despite these early stage iron changes with disease and the potential for its use as a biomarker for disease progression, it still remains to be determined whether iron is causal or a downstream effect of PD.…”

The role of high‐field magnetic resonance imaging in parkinsonian disorders: Pushing the boundaries forward

“…Iron content can be quantified using iron‐sensitive techniques such as the R2* relaxation rate or susceptibility‐weighted imaging and QSM, 2 techniques that use information in phase images about variations in the local magnetic field. Nigral changes reflecting increases have been consistently reported in PD at 1.5T and 3T . However, PD values overlapped with those of HCs, and a few studies found no changes in PD, limiting its clinical use as disease marker today .…”