Magnetic susceptibility is predictive of future clinical severity in Parkinson’s disease

Abstract

AbstractDementia is common in Parkinson’s disease, but there is wide variation in its timing. With the emergence of disease modifying treatments in neurodegeneration, there is increasing need to detect and treat disease at the earliest stages and to monitor disease progression. A critical gap in Parkinson’s disease is the lack of quantifiable markers of progression, and methods to identify early stages. Until recently, MRI has had limited sensitivity to detect or track changes relating to Parkinson’s dementia, but advanced techniques, especially quantitative magnetic susceptibility mapping (QSM) which is sensitive to brain tissue iron, show potential for these purposes. So far, QSM, applied to cognition in Parkinson’s, has only been investigated in detail in cross-sectional cohorts. Here we present a longitudinal study throughout the brain using QSM in Parkinson’s disease. We included 59 Parkinson’s patients (with no dementia at study onset), and 22 controls, at baseline and after 3-year follow-up. Participants underwent detailed assessments of motor and cognitive severity at both timepoints. We found that increased magnetic susceptibility values in right temporal cortex and right putamen in patients were associated with poorer cognition at baseline. Strikingly, increased baseline susceptibility values within right temporal cortex, nucleus basalis of Meynert and putamen in patients were associated with greater cognitive severity after 3-year follow-up; and increased baseline susceptibility in basal ganglia, substantia nigra, red nucleus, insular cortex and dentate nucleus in patients were associated with greater motor severity after 3-year follow-up. We further found that after 3-years, increased follow-up susceptibility in these regions was associated with increased follow-up cognitive and motor severity, with further involvement of hippocampus relating to cognitive severity. However, region of interest analyses revealed that, in cortical regions, increases in paramagnetic susceptibility relating to iron could not alone explain the associations with increased clinical severity that were observed; and, similar to other studies, we did not find consistent increases in susceptibility within the 3-year follow-up period. Our study suggests that QSM has predictive sensitivity to detect changes in clinical severity many months prior to overt cognitive involvement in Parkinson’s. However, it also suggests that susceptibility within brain tissue over time may relate to changes in tissue composition other than iron concentration, such as in the relative proportion of myelin. Whilst our findings open the door for QSM to detect patients at the earliest stages of Parkinson’s dementia, we will require additional tissue metrics to augment the interpretation QSM, such that it can be used robustly in clinical practice or to provide outcome measures in therapeutic trials for disease modifying treatments in neurodegeneration.