Surrogate markers of progression in Parkinson disease: Correlation between clinical features and neuroimaging (2015)

Parkinson disease is a progressive neurodegenerative disorder affecting approximately 100,000 Canadians. Loss of dopaminergic neurons in the substantia nigra of the basal ganglia is the prominent pathology associated with many of the motor features that characterise Parkinson disease. Increased levels of iron in the substantia nigra are seen in Parkinson disease although the mechanistic significance is uncertain. It is becoming increasingly clear that the disability associated with Parkinson disease extends beyond motor features and that changes in cognition are prominent features, even in early disease. The debilitating phenomenon “freezing of gait” (FOG) emerges in some with Parkinson disease, often accompanying this decline in cognitive function. The purpose of this research was to test the hypothesis that Parkinson disease is associated with longitudinal changes in motor function and cognition which can be quantified clinically and with brain imaging (magnetic resonance imaging and/or spectroscopy). We hypothesized that imaging markers of abnormal brain structure and function will correlate with these clinical changes and serve as biomarkers of disease progression. In order to investigate this, we evaluated the evolving relationship between clinical manifestations, reflected in changes of gait and cognition, and in vivo structural and functional changes as measured by high field magnetic resonance imaging and spectroscopy in early, untreated individuals with Parkinson disease over a period of 36 months. In the first study (Chapter 2), we evaluated changes in midbrain iron content in a group of early untreated Parkinson disease subjects compared to a control group and correlated evolving motor dysfunction with these changes. Results suggested that the change in midbrain iron content, as estimated by R2*, correlated with a change in motor symptoms over three years in the Parkinson disease group. This provides evidence that this measure may have utility as an imaging marker for Parkinson disease progression. In the second study (Chapter 3), we investigated changes in this same iron-rich midbrain region to determine if changes were associated differently between a cohort of early, untreated Parkinson disease subjects who developed FOG over three years compared to one who did not. While the measured R2* values of both groups changed over time, the FOG group showed more rapid deterioration in motor function and SNc changes suggestive of increased iron content. This result suggests a difference in midbrain pathology between these groups, with increased nigral iron content appearing to be closely associated with severity of motor features in Parkinson disease. To our knowledge, this is the first longitudinal study to observe differences in midbrain iron content, as measured R2* values, to differentiate subjects in whom FOG emerged from those with similar disease duration who did not. In the third study (Chapter 4), we examined the relationship of cognitive changes and clinical motor features, including FOG, with a magnetic resonance spectroscopy maker of regional neuronal loss, NAA/Cr ratio, in the pre-supplementary motor area. We compared a group of early, untreated Parkinson disease to controls and, separately, a group who developed FOG to one that did not, over 36 months. Significant cognitive deficits associated with frontal lobe dysfunction were present in patients with early, untreated Parkinson disease but impaired cognition was not predictive of the development of FOG. In contrast, individuals who developed FOG had worse motor function at baseline and more rapid decline in motor scores over 36 months indicating an association between disease burden and the development of FOG. Together, these results suggest that measures of neuronal loss in the pre-supplementary motor area, reflected in NAA/Cr ratios, are a poor correlate of impaired cognitive and/or motor function, at least in this study cohort with early disease. Midbrain iron content, estimated by R2* values, however, may be a marker of disease progression and may help differentiate those with Parkinson disease who are destined to develop FOG from those who are not.