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Movement Disorders Parkinson’s Disease New Magnetic Resonance Imaging Biomarkers Advance the Characterization of Parkinson Disease David A Ziegler, PhD 1 and Suzanne Corkin, PhD 2 1. Post-doctoral Fellow, Department of Neurology and the Center for Integrative Neuroscience, University of California San Francisco, San Francisco, California, US; 2. Professor of Behavioral Neuroscience, Emerita, Department of Brain & Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts, US Abstract The pathophysiology of idiopathic Parkinson disease (PD) is traditionally characterized as substantia nigra degeneration, but careful examination of the widespread neuropathologic changes suggests individual differences in neuronal vulnerability. A major limitation to studies of disease progression in PD has been that conventional magnetic resonance imaging (MRI) techniques provide relatively poor contrast for the structures that are affected by the disease, and thus are not typically used in experimental or clinical studies. Here, we review the current state of structural MRI as applied to the analysis of the PD brain. We also describe a new multispectral MRI method that provides improved contrast for the substantia nigra and basal forebrain, which we recently used to show that these structures display different trajectories of volume loss early in the disease. Keywords Parkinson’s disease, MRI, substantia nigra, basal forebrain, neurodegeneration, biomarkers Disclosure: The authors have no conflicts of interest to declare. Received: March 20, 2013 Accepted: April 25, 2013 Citation: US Neurology, 2013;9(1):8–12 Correspondence: David A Ziegler, PhD, University of California, San Francisco, Sandler Neurosciences Center, 675 Nelson Rising Lane, UCSF MC 0444, San Francisco, CA 94158, US. E: david@gazzaleylab.ucsf.edu Parkinson disease (PD) is a devastating neurodegenerative disorder characterized by its cardinal motor symptoms: resting tremor, muscular rigidity, bradykinesia, postural instability, and gait abnormality. 1 PD currently affects 1–2 % of individuals over age 65, totaling five million people worldwide. During the next 20 years, the incidence of PD is projected to double, making research on its causes and treatments timelier and more relevant to global public health than ever before. A major impediment to such research is a paucity of safe, fast, and effective brain imaging methods for visualizing the structures affected by PD. Because conventional structural magnetic resonance imaging (MRI) techniques cannot visualize the brain changes that are at the core of this disease, MRI-based biomarkers for diagnosis and tracking disease progression do not currently exist. The cardinal motor features of PD are typically attributed to a loss of nigrostriatal dopaminergic neurons in the substantia nigra pars compacta (SNpc), which is accompanied by the aggregation of Lewy bodies and neurites in this structure. 2–4 While denervation of dopaminergic nigrostriatal projections may explain the primary motor symptoms of PD, as shown by the dramatic motor improvement associated with dopamine replacement therapy, 5,6 abnormalities beyond the SNpc 7–10 likely underlie the serious and potentially debilitating non-motor features, including cognitive and memory impairments and progression to dementia. 11,12 Notably, degeneration of the cholinergic basal forebrain (BF) 13–15 and noradrenergic locus coeruleus 16,17 in PD probably contribute to non-motor deficits. Although deterioration in the BF and LC is most often associated with late-stage PD with dementia, 18 subtle changes in earlier stages could result in poor performance on tests of memory and attention. 19 Research on these non-motor aspects of the disease has been hindered by a lack of 8 sensitive MRI biomarkers for the affected structures. This article reviews recent progress in developing new MRI-based biomarkers to visualize and characterize abnormalities in some of the brain structures affected by PD. Imaging the Substantia Nigra The substantia nigra comprises two structurally and functionally segregated regions: the SNpc, which projects mainly to the striatum and basal ganglia, and the substantia nigra pars reticulata (SNr), which sends its primary efferent projections to the thalamus and superior colliculus. In PD, neuronal loss in the SNpc is prevalent in the caudal and mediolateral part and more limited in mediorostral areas. 20 This loss of SNpc neurons results in a marked depletion of dopamine in the striatum, and to a lesser extent in other basal ganglia nuclei. The pattern of dopamine loss in the striatum parallels the lateral to medial gradient of cell loss in the SNpc, with cells projecting to the putamen showing signs of atrophy first, followed by those that project to the caudate nucleus and nucleus accumbens. 21 Functionally segregated circuits link the basal ganglia and cortex in a topographical manner, 4–6 with dense reciprocal fronto-striatal connections, which are known to support high-order cognitive functions. 22,23 Because abnormalities in any part of the complex basal ganglia-thalamocortical circuitry could have significant downstream consequences, 24 PD may be considered a network disease. Significant progress has been made using MRI to accurately segment the structures of the basal ganglia, 25,26 but few tools exist for measuring the size and structure of the SNpc. One hindrance to the development of effective morphometric tools is that the borders of the SNpc are nearly impossible to visualize on conventional T1-weighted MRI. 27 As a result, numerous attempts have © TOU C H ME D ICA L ME D IA 2013