This is a proposal to support my career development and research efforts in clarifying the role of dopamine receptors in primary focal dystonias. I have received clinical training in Movement Disorders under Dr. Joel Perlmutter's tutelage and participated intensively on numerous projects in his lab, as well as worked towards developing my own unique interests and funding. My long term goal is to achieve a better understanding of the basal ganglia network and its role in the pathophysiology of movement disorders with the use of neuroimaging techniques. I have access to world-class facilities at Washington University, numerous didactic courses and seminars, and excellent mentorship by Drs. Perlmutter, Mach and Schlaggar. Receiving this award would be a unique opportunity to secure protected time and the resources much needed for a goal-oriented effort. Dystonia is an involuntary movement disorder characterized by repetitive patterned or sustained muscle contractions causing abnormal postures. This disabling disease may afflict 250,000 people in the U.S. Although specific genetic defects may cause some forms of dystonia its etiology remains unknown and treatment options unsatisfactory. Conventional dystonia models incorporate abnormalities in dopaminergic pathways with main focus on D2-like receptors, but studies have yet to identify which dopamine receptor subtypes are most involved, and how these changes affect downstream functional pathways. Thus, using neuroimaging, this application will refine the current models by distinguishing whether D3 and D1-like receptors are affected, and whether abnormal receptor levels affect the functional connectivity of relevant brain networks. Most previous neuroimaging work in dystonia has focused on D2-like (D2, D3, D4) receptors. However, the ability of PET to distinguish receptor subtypes depends upon the selectivity of the radioligands. We found that striatal spiperone binding in primary focal dystonia was reduced, but this ligand also binds to 5-HT(2A) receptors. Other studies have found reduced raclopride uptake, which has a low selectivity for 5-HT(2A) but near equal selectivity for D2 and D3 receptors. Subsequently, we did not find reduced binding with a highly selective D2 ligand NMB (200-fold more selective for D2 than D3) in dystonia. These findings suggest that an abnormality of D3 receptors (D3 R) may account for these discrepancies and thus be the critical dopaminergic abnormality in dystonia. In addition it will be important to establish whether D1-like receptors are also abnormal as there is emerging evidence for the synergistic function of D1 and D3 receptors, and existing data with regard to the role of D1-like receptors in dystonia are quite limited. Finally, alterations in endogenous dopamine level could explain receptor binding abnormalities and need to be clarified. Dopaminergic pathways play a central role in mediating synaptic plasticity in striatum, and D3 R may facilitate this role through autoregulatory properties, interaction with D1-like receptors and regulatory effects on striatal dopamine level. Hence, a disturbance of striatal D3 R could perturb the function of cortico-thalamo-cerebellar circuits leading to dystonia. We will examine the integrity of these functional networks in dystonia using resting state functional connectivity MRI. We propose to test hypotheses about the critical dopaminergic abnormalities in dystonia and their consequences for functional networks in the brain using novel neuroimaging techniques. Specifically, we will determine whether adult patients with primary focal dystonia have reduced striatal D1-like binding, reduced striatal dopamine, reduced striatal D3 binding (after validating the use of the proposed D3 radioligand in nonhuman primates) and altered functional networks associated with regional dopamine binding abnormalities. This information could translate into new therapeutic targets, open new avenues of research in other populations using our novel D3 receptor ligand and refine current dystonia models. I plan to apply for an R01 toward the end of the award period using the experience and data gathered from this proposal. The R01 could include investigation of dopamine receptors and the functional connectivity in other forms of dystonia to look for commonality or differences in the pathophysiology of dystonia subtypes. Selective ligands for D2 R, D3 R and D1-like receptors could be used to investigate the pathophysiology of dyskinesias in PD given their likely role in development of this disabling side effect of PD therapy. Further, I could study whether the slow response to chronic GPi DBS in dystonia is associated with any alteration of dopamine receptor subtypes. The knowledge and experience gained from the radioligand validation for D3 R can be applied to other radioligands crucial for investigation of dystonias as well. The cholinergic system is thought to contribute to the pathophysiology of dystonia and Dr. Mach's lab is developing a ligand to label the vesicular acetylcholine transporter. I will design and perform validation studies and apply the radioligand to dystonia. In summary, my goals of applying for this career development grant are to complete the above project, to obtain substantial research and clinical skills, publish at least one first-authored paper each year, present research at national meetings on a yearly basis, and apply for an R01 by the third year of this mentored career award with the aim of developing my own independent research program.

Public Health Relevance

Dystonia is a disabling movement disorder characterized by repetitive patterned or sustained muscle contractions causing twisting or abnormal postures that may afflict 250,000 people in the U.S. While the pathophysiology of dystonia remains uncertain the treatment is rather rudimentary. A better understanding of neural mechanisms of dystonias is not only an invaluable prerequisite for developing better treatment options but also a step toward better understanding of the complex network of basal ganglia.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Mentored Patient-Oriented Research Career Development Award (K23)
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NST-2 Subcommittee (NST)
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Sieber, Beth-Anne
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Washington University
Schools of Medicine
Saint Louis
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Karimi, Morvarid; Tian, LinLin; Brown, Christopher A et al. (2013) Validation of nigrostriatal positron emission tomography measures: critical limits. Ann Neurol 73:390-6