Neuropharmacology Laboratory

Raymon Durso, MD, Director

Description: Parkinson disease (PD) is a disorder characterized by severe reductions in striatal brain concentrations of the neurotransmitter dopamine (DA). The most effective form of therapy involves administering levodopa (LD), the immediate precursor of DA. While such therapy often relieves the major PD signs, there remain complications and less than optimal responsesnot readily explained by current understanding. One very important area which has not been adequately investigated involves LD catabolism. Specifically, in addition to LD being metabolized to DA, further metabolism of DA to a second neurotransmitter norepinephrine (NE) readily occurs after administration of LD. Production of NE from an LD dose, or lack thereof, may very well be the crucial piece of information missing to explain complications and variable response to LD and yet the issue has never been adequately studied in vivo. We use a labeling technique for LD which employs the stable isotope 13C. Currently, there are no other existing technologies that can adequately address the issue of how LD conversion to NE might affect treatment in PD. The fundamental strength of our stable isotope labeling technique relates to the virtual absence of toxicity associated with this 13C label. Stable isotope labeled LD is not a radioisotope and is not radioactive. Thus, we can administer a full pharmacologic dose which is completely labeled. This capability allows for the first time the accurate quantitation of labeled LD metabolites (including NE). We can mimic the clinical setting almost exactly. Use of radioisotopes, on the other hand, due to inherent toxicity is limited to administration of tiny tracer doses of labeled drug. It is extremely difficult to accurately quantitate a drug’s metabolism using tiny tracer doses. In this research we investigate three important issues which may be mediated through LD metabolism to NE:

1) whether diminished NE production from an administered LD dose plays a role in the PD complication of gait freezing,

2) whether enhanced production of NE from an administered LD dose exacerbates LD-induced dyskinesia and

3) whether systemic production of NE protects against LD-induced hypotension. Our use of infused stable isotope labeled LD represents the only existing current methodology which can address these important issues in patients themselves.

Approximately 80% of patients with Parkinson’s Disease (PD) develop age-related and clinically significant cognitive and affective dysfunction as the disease progresses. “Executive cognitive functions” (such as planning, insight, cognitive fluency, set-shifting and attention) mediated by prefrontal sites are the most seriously affected cognitive fimctions and depression is the most frequently reported affective dysfunction. It is not known what causes these disorders in PD or how best to treat them. Although levodopa (LD) appears to ameliorate some of these cognitive and affective impairments in PD it is not known whether LD’s beneficial effect is mediated by dopaminergic or noradrenergic mechanisms. Understanding the separate contributions of each of these catecholaminergic transmitters to cognitive and affective deficits in PD is a vitally important step in developing effective pharmacologic therapies for treatment. We attempt to quantify the separate contributions of each of these catecholaminergic transmitters to cognitive and affective deficits in PD by using a new labeling technique for LD based on stable isotopes. Stable isotopes are not radioactive so the experimenter can administer a full pharmacologic dose of LD which is completely labeled. With isotope labeling all quantitation of metabolites (e.g,, CSF HVA and CSF MHPG) represent actual amounts produced from an administered dose of LD and is not subject to errors related to estimation based on tiny radioactive tracer doses. This stable isotope methodology allow us to accurately quantify the acute effects of levodopa on dopaminergic and noradrenergic activity and these results can then be correlated with cognitive and affective performance in PD patients.

Research faculty: Raymon Durso, MD (Associate Professor of Neurology) and Patrick McNamara, PhD (Associate Professor of Neurology)

Representative Publications:

Morgan J, Clark D, Tripodis Y, Halloran CS, Minsky A, Wildman WJ, Durso R, McNamara P. Impacts of religious semantic priming on an intertemporal discounting task: Response time effects and neural correlates. Neuropsychologia. 2016 Aug;89:403-13. doi: 10.1016/j.neuropsychologia.2016.07.020. Epub 2016 Jul 20.

Smart K, Durso R, Morgan J, McNamara P. A potential case of remission of Parkinson’s disease. J Complement Integr Med. 2016 Jul 5. pii: /j/jcim.ahead-of-print/jcim-2016-0019/jcim-2016-0019.xml. doi: 10.1515/jcim-2016-0019. [Epub ahead of print]

Harris E, McNamara P, Durso R. Possible selves in patients with right- versus left-onset Parkinson’s disease. Neuropsychol Dev Cogn B Aging Neuropsychol Cogn. 2016 May 4:1-18. [Epub ahead of print]

Ratner MH, Farb DH, Ozer J, Feldman RG, Durso R. Younger age at onset of sporadic Parkinson’s disease among subjects occupationally exposed to metals and pesticides. Interdiscip Toxicol. 2014 Sep;7(3):123-33. doi: 10.2478/intox-2014-0017. Epub 2014 Dec 30.

Harris E, McNamara P, Durso R. Novelty seeking in patients with right- versus left-onset Parkinson disease. Cogn Behav Neurol. 2015 Mar; 28(1):11-6.

Harris E, McNamara P, Durso R. Apathy in patients with Parkinson disease as a function of side of onset. J Geriatr Psychiatry Neurol. 2013 Jun;26(2):95-104. doi: 10.1177/0891988713481267.

Modak A, Durso R, Josephs E, Rosen D. A rapid non invasive L-DOPA-¹³C breath test for optimally suppressing extracerebral AADC enzyme activity – toward individualizing carbidopa therapy in Parkinson’s disease. J Parkinsons Dis. 2012;2(4):349-56.

Butler PM, McNamara P, Ghofrani J, Durso R. Disease-associated differences in religious cognition in patients with Parkinson’s disease. J Clin Exp Neuropsychol. 2011 Oct;33(8):917-28. doi: 10.1080/13803395.2011.575768.

Butler PM, McNamara P, Durso R. Side of onset in Parkinson’s disease and alterations in religiosity: novel behavioral phenotypes. Behav Neurol. 2011;24(2):133-41. doi: 10.3233/BEN-2011-0282.

McNamara P, Stavitsky K, Durso R, Harris E. The Impact of Clinical and Cognitive Variables on Social Functioning in Parkinson’s Disease: Patient versus Examiner Estimates. Parkinsons Dis. 2010 Mar 11;2010. pii: 263083. doi: 10.4061/2010/263083.

McNamara P, Holtgraves T, Durso R, Harris E. Social cognition of indirect speech: Evidence from Parkinson’s Disease. J Neurolinguistics. 2010 Mar 1;23(2):162.

Butler PM, McNamara P, Durso R. Deficits in the automatic activation of religious concepts in patients with Parkinson’s disease. J Int Neuropsychol Soc. 2010 Mar;16(2):252-61. doi: 10.1017/S1355617709991202.

Holtgraves T, McNamara P, Cappaert K, Durso R. Linguistic correlates of asymmetric motor symptom severity in Parkinson’s Disease. Brain Cogn. 2010 Mar;72(2):189-96. doi: 10.1016/j.bandc.2009.08.004.

McNamara P, Stavitsky K, Harris E, Szent-Imrey O, Durso R. Mood, side of motor symptom onset and pain complaints in Parkinson’s disease. Int J Geriatr Psychiatry. 2010 May;25(5):519-24. doi: 10.1002/gps.2374.