Microvascular Changes in Parkinson’s Disease: Relationship to Levodopa-Induced Dyskinesia (LID)


Investigating How Blood Flow in the Brain Is Altered by Levodopa-Induced Dyskinesia

Team Leaders: David Eidelberg, MD, and Angela M. Cenci-Nilsson, MD

Brain scans of Parkinson’s disease patients on levodopa therapy show regions where blood flow is elevated (over normal levels), whereas glucose metabolism is depressed. In Parkinson’s patients not on levodopa, no such dissociation occurs: where blood flow is elevated, so is glucose metabolism, and vice versa. The composite image portrays regions of significant dissociation in blue.

Overview and Specific Aims

The most effective medication available for the treatment of Parkinson’s disease (PD) is dopamine precursor levodopa, which is given to restore dopamine levels by increasing the release of dopamine from surviving nigrostriatal terminals. Levodopa pharmacotherapy is initially quite effective in treating PD patients, but ultimately not only does it lose its beneficial potency, it also causes particularly disruptive motor side-effects in most patients: levodopa-induced dyskinesias (LID). After 9 or 10 years of levodopa pharmacotherapy as many as 90 percent of PD patients are affected by LID [1]. Levodopa-induced dyskinesias can present a major challenge to the quality of life of patients and caregivers.

The pathophysiology of LID is multilayered. Both pre- and post-synaptic abnormalities arise in the nigrostriatal system, which alter activity patterns in basal ganglionic-cortical networks [2, 3]. Animal models and patient studies indicate that LID is triggered by large, transient increases in striatal levels of dopamine (DA) following peripheral levodopa administration: dyskinetic patients show a significantly larger and more rapid surge of striatal DA levels than non-dyskinetic patients [4, 5].

We hypothesize that this difference depends, at least in part, on functional and structural alterations of the brain microvasculature: treatment with levodopa induces endothelial proliferation and angiogenesis [5, 6], and increases blood flow in the basal ganglia [7]. In resting patients not taking levodopa, tight correlations have been demonstrated between regional cerebral metabolic rate (CMR) and blood flow (CBF) (both become elevated), consistent with the idea that both measures are associated with local synaptic activity [8, 9].

In patients taking levodopa, however, we have observed that levodopa has opposing effects on cerebral metabolism and blood flow [7]. Whereas effective PD treatment reduces abnormally elevated metabolic activity (CMR) [10, 11], levodopa has been noted to increase CBF in the basal ganglia of PD patients (as well as in healthy subjects) [12, 13]. Moreover, the microvascular/hemodynamic effects of levodopa appear to be significantly more pronounced in dyskinetic, compared to non-dyskinetic, patients.

Because the passage of levodopa from blood to brain is critically regulated at the level of the brain endothelium (reviewed in [2]), we are focusing in this project on using functional imaging tools in rigorously delineating neurovascular alterations in human patients as a possible contributing factor in LID.

Understanding the cause of LID should open avenues for treating this troubling side effect.

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The project has the following Specific Aims:


  • Aim 1: Determine whether blood flow and metabolism are consistently dissociated in PD patients with LID.


As noted earlier, chronic levodopa therapy has opposing, or dissociated, effects on cerebral metabolism and blood flow. We have previously shown that such dissociation is observed in the Parkinson’s disease motor-related pattern (PDRP), but it does not appear in the Parkinson’s disease cognitive-related pattern (PDCP). Furthermore, among patients on chronic levodopa therapy, dyskinetic patients exhibited greater dissociated effects (in PDRP) than non-dyskinetic patients—both regionally and across the entire brain network . In Aim 1 we are using various radiotracers in whole-brain studies with PET to confirm those findings, as well as to determine whether these changes reflect abnormal vasomotor reactivity.


  • Aim 2: Determine whether levodopa alters local vasoreactivity. 


Experimental evidence suggests that angiogenesis does not necessarily alter resting cerebral blood flow (CBF), but can increase capillary reserve, and with it, the hypercapnic CBF response (one of the body’s responses to hypercapnia, or excess carbon dioxide gas in the blood) [14, 15]. The presence of flow-metabolism dissociation with levodopa administration does not necessarily imply the presence of angiogenesis, given that such a response could occur solely through denervation supersensitivity of vascular dopamine receptors. That said, such a dissociation is more likely to indicate an underlying angiogenic process if capillary reserve is also found to be abnormally high. Thus the presence of both enhanced vasoreactivity (with hypercapnia) and flow-metabolism dissociation (with dopaminergic medication) would be more consistent with underlying angiogenesis.

Even without evidence of altered vasoreactivity in the pre-treatment baseline condition, it is possible that different forms of dopaminergic therapy have specific effects on the underlying microvascular process. Indeed, in the experimental rat model, it was found that D1 agonist but not D2 (as with levodopa) is needed for the development of angiogenesis, accounting for the absence of such changes with chronic bromocriptine treatment [16]. In Aim 2, we are studying drug-naïve patients following the start of treatment with either levodopa or a dopamine agonist to evaluate the time course for the development of flow-metabolism dissociation in the two treatment groups.


  • Aim 3: Assess hemodynamics and vascular changes in an experimental rodent model of LID.


In Aim 3 we are using the 6-hydroxyopamine (6-OHDA) lesioned rat model of PD to address the relation between flow-metabolism dissociation and structural alterations of the microvascular bed: alterations in endothelial proliferation, increased capillary density (or vessel elongation), and increased BBB (blood-brain barrier) permeability. Animals are examined following acute or chronic treatment with levodopa. (Studies for Aim 3 are performed through a collaboration with the University of Lund, Sweden, under the direction of Dr. Angela Cenci-Nilsson.)

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Key Personnel
Principal Investigator and Team Leader: David Eidelberg, MD

Team Leader and Site Principal Investigator: Angela M. Cenci-Nilsson, MD, Professor of Experimental Medical Research, Basal Ganglia Pathophysiology Unit, Department of Experimental Medical Science, Lund University, Sweden

Co-Investigator: Vijay Dhawan, PhD

Co-Investigator: Martin Niethammer, MD, PhD

Site Principal Investigator: Steven Frucht, MD, Professor of Neurology, Director of Movement Disorders in the Robert and John M. Bendheim Parkinson and Movement Disorders Center at Mount Sinai Medical Center, New York, NY

Literature Cited

1. Manson A, Schrag A. Levodopa-induced dyskinesias, theclinical problem: clinical features, incidence, risk factors, management and impact on quality of life. In: Bezard E, editor. Recent breakthroughs in basal ganglia research. New York, NY: Nova Science Publishers; 2006. p. 369-80.

2. Cenci MA, Lundblad M. Post- versus presynaptic plasticity in L-DOPA-induced dyskinesia. J Neurochem 2006;99:381-92.

3. Cenci MA, Lindgren HS. Advances in understanding L-DOPA-induced dyskinesia. Curr Opin Neurobiol 2007; 17:665-71.

4. Pavese N, Evans AH, Tai YF, Hotton G, Brooks DJ, Lees AJ, Piccini P. Clinical correlates of levodopa-induced dopamine release in Parkinson disease: a PET study. Neurology 2006;67:1612-7.

5. Lindgren HS, Andersson D, Lagerkvist S, Nissbrandt H, Cenci MA. L-DOPA-induced dopamine efflux in the striatum and the substantia nigra in a rat model of Parkinson’s disease: temporal and quantitative relationship to the expression of dyskinesia. J Neurochem 2009;in press.

6. Westin JE, Vercammen L, Strome EM, Konradi C, Cenci MA. Spatiotemporal pattern of striatal ERK1/2 phosphorylation in a rat model of L-DOPA-induced dyskinesia and the role of dopamine D1 receptors. Biol Psychiatry 2007;62:800-10.

7. Hirano S, Asanuma K, Ma Y, Tang C, Feigin A, Dhawan V, Carbon M, Eidelberg D. Dissociation of metabolic and neurovascular responses to levodopa in the treatment of Parkinson’s disease. J Neurosci 2008;28:4201-9 [NIHMS#57771].

8. Herscovitch P. Can [15O]water be used to evaluate drugs? Journal of Clinical Pharmacology 2001;Suppl:11S-20S.

9. Ma Y, Eidelberg D. Functional imaging of cerebral blood flow and glucose metabolism in Parkinson’s disease and Huntington’s disease. Mol Imag Biol 2007;9:223-3.

10. Asanuma K, Tang C, Ma Y, Dhawan V, Mattis P, Edwards C, Kaplitt MG, Feigin A, Eidelberg D. Network modulation in the treatment of Parkinson’s disease. Brain 2006;129:2667-78 [NIHMS#57753].

11. Feigin A, Kaplitt MG, Tang C, Lin T, Mattis P, Dhawan V, During MJ, Eidelberg D. Modulation of metabolic brain networks after subthalamic gene therapy for Parkinson’s disease. Proc Natl Acad Sci U S A 2007;104:19559-64.

12. Hershey T, Black KJ, Carl JL, McGee-Minnich L, Snyder AZ, Perlmutter JS. Long term treatment and disease severity change brain responses to levodopa in Parkinson’s disease. J Neurol Neurosurg Psychiatry 2003;74:844-51.

13. Kobari M, Fukuuchi Y, Shinohara T, Obara K, Nogawa S. Levodopa-induced local cerebral blood flow changes in Parkinson’s disease and related disorders. J Neurol Sci 1995;128:212-8.

14. Swain RA, Harris AB, Wiener EC, Dutka MV, Morris HD, Theien BE, Konda S, Engberg K, Lauterbur PC, Greenough WT. Prolonged exercise induces angiogenesis and increases cerebral blood volume in primary motor cortex of the rat. Neuroscience 2003;117:1037-46.

15. Vogel J, Gehrig M, Kuschinsky W, Marti HH. Massive inborn angiogenesis in the brain scarcely raises cerebral blood flow. J Cereb Blood Flow Metab 2004;24:849-59.

16. Lindgren HS, Ohlin KE, Cenci MA. Differential involvement of D1 and D2 dopamine receptors in L-DOPA-induced angiogenic activity in a rat model of Parkinson’s disease. Neuropsychopharmacology 2009;34:2477-88

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