Adrenergic Blockers for Cardiac Changes in Early Parkinson's Disease (Protocol 53136)

Summary

REM Behavior Sleep Disorder (RBD) is a sleep disorder causing people to 'act out' their dreams. A high percentage of individuals with idiopathic RBD (iRBD) are known to develop conditions affecting the neurons in the brain such as Parkinson's disease (PD). Based on the increased risk to develop PD, individuals with iRBD are currently considered ideal candidates for therapies that can possibly protects brain cells, due to the critical window of opportunity to intervene early before brain cell loss progresses significantly. Early changes of PD are associated with a number of symptoms including loss of smell, constipation, anxiety and depression. In addition, early heart and brain abnormalities can be visualized using specialized imaging techniques called 123I-MIBG myocardial scintigraphy (MIBG) and dopamine transporter (DAT) single photon emission computerized tomography (SPECT) respectively. The combined presence of certain symptoms and the use of these imaging techniques are considered early markers of PD in individuals with iRBD. In other conditions, like heart failure, MIBG abnormalities are reversed by drugs able to block excessive adrenergic stimulation, known as beta-blockers. In this study the investigators want to learn about the effect of treatment with the beta-blocker carvedilol on MIBG abnormalities found in iRBD patients at risk to develop PD. The investigators believe that reversing the MIBG abnormality might prelude to a slowing of the neurodegenerative process. This drug is approved by the U.S. Food and Drug Administration (FDA) for congestive heart failure, hypertension and left ventricular dysfunction after myocardial infarction. However, carvedilol is not approved by the FDA in patients with iRBD at risk for PD. The available doses for this drug oral formulations are 3.125mg, 6.25mg, 12.5mg and 25mg. Changes visualized with the MIBG imaging technique will be correlated to the presence and severity of neurological (i.e. tremors, stiffness, slow movements, walking difficulties) and other symptoms associated with PD (i.e. abnormal smell, constipation, depression, color vision abnormalities), as measured by specific clinical scales and exams.

Timeline

Start

2019-04-04

Primary completion

2026-07-01

Completion

2026-07-01

Publications

• Background Amino T, Orimo S, Itoh Y, Takahashi A, Uchihara T, Mizusawa H. Profound cardiac sympathetic denervation occurs in Parkinson disease. Brain Pathol. 2005 Jan;15(1):29-34. doi: 10.1111/j.1750-3639.2005.tb00097.x.
• Background Boeve BF. REM sleep behavior disorder: Updated review of the core features, the REM sleep behavior disorder-neurodegenerative disease association, evolving concepts, controversies, and future directions. Ann N Y Acad Sci. 2010 Jan;1184:15-54. doi: 10.1111/j.1749-6632.2009.05115.x.
• Background Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging. 2003 Mar-Apr;24(2):197-211. doi: 10.1016/s0197-4580(02)00065-9.
• Background Bugalho P, Mendonca M, Lampreia T, Miguel R, Barbosa R, Salavisa M. Heart rate variability in Parkinson disease and idiopathic REM sleep behavior disorder. Clin Auton Res. 2018 Dec;28(6):557-564. doi: 10.1007/s10286-018-0557-4. Epub 2018 Aug 20.
• Background de Milliano PA, van Eck-Smit BL, de Groot AC, Lie KI. Metoprolol-induced changes in myocardial (123)I-metaiodobenzylguanidine uptake in Parkinson's disease. Circulation. 2000 Nov 14;102(20):2553-4. doi: 10.1161/01.cir.102.20.2553. No abstract available.
• Background de Peuter OR, Verberne HJ, Kok WE, van den Bogaard B, Schaap MC, Nieuwland R, Meijers JC, Somsen GA, Bakx A, Kamphuisen PW. Differential effects of nonselective versus selective beta-blockers on cardiac sympathetic activity and hemostasis in patients with heart failure. J Nucl Med. 2013 Oct;54(10):1733-9. doi: 10.2967/jnumed.113.120477. Epub 2013 Aug 22.
• Background Dinan TG, Cryan JF. Regulation of the stress response by the gut microbiota: implications for psychoneuroendocrinology. Psychoneuroendocrinology. 2012 Sep;37(9):1369-78. doi: 10.1016/j.psyneuen.2012.03.007. Epub 2012 Apr 5.
• Background Dorschner J, Farmakis G, Behnke S, Hellwig D, Schneider S, Fassbender K, Kirsch CM, Dillmann U, Spiegel J. Myocardial MIBG scintigraphy may predict the course of motor symptoms in Parkinson's disease. Parkinsonism Relat Disord. 2011 Jun;17(5):372-5. doi: 10.1016/j.parkreldis.2011.03.001. Epub 2011 Mar 21.
• Background Fereshtehnejad SM, Montplaisir JY, Pelletier A, Gagnon JF, Berg D, Postuma RB. Validation of the MDS research criteria for prodromal Parkinson's disease: Longitudinal assessment in a REM sleep behavior disorder (RBD) cohort. Mov Disord. 2017 Jun;32(6):865-873. doi: 10.1002/mds.26989. Epub 2017 Apr 21.
• Background Goldstein DS, Holmes C, Li ST, Bruce S, Metman LV, Cannon RO 3rd. Cardiac sympathetic denervation in Parkinson disease. Ann Intern Med. 2000 Sep 5;133(5):338-47. doi: 10.7326/0003-4819-133-5-200009050-00009.
• Background Halsband C, Zapf A, Sixel-Doring F, Trenkwalder C, Mollenhauer B. The REM Sleep Behavior Disorder Screening Questionnaire is not Valid in De Novo Parkinson's Disease. Mov Disord Clin Pract. 2018 Mar 1;5(2):171-176. doi: 10.1002/mdc3.12591. eCollection 2018 Mar-Apr.
• Background He SC, Niu Q. Subclinical neurophysiological effects of manganese in welding workers. Int J Immunopathol Pharmacol. 2004 May-Aug;17(2 Suppl):11-6. doi: 10.1177/03946320040170S203.
• Background Heffernan DS, Inaba K, Arbabi S, Cotton BA. Sympathetic hyperactivity after traumatic brain injury and the role of beta-blocker therapy. J Trauma. 2010 Dec;69(6):1602-9. doi: 10.1097/TA.0b013e3181f2d3e8. No abstract available.
• Background Hogg E, Athreya K, Basile C, Tan EE, Kaminski J, Tagliati M. High Prevalence of Undiagnosed Insulin Resistance in Non-Diabetic Subjects with Parkinson's Disease. J Parkinsons Dis. 2018;8(2):259-265. doi: 10.3233/JPD-181305.
• Background Iranzo A, Santamaria J. Bisoprolol-induced rapid eye movement sleep behavior disorder. Am J Med. 1999 Oct;107(4):390-2. doi: 10.1016/s0002-9343(99)00245-4. No abstract available.
• Background Iwanaga K, Wakabayashi K, Yoshimoto M, Tomita I, Satoh H, Takashima H, Satoh A, Seto M, Tsujihata M, Takahashi H. Lewy body-type degeneration in cardiac plexus in Parkinson's and incidental Lewy body diseases. Neurology. 1999 Apr 12;52(6):1269-71. doi: 10.1212/wnl.52.6.1269.
• Background Jacob S, Rett K, Wicklmayr M, Agrawal B, Augustin HJ, Dietze GJ. Differential effect of chronic treatment with two beta-blocking agents on insulin sensitivity: the carvedilol-metoprolol study. J Hypertens. 1996 Apr;14(4):489-94.
• Background Jacobson AF, Senior R, Cerqueira MD, Wong ND, Thomas GS, Lopez VA, Agostini D, Weiland F, Chandna H, Narula J; ADMIRE-HF Investigators. Myocardial iodine-123 meta-iodobenzylguanidine imaging and cardiac events in heart failure. Results of the prospective ADMIRE-HF (AdreView Myocardial Imaging for Risk Evaluation in Heart Failure) study. J Am Coll Cardiol. 2010 May 18;55(20):2212-21. doi: 10.1016/j.jacc.2010.01.014. Epub 2010 Feb 25.
• Background Johnson ME, Stecher B, Labrie V, Brundin L, Brundin P. Triggers, Facilitators, and Aggravators: Redefining Parkinson's Disease Pathogenesis. Trends Neurosci. 2019 Jan;42(1):4-13. doi: 10.1016/j.tins.2018.09.007. Epub 2018 Oct 17.
• Background Joyner MJ, Barnes JN, Hart EC, Wallin BG, Charkoudian N. Neural control of the circulation: how sex and age differences interact in humans. Compr Physiol. 2015 Jan;5(1):193-215. doi: 10.1002/cphy.c140005.
• Background Keating GM, Jarvis B. Carvedilol: a review of its use in chronic heart failure. Drugs. 2003;63(16):1697-741. doi: 10.2165/00003495-200363160-00006.
• Background Langston JW, Wiley JC, Tagliati M. Optimizing Parkinson's disease diagnosis: the role of a dual nuclear imaging algorithm. NPJ Parkinsons Dis. 2018 Feb 23;4:5. doi: 10.1038/s41531-018-0041-9. eCollection 2018.
• Background Lotsch J, Daiker H, Hahner A, Ultsch A, Hummel T. Drug-target based cross-sectional analysis of olfactory drug effects. Eur J Clin Pharmacol. 2015 Apr;71(4):461-71. doi: 10.1007/s00228-015-1814-2. Epub 2015 Feb 11.
• Background Marek KL, Seibyl JP, Zoghbi SS, Zea-Ponce Y, Baldwin RM, Fussell B, Charney DS, van Dyck C, Hoffer PB, Innis RP. [123I] beta-CIT/SPECT imaging demonstrates bilateral loss of dopamine transporters in hemi-Parkinson's disease. Neurology. 1996 Jan;46(1):231-7. doi: 10.1212/wnl.46.1.231.
• Background Martinelli N, Olivieri O, Girelli D. Air particulate matter and cardiovascular disease: a narrative review. Eur J Intern Med. 2013 Jun;24(4):295-302. doi: 10.1016/j.ejim.2013.04.001. Epub 2013 May 4.
• Background Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985 Jul;28(7):412-9. doi: 10.1007/BF00280883.
• Background Mitsui J, Saito Y, Momose T, Shimizu J, Arai N, Shibahara J, Ugawa Y, Kanazawa I, Tsuji S, Murayama S. Pathology of the sympathetic nervous system corresponding to the decreased cardiac uptake in 123I-metaiodobenzylguanidine (MIBG) scintigraphy in a patient with Parkinson disease. J Neurol Sci. 2006 Apr 15;243(1-2):101-4. doi: 10.1016/j.jns.2005.11.034. Epub 2006 Jan 27.
• Background Miyamoto T, Miyamoto M, Inoue Y, Usui Y, Suzuki K, Hirata K. Reduced cardiac 123I-MIBG scintigraphy in idiopathic REM sleep behavior disorder. Neurology. 2006 Dec 26;67(12):2236-8. doi: 10.1212/01.wnl.0000249313.25627.2e.
• Background Mizutani Y, Nakamura T, Okada A, Suzuki J, Watanabe H, Hirayama M, Sobue G. Hyposmia and cardiovascular dysautonomia correlatively appear in early-stage Parkinson's disease. Parkinsonism Relat Disord. 2014 May;20(5):520-4. doi: 10.1016/j.parkreldis.2014.02.010. Epub 2014 Feb 20.
• Background Morrison I, Frangulyan R, Riha RL. Beta-blockers as a cause of violent rapid eye movement sleep behavior disorder: a poorly recognized but common cause of violent parasomnias. Am J Med. 2011 Jan;124(1):e11. doi: 10.1016/j.amjmed.2010.04.023. Epub 2010 Sep 29. No abstract available.
• Background Nakajo M, Shapiro B, Glowniak J, Sisson JC, Beierwaltes WH. Inverse relationship between cardiac accumulation of meta-[131I]iodobenzylguanidine (I-131 MIBG) and circulating catecholamines in suspected pheochromocytoma. J Nucl Med. 1983 Dec;24(12):1127-34.
• Background Searles Nielsen S, Gross A, Camacho-Soto A, Willis AW, Racette BA. beta2-adrenoreceptor medications and risk of Parkinson disease. Ann Neurol. 2018 Nov;84(5):683-693. doi: 10.1002/ana.25341. Epub 2018 Oct 30.
• Background Nomura T, Inoue Y, Kagimura T, Uemura Y, Nakashima K. Utility of the REM sleep behavior disorder screening questionnaire (RBDSQ) in Parkinson's disease patients. Sleep Med. 2011 Aug;12(7):711-3. doi: 10.1016/j.sleep.2011.01.015. Epub 2011 Jun 22.
• Background Nul D, Zambrano C, Diaz A, Ferrante D, Varini S, Soifer S, Grancelli H, Doval H; Grupo de Estudio de la Sobrevida en la Insuficiencia Cardiaca en Argentina. Impact of a standardized titration protocol with carvedilol in heart failure: safety, tolerability, and efficacy-a report from the GESICA registry. Cardiovasc Drugs Ther. 2005 Mar;19(2):125-34. doi: 10.1007/s10557-005-1497-5.
• Background Orimo S, Ozawa E, Nakade S, Sugimoto T, Mizusawa H. (123)I-metaiodobenzylguanidine myocardial scintigraphy in Parkinson's disease. J Neurol Neurosurg Psychiatry. 1999 Aug;67(2):189-94. doi: 10.1136/jnnp.67.2.189.
• Background Orimo S, Uchihara T, Nakamura A, Mori F, Kakita A, Wakabayashi K, Takahashi H. Axonal alpha-synuclein aggregates herald centripetal degeneration of cardiac sympathetic nerve in Parkinson's disease. Brain. 2008 Mar;131(Pt 3):642-50. doi: 10.1093/brain/awm302. Epub 2007 Dec 13.
• Background Orimo S, Suzuki M, Inaba A, Mizusawa H. 123I-MIBG myocardial scintigraphy for differentiating Parkinson's disease from other neurodegenerative parkinsonism: a systematic review and meta-analysis. Parkinsonism Relat Disord. 2012 Jun;18(5):494-500. doi: 10.1016/j.parkreldis.2012.01.009. Epub 2012 Feb 8.
• Background Otsuka N, Ohi M, Chin K, Kita H, Noguchi T, Hata T, Nohara R, Hosokawa R, Fujita M, Kuno K. Assessment of cardiac sympathetic function with iodine-123-MIBG imaging in obstructive sleep apnea syndrome. J Nucl Med. 1997 Apr;38(4):567-72.
• Background Packer M, Bristow MR, Cohn JN, Colucci WS, Fowler MB, Gilbert EM, Shusterman NH. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N Engl J Med. 1996 May 23;334(21):1349-55. doi: 10.1056/NEJM199605233342101.
• Background Pagano G, Tan EE, Haider JM, Bautista A, Tagliati M. Constipation is reduced by beta-blockers and increased by dopaminergic medications in Parkinson's disease. Parkinsonism Relat Disord. 2015 Feb;21(2):120-5. doi: 10.1016/j.parkreldis.2014.11.015. Epub 2014 Nov 25.
• Background Postuma RB, Montplaisir J, Lanfranchi P, Blais H, Rompre S, Colombo R, Gagnon JF. Cardiac autonomic denervation in Parkinson's disease is linked to REM sleep behavior disorder. Mov Disord. 2011 Jul;26(8):1529-33. doi: 10.1002/mds.23677. Epub 2011 Apr 29.
• Background Sakakibara R, Tateno F, Kishi M, Tsuyusaki Y, Terada H, Inaoka T. MIBG myocardial scintigraphy in pre-motor Parkinson's disease: a review. Parkinsonism Relat Disord. 2014 Mar;20(3):267-73. doi: 10.1016/j.parkreldis.2013.11.001. Epub 2013 Nov 21.
• Background Sakata K, Shirotani M, Yoshida H, Kurata C. Cardiac sympathetic nervous system in early essential hypertension assessed by 123I-MIBG. J Nucl Med. 1999 Jan;40(1):6-11.
• Background Scheer FA, Morris CJ, Garcia JI, Smales C, Kelly EE, Marks J, Malhotra A, Shea SA. Repeated melatonin supplementation improves sleep in hypertensive patients treated with beta-blockers: a randomized controlled trial. Sleep. 2012 Oct 1;35(10):1395-402. doi: 10.5665/sleep.2122.
• Background Scott LA, Kench PL. Cardiac autonomic neuropathy in the diabetic patient: does 123I-MIBG imaging have a role to play in early diagnosis? J Nucl Med Technol. 2004 Jun;32(2):66-71.
• Background Seravalle G, Piperno A, Mariani R, Pelloni I, Facchetti R, Dell'Oro R, Cuspidi C, Mancia G, Grassi G. Alterations in sympathetic nerve traffic in genetic haemochromatosis before and after iron depletion therapy: a microneurographic study. Eur Heart J. 2016 Mar 21;37(12):988-95. doi: 10.1093/eurheartj/ehv696. Epub 2015 Dec 28.
• Background Spiegel J, Mollers MO, Jost WH, Fuss G, Samnick S, Dillmann U, Becker G, Kirsch CM. FP-CIT and MIBG scintigraphy in early Parkinson's disease. Mov Disord. 2005 May;20(5):552-61. doi: 10.1002/mds.20369.
• Background Spiegel J, Hellwig D, Samnick S, Jost W, Mollers MO, Fassbender K, Kirsch CM, Dillmann U. Striatal FP-CIT uptake differs in the subtypes of early Parkinson's disease. J Neural Transm (Vienna). 2007 Mar;114(3):331-5. doi: 10.1007/s00702-006-0518-2. Epub 2006 May 24.
• Background Spiegel J, Hellwig D, Jost WH, Farmakis G, Samnick S, Fassbender K, Kirsch CM, Dillmann U. Cerebral and Extracranial Neurodegeneration are Strongly Coupled in Parkinson's Disease. Open Neurol J. 2007;1:1-4. doi: 10.2174/1874205X00701010001. Epub 2007 Aug 22.
• Background Stoschitzky K, Koshucharova G, Lercher P, Maier R, Sakotnik A, Klein W, Liebmann PM, Lindner W. Stereoselective effects of (R)- and (S)-carvedilol in humans. Chirality. 2001 Jul;13(7):342-6. doi: 10.1002/chir.1042.
• Background Taki J, Nakajima K, Hwang EH, Matsunari I, Komai K, Yoshita M, Sakajiri K, Tonami N. Peripheral sympathetic dysfunction in patients with Parkinson's disease without autonomic failure is heart selective and disease specific. [email protected]. Eur J Nucl Med. 2000 May;27(5):566-73. doi: 10.1007/s002590050544.
• Background Travin MI, Matsunari I, Thomas GS, Nakajima K, Yoshinaga K. How do we establish cardiac sympathetic nervous system imaging with 123I-mIBG in clinical practice? Perspectives and lessons from Japan and the US. J Nucl Cardiol. 2019 Aug;26(4):1434-1451. doi: 10.1007/s12350-018-1394-5. Epub 2018 Sep 3.
• Background Treglia G, Stefanelli A, Bruno I, Giordano A. Clinical usefulness of myocardial innervation imaging using Iodine-123-meta-iodobenzylguanidine scintigraphy in evaluating the effectiveness of pharmacological treatments in patients with heart failure: an overview. Eur Rev Med Pharmacol Sci. 2013 Jan;17(1):56-68.
• Background Valappil RA, Black JE, Broderick MJ, Carrillo O, Frenette E, Sullivan SS, Goldman SM, Tanner CM, Langston JW. Exploring the electrocardiogram as a potential tool to screen for premotor Parkinson's disease. Mov Disord. 2010 Oct 30;25(14):2296-303. doi: 10.1002/mds.23348.
• Background Varrone A, Dickson JC, Tossici-Bolt L, Sera T, Asenbaum S, Booij J, Kapucu OL, Kluge A, Knudsen GM, Koulibaly PM, Nobili F, Pagani M, Sabri O, Vander Borght T, Van Laere K, Tatsch K. European multicentre database of healthy controls for [123I]FP-CIT SPECT (ENC-DAT): age-related effects, gender differences and evaluation of different methods of analysis. Eur J Nucl Med Mol Imaging. 2013 Jan;40(2):213-27. doi: 10.1007/s00259-012-2276-8. Epub 2012 Nov 16.
• Background Velseboer DC, de Haan RJ, Wieling W, Goldstein DS, de Bie RM. Prevalence of orthostatic hypotension in Parkinson's disease: a systematic review and meta-analysis. Parkinsonism Relat Disord. 2011 Dec;17(10):724-9. doi: 10.1016/j.parkreldis.2011.04.016. Epub 2011 May 14.
• Background Verberne HJ, Brewster LM, Somsen GA, van Eck-Smit BL. Prognostic value of myocardial 123I-metaiodobenzylguanidine (MIBG) parameters in patients with heart failure: a systematic review. Eur Heart J. 2008 May;29(9):1147-59. doi: 10.1093/eurheartj/ehn113. Epub 2008 Mar 17.
• Background Wieland DM, Brown LE, Rogers WL, Worthington KC, Wu JL, Clinthorne NH, Otto CA, Swanson DP, Beierwaltes WH. Myocardial imaging with a radioiodinated norepinephrine storage analog. J Nucl Med. 1981 Jan;22(1):22-31.
• Background Zimnik NC, Treadway T, Smith RS, Araneda RC. alpha(1A)-Adrenergic regulation of inhibition in the olfactory bulb. J Physiol. 2013 Apr 1;591(7):1631-43. doi: 10.1113/jphysiol.2012.248591. Epub 2012 Dec 24.

Drugs

Indications