Cardiac Changes in Early Parkinson's Disease: A Follow up Study

Study Overview
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Brief Summary
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The purpose of this study is to investigate the long-term effects of treatment with the adrenergic blocker carvedilol on serial DaTscan, a dopamine transporter (DAT) single photon emission computerized tomography (SPECT) imaging technique in a population of subjects with defined pre-motor Parkinson's disease risks (i.e., REM sleep Behavior Disorder (RBD) and at least one among hyposmia, constipation, depression and color vision abnormality) and abnormal 123I-Metaiodobenzylguanidine (MIBG) scintigraphy.

Detailed Description
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Primary procedures in this study are MIBG scan, DAT scan, Neuromelanin Magnetic Resonance Imaging (NM-MRI), and carvedilol treatment. Subjects will return for research visits and imaging tests every six months for three years. We hypothesize that the rate of decline in DAT scan123I-Ioflupane uptake will be slower in subjects who have received the adrenergic blocker carvedilol, resulting in a decreased clinical phenoconversion rate to parkinsonism. If this is true, it might create a considerable window of opportunity for treatment with adrenergic blockers - or similar compounds able to reduce Sympathetic Nervous System (SNS) hyperactivity - which may result in long-term benefits such as delaying the neurodegenerative process and the onset of neurological symptoms.

Official Title
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The Effect of Adrenergic Blocker Therapy on Cardiac and Striatal Transporter Uptake in Pre-Motor and Symptomatic Parkinson's Disease: A Follow up Study

Conditions
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REM Sleep Behavior Disorder, Pre-motor Parkinson Disease, Symptomatic Parkinson Disease

Intervention / Treatment
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* Drug: Carvedilol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Enrolled in the study The Effect of Adrenergic Blocker Therapy on Cardiac and Striatal Transporter Uptake in Pre-Motor and Symptomatic Parkinson's Disease (Pro#00053136) Capacity to give informed consent Exclusion Criteria: Secondary Parkinsonism, including tardive Concurrent dementia defined by a score lower than 22 on the MoCA Concurrent severe depression defined by a BDI fast screen score greater than 13 Comorbidities related to SNS hyperactivity Heart failure (LVEF <45%) Recent myocardial revascularization (<12 weeks) Hypertension (SBP>150mmHg or DBP>100mmHg) Chronic Atrial fibrillation Concurrent Use of Beta-adrenergic antagonist Diabetes mellitus COPD Untreated Sever Sleep Apnea; Apnea-Hypopnea Index (AHI) > 30/h. Severely reduced kidney function (Glomerular Filtration Rate<30ml/min) Contraindications to the use of carvedilol Asthma or bronchospasm Recent myocardial infarction (<48 h) Ongoing unstable angina Cardiogenic shock or prolonged hypotension Second or Third-Degree AV block Significant valvular aortic stenosis Obstructive cardiomyopathy, or constrictive pericarditis Resting Heart Rate (RHR)< 45 Or Bradycardia (HR<60) with at least one of the following symptoms; Lightheadedness, dizziness, weakness, Altered mental status, Shortness of breath, Pre-Syncope, Syncope, Sick Sinus Syndrome, Stroke within the past 1 month, Severe Hepatic Dysfunction Allergy/hypersensitivity to iodine or study medication

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: carvedilol therapy<br>Twice daily oral doses of adrenergic blocker 12.5 mg or 25mg, according to patient tolerability. | Drug: Carvedilol<br>* Primary procedures in this study are MIBG scan, DAT scan, NM-MRI, and carvedilol titration. Subjects will return for research visits and imaging every six months for three years. The investigators hypothesize that the rate of decline in DAT scan123I-Ioflupane uptake will be slower in subjects who have received the adrenergic blocker carvedilol, resulting in a decreased clinical phenoconversion rate to parkinsonism.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in 123I-Ioflupane uptake - DATscan | Changes in 123I-Ioflupane uptake, as measured by specific binding ratio (SBR), between baseline, year one, year two and year three. | Every year for three years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Diagnosis of PD or other synucleinopathies by the end of 3 years in the study population | Clinical evaluation | Every year for 3 years | 
| Changes in 123I-MIBG late H/M | Changes in 123I-MIBG reuptake, as measured by late H/M ratio, between baseline and every six months for three years | Every 6 months for 3 years | 
| Changes in 123I-MIBG WR rate | Changes in 123I-MIBG WR reuptake, as measured by WR rate, between baseline and every six months for three years | Every 6 months for 3 years | 
| Sensitivity and specificity of DAT Scan compared to MIBG in predicting RBD conversion to PD/other synucleinopathies | Changes in 123I-Ioflupane uptake, as measured by specific binding ratio (SBR), between baseline, year one, year two and year three. | Every year for3 years |