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

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.

• Carvedilol (Drug): 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.

Primary outcomes

• Changes in 123I-Ioflupane uptake - DATscan [Every year for three years]: Changes in 123I-Ioflupane uptake, as measured by specific binding ratio (SBR), between baseline, year one, year two and year three.

Secondary outcomes

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

Other outcomes

• MDS-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III [Every 6 months for 3 years]: MDS-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III changes from OFF medication between baseline and every 6 months for three years
• Non-Motor Symptoms Scale (NMSS) changes [Every 6 months for 3 years]: Non-Motor Symptoms Scale (NMSS) changes between baseline and every 6 months for three years
• Scales for Outcomes in Parkinson's Disease - Autonomic Dysfunction (SCOPA-AUT) [Every 6 months for 3 years]: Scales for Outcomes in Parkinson's Disease - Autonomic Dysfunction (SCOPA-AUT) changes between baseline and every 6 months for three years
• REM sleep Behavior Disorder Screening questionnaire (RBDSQ) [Every 6 months for 3 years]: REM sleep Behavior Disorder Screening questionnaire (RBDSQ) changes between baseline and every 6 months for three years
• University of Pennsylvania Smell Identification Test (UPSIT) [Every 6 months for 3 years]: University of Pennsylvania Smell Identification Test (UPSIT) changes between baseline and every 6 months for three years
• Functional constipation score changes [Every 6 months for 3 years]: Functional constipation score changes between baseline and every 6 months for three years. The total score has a range of 0 to 12, with scores > 4 identifying functional constipation
• Color vision changes [Every 6 months for 3 years]: Color vision changes, as assessed using HRR Pseudoisochromatic Plates, between baseline and every 6 months for three years
• Central and peripheral insulin resistance changes [Every 6 months for 3 years]: Peripheral Insulin Resistance (IR) will be defined by testing for fasting plasma insulin (FPI), fasting plasma glucose (FPG) and glycated hemoglobin (HbA1c). HOMA index will be calculated by the formula: HOMA-IR = (FPI x FPG)/405 . A cutoff HOMA index of 2.0, equivalent to <50% sensitivity, will be used to define IR. Subjects were considered to have IR if they either had a HOMA≥2.0 and/or HbA1c≥5.7 . In addition, measures of insulin sensitivity in neuronal-origin enriched plasma EVs (central IR) will be used to test the association of changes in such sensitivity to changes in MIBG uptake and clinical scores from baseline and every 6 months. For that purpose, plasma samples will be collected and stored and -80oC to allow for isolation of neuronal origin EVs at the completion of the study
• Differences in integrity of pigmented neurons in the locus coeruleus and substantia nigra between baseline, year one, year two and year three [3 years]: This outcome will be measured by the content of neuromelanin, a product of cathecolamine metabolism in LC and SN.
• Correlation between changes in integrity of pigmented neurons of substantia nigra as measured by neuromelanin-sensitive magnetic resonance imaging (MRI) and 123I-Ioflupane uptake as measured by Dopamine Transporter Imaging (DAT scan) [3 years]: These measurements will be aggregated to calculate the correlation between changes in neuromelanin content as measured by NM-MRI and dopamine content as measured by DAT scan
• Heart Rate Variability (HRV) changes between baseline and every 6 months for three years [Every 6 months for 3 years]: Beat-to-beat intervals will be registered to assess sympatho-vagal balance every 6 months for 3 years

Sex: All, ages: 18 Years to 85 Years

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

• Michele L Lima Gregorio, MD, FAAN, Principal investigator, Cedars-Sinai Medical Center