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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| carvedilol therapy | Experimental | Twice daily oral doses of adrenergic blocker 12.5 mg or 25mg, according to patient tolerability. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 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. |
| 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 |
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| MDS-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III | MDS-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III changes from OFF medication between baseline and every 6 months for three years | Every 6 months for 3 years |
| Non-Motor Symptoms Scale (NMSS) changes |
Inclusion Criteria:
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
Contraindications to the use of carvedilol
Allergy/hypersensitivity to iodine or study medication
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| Name | Affiliation | Role |
|---|---|---|
| Michele L Lima Gregorio, MD, FAAN | Cedars-Sinai Medical Center | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Michele L Lima Gregorio | Los Angeles | California | 90046 | United States |
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| ID | Term |
|---|---|
| D020187 | REM Sleep Behavior Disorder |
| D010302 | Parkinson Disease, Secondary |
| ID | Term |
|---|---|
| D020923 | REM Sleep Parasomnias |
| D020447 | Parasomnias |
| D012893 | Sleep Wake Disorders |
| D009422 | Nervous System Diseases |
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| ID | Term |
|---|---|
| D000077261 | Carvedilol |
| ID | Term |
|---|---|
| D011412 | Propanolamines |
| D000605 | Amino Alcohols |
| D000438 | Alcohols |
| D009930 | Organic Chemicals |
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|
| 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 |
Non-Motor Symptoms Scale (NMSS) changes between baseline and every 6 months for three years |
| Every 6 months for 3 years |
| Scales for Outcomes in Parkinson's Disease - Autonomic Dysfunction (SCOPA-AUT) | Scales for Outcomes in Parkinson's Disease - Autonomic Dysfunction (SCOPA-AUT) changes between baseline and every 6 months for three years | Every 6 months for 3 years |
| REM sleep Behavior Disorder Screening questionnaire (RBDSQ) | REM sleep Behavior Disorder Screening questionnaire (RBDSQ) changes between baseline and every 6 months for three years | Every 6 months for 3 years |
| University of Pennsylvania Smell Identification Test (UPSIT) | University of Pennsylvania Smell Identification Test (UPSIT) changes between baseline and every 6 months for three years | Every 6 months for 3 years |
| Functional constipation score changes | 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 | Every 6 months for 3 years |
| Color vision changes | Color vision changes, as assessed using HRR Pseudoisochromatic Plates, between baseline and every 6 months for three years | Every 6 months for 3 years |
| Central and peripheral insulin resistance changes | 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 | Every 6 months for 3 years |
| Differences in integrity of pigmented neurons in the locus coeruleus and substantia nigra between baseline, year one, year two and year three | This outcome will be measured by the content of neuromelanin, a product of cathecolamine metabolism in LC and SN. | 3 years |
| 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) | 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 | 3 years |
| Heart Rate Variability (HRV) changes between baseline and every 6 months for three years | Beat-to-beat intervals will be registered to assess sympatho-vagal balance every 6 months for 3 years | Every 6 months for 3 years |
| D001523 |
| Mental Disorders |
| D020734 | Parkinsonian Disorders |
| D001480 | Basal Ganglia Diseases |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009069 | Movement Disorders |
| D020005 |
| Propanols |
| D000588 | Amines |
| D002227 | Carbazoles |
| D007211 | Indoles |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
| D006575 | Heterocyclic Compounds, 3-Ring |