Adrenergic Blockers for Cardiac Changes in Early Parkinson's Disease
Adrenergic Blockers for Cardiac Changes in Early Parkinson's Disease
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.
Idiopathic Parkinson's disease (PD) is a progressive neurodegenerative disorder of unknown
 etiology, characterized by bradykinesia (slowness of movements) associated with tremor at
 rest and/or muscle rigidity. PD is typically associated with a significant loss of
 dopaminergic neurons in the substantia nigra pars compacta(SNpc).The resulting nigro-striatal
 degeneration can be detected and quantified using a dopamine transporter (DAT) single photon
 emission computerized tomography (SPECT) imaging technique. This type of imaging, recently
 approved for clinical use in the United States, uses a labeled ligand (123I-Ioflupane) with
 high affinity to the DAT in the striatum. The amount of transporter, which plays a crucial
 role in the health of the presynaptic dopaminergic neurons, is then visualized by SPECT.
 123I-Ioflupane uptake is reduced 50-70% in patients with early PD.

 In addition to cardinal motor symptoms, PD is characterized by a large number of "non-motor"
 symptoms (NMS), which add to the overall morbidity burden. Importantly, non--motor features
 may precede the diagnosis of PD, sometimes by several years. They include autonomic
 (gastrointestinal dysfunction, cardiovascular dysfunction with orthostatic hypotension (OH),
 urinary and sexual dysfunction, and hyperhidrosis), sleep (impaired sleep initiation and
 maintenance, rapid eye movement behavior disorder (RBD), sleep apnea and excessive daytime
 sleepiness), sensory (pain, hyposmia, and visual dysfunction), and neuropsychiatric
 disturbances (anhedonia, apathy, anxiety, depression, panic attacks, dementia, and
 psychosis).

 Among NMS, cardiac dysautonomia is a common feature of PD, manifesting in 30% of patients as
 orthostatic hypotension, a symptom that is correlated to disease duration and severity.
 Cardiac sympathetic innervation (CSI) is also affected in PD and other synucleinopathies.
 Lewy Body (LB) pathology, widely considered a marker of PD when detected in the SNpc, is also
 found in the sinoatrial nodal ganglion and myocardium of PD patients at autopsy. Despite the
 high prevalence of both conditions, the relationship between CSI impairment and cardiac
 dysautonomia is still poorly understood.

 Iodine-123 meta-iodobenzylguanidine (123I-MIBG) is an inactive physiological analogue that
 mimics the kinetics of norepinephrine (NE) and competes with NE for active cardiac uptake
 into the postganglionic sympathetic nerve terminal, where it is stored into granules by NE
 transport proteins. 123I-MIBG myocardial scintigraphy, an accepted measure of CSI, is
 abnormal in PD patients, with a characteristic reduction of Heart/Mediastinum (H/M) ratio
 (early and late uptake) and an increased Washout Rate (WR). 123I-MIBG uptake impairment is
 specific to PD and other synucleinopathies and can be used to differentiate PD and dementia
 with Lewy bodies (DLB) from other disorders with similar neurological phenomenology such as
 multiple system atrophy (MSA), progressive supranuclear palsy (PSP) and corticobasal
 degeneration (CBD).

 123I-MIBG uptake deficit in PD is attributed to cardiac sympathetic denervation, based on
 neuropathological studies using tyrosine hydroxylase (TH) immunostaining in epicardial
 nerves. There is evidence of alpha-synuclein aggregation in the epicardial nerve fascicles -
 the distal axons of the cardiac sympathetic nerve - in subjects with incidental Lewy Body
 Disease (ILBD) at stage 2 or 3 of Braak staging with preserved TH immunoreactive axons,
 suggesting a preliminary stage in the development of cardiac sympathetic denervation.
 However, while 123I-MIBG myocardial scintigraphy abnormalities have been correlated with
 pre-motor symptoms like RBD, hyposmia and constipation, there is no pathological evidence of
 cardiac sympathetic denervation in subjects with signs of 123I-MIBG myocardial scintigraphy
 abnormality and recognized pre-motor symptoms of PD. Finally, despite the specific
 association with PD diagnosis, the relationship between CSI impairment and nigrostriatal
 degeneration is poorly understood. Two studies found a strong correlation between
 nigrostriatal dopaminergic degeneration, as measured by 123I Ioflupane SPECT, and CSI
 impairment at different stages of disease. 123I-MIBG uptake deficits have been correlated
 with the progression of the disease.

 Interestingly, CSI - and therefore 123I-MIBG cardiac uptake - is impaired in other chronic
 conditions such as Heart Failure (HF), Hypertension, Diabetes Mellitus, Chronic Obstructive
 Pulmonary Disease and Sleep Apnea, with an identical pattern of abnormality as the one
 detected in PD patients. As opposed to cardiac sympathetic denervation, 123I-MIBG cardiac
 uptake impairment in these chronic conditions - and in particular HF - is explained with the
 hyperactivity of the sympathetic nervous system (SNS) acting as compensatory mechanism
 related to specific organ failure (i.e. post-ischemic/idiopathic heart failure). In fact,
 123I-MIBG cardiac uptake is of prognostic value and can be used to stratify HF patients at
 risk for ventricular arrhythmias and sudden death. By reducing SNS hyperactivity, chronic
 treatment with beta-blockers improves 123I-MIBG cardiac uptake and reduces mortality in
 patients with HF.

 Many recognizable triggers for PD appear to be associated with increased sympathetic tone,
 including most notably brain traumatic injuries, but also microbiota perturbations, air
 pollution, heavy metals like iron and manganese, and finally aging itself. In addition, there
 is reason to believe that SNS overactivity might trigger the principal pre-motor symptoms of
 PD, including hyposmia, constipation and RBD. Finally, SNS overactivity typically drives
 reduced low-frequency heart rate variability (HRV), another clinical sign associated with
 pre-motor - particularly RBD - and early PD. Interestingly, low delayed uptake and high
 washout rate, the 123I-MIBG scintigraphy indices of increased adrenergic drive, are typically
 described in PD patients.

 Based on these considerations, the investigators hypothesize that 123I-MIBG cardiac
 impairment in neurodegenerative disease shares the same pathophysiology of other chronic
 conditions like HF, at least in the very early, pre-motor stages of development. Therefore,
 treatment of SNS hyperactivity with adrenergic blockers will improve cardiac sympathetic
 denervation in PD patients, providing evidence that this process is reversible. If this is
 true, the early detection of 123I-MIBG cardiac impairment in PD, particularly in the
 pre-motor phase, might create a considerable window of opportunity for treatment with
 adrenergic blockers - or similar compounds able to reduce SNS hyperactivity - which may
 result in long-term benefit such as delaying the neurodegenerative process and the onset of
 neurological symptoms. This may be documented and monitored using nigrostriatal dopaminergic
 scintigraphy (DAT scan), a strategy that would implement a dual imaging algorithm to provide
 early and viable biomarkers of the neurodegenerative process.

 Among adrenergic blockers, carvedilol is particularly well-suited to block impaired
 sympathetic over-activation in virtue of several effects on the adrenoceptors, including β-1
 and β-2 adrenergic blockade and α-1 adrenergic blockade, in addition to antioxidant activity,
 L-type calcium channel blockade, and inhibition of stress-activated protein kinase.
 Absorption of current oral formulations of carvedilol is typically rapid and complete, with
 an average elimination half -life of about 8 hours. The high lipophilic structure of
 carvedilol makes it one of the beta-blockers most readily crossing the blood brain barrier.
 Carvedilol is associated with greater reduction of sympathetic activity, as measured by
 123I-MIBG myocardial uptake, than metoprolol and other selective beta-blockers. In addition,
 due to its α-1 adrenergic blockade properties, carvedilol may exert beneficial effects on
 olfactory dysfunction and insulin resistance, two abnormalities frequently associated with
 the neurodegenerative process in PD. Adrenergic blockers have been associated with sleep
 disturbances including RBD, although the latter is based on isolated anecdotal reports. The
 negative effect of beta-blockers on sleep quality and duration appears to be related with the
 suppression of night time levels of melatonin. Interestingly however, carvedilol is not
 associated with melatonin suppression.

 The purpose of this pilot study is to investigate the effect of treatment with the adrenergic
 blocker carvedilol on 123I-MIBG myocardial uptake in a population of subjects with defined
 pre-motor PD risks (i.e. hyposmia and RBD) and abnormal baseline 123I-MIBG uptake, with or
 without 123I-Ioflupane uptake abnormality or PD motor symptoms. Scintigraphic changes will be
 correlated to motor and non-motor severity of PD, measured by validated clinical scales and
 cardiac autonomic function tests.
Inclusion Criteria:

 Male or female of age between 30 and 75 years at time of enrollment.

 Diagnosis of idiopathic REM sleep behavior disorder (iRBD) or Diagnosis of hyposmia.
 Diagnosis of RBD will be, established either as 'definite RBD' according to the criteria
 proposed by the International Classification of Sleep Disorders (ICSD)-2 [AASM, 2005] or
 'probable RBD' following a score of 6 or higher in the RBD questionnaire (RBDSQ) with a
 score of at least 1 in subitems 6.1 to 6.4 of question 6.

 At least one of the following:

 1. Diagnosis of hyposmia. Diagnosis of hyposmia will be established as a University of
 Pennsylvania Smell Identification Test (UPSIT) score < 20th percentile for the
 individual's age group and sex.

 2. Functional constipation, assessed by a scores > 4 on a questionnaire based on modified
 ROME III diagnostic criteria.

 3. Color vision abnormality, as assessed using HRR Pseudoisochromatic Plates, in the
 absence of congenital dyschromatopsia.

 4. Symptoms of depression, as assessed by a Beck Depression Inventory (BDI) fast screen
 score >3 or concurrent use of antidepressant medications

 -  Abnormal 123I-MIBG myocardial scintigraphy, as defined by a Late H/M ratio < 2.2
 and/or a WR >30%, with normal cardiac ejection fraction (LVEF >55%).

 -  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)

 Chronic Hypertension (SBP>140mmHg-DBP>90mmHg)

 Atrial fibrillation

 Diabetes mellitus

 COPD

 Sleep Apnea

 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

 Symptomatic Bradycardia (HR<60) or Sick Sinus Syndrome

 Stroke within the past 1 month

 Severe Hepatic Dysfunction

 Allergy/hypersensitivity to iodine or study medication