The Effect of Adrenergic Blocker Therapy on Cardiac and Striatal Transporter Uptake in Pre-Motor and Symptomatic Parkinson's Disease
The Effect of Adrenergic Blocker Therapy on Cardiac and Striatal Transporter Uptake in Pre-Motor and Symptomatic 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 50 and 85 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:
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.
Functional constipation, assessed by a scores > 4 on a questionnaire based on modified ROME III diagnostic criteria.
Color vision abnormality, as assessed using HRR Pseudoisochromatic Plates, in the absence of congenital dyschromatopsia.
Symptoms of depression, as assessed by a Beck Depression Inventory (BDI) fast screen score >3 or concurrent use of antidepressant medications
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