Clinical Laboratory Evaluation of Chronic Autonomic Failure

Summary

Participation Requirements

Description

Objective: In dysautonomias, altered functions of one or more components of the autonomic nervous system adversely affect health. A subset of dysautonomias consists of chronic autonomic failure (CAF) syndromes. A key sign of CAF is orthostatic hypotension (OH) due to sympathetic neurocirculatory fai...

Objective: In dysautonomias, altered functions of one or more components of the autonomic nervous system adversely affect health. A subset of dysautonomias consists of chronic autonomic failure (CAF) syndromes. A key sign of CAF is orthostatic hypotension (OH) due to sympathetic neurocirculatory failure (neurognic OH, or nOH). Primary CAF has been classified based on clinical manifestations into three forms-pure autonomic failure (PAF), multiple system atrophy (MSA), and Parkinson s disease with OH (PD+OH). All three forms involve deposition of the protein, alpha-synuclein (AS), in neurons (PD, PAF) or glial cells (MSA) and therefore are called autonomic synucleinopathies. Clinical assessment alone often is inadequate for distinguishing among these conditions in individual patients. Dementia with Lewy bodies (DLB) is another form of autonomic synucleinopathy. This observational study continues and expands on Protocol 03-N-0004, Clinical Laboratory Evaluation of Primary Chronic Autonomic Failure. The objective is to conduct multi-modality testing of catecholaminergic and autonomic systems in patients with neurodegenerative chronic autonomic failure (CAF). The goals are to: (a) build up rosters of well characterized patients for future experimental therapeutic trials; (b) test predictions derived from the catecholaldehyde hypothesis for the pathogenesis of autonomic synucleinopathies; (c) follow the natural history of neurodegenerative chronic autonomic failure (CAF); and (d) discover new clinical entities involving catecholaminergic neurodegeneration. Study Population: The study population consists of patients with neurodegenerative chronic autonomic failure (neurodegenerative CAF) identified by on site screening at the NIH Clinical Center. Comparison groups include a group on control patients with iatrogenic CAF (e.g., status-post cardiac transplantation, pre/post renal sympathetic ablation, pre/post bilateral thoracic sympathectomies) or PD and without OH (PD No OH), and a group of Healthy Volunteers (HVs), some of whom have genetic abnormalities known to increase the risk of developing PD. A group of MSA patients is included, to build up a subject roster for a planned clinical trial. Design: This is an observational pathophysiology/natural history study with a planned duration of 3 years. Descriptive statistics will be done in diagnostic groups with neurodegenerative CAF. Outcome Measures: The primary outcome measure is results of clinical laboratory research tests in neurodegenerative CAF patients. Neuroimaging data are from MRI and from 18F-DOPA and 18F-dopamine PET scanning. Neurochemical data are from assays of catechols in plasma and cerebrospinal fluid. Immunofluorescence microscopy data are from analyses of immunoreactive tyrosine hydroxylase and AS in skin biopsy samples. Neurobehavioral rating scale data are from the University of Pennsylvania Smell Identification Test (UPSIT), Montreal Cognitive Assessment (MoCA), and Uniform Parkinson s Disease Rating Scale (UPDRS). Correlation analyses will be done among individual values for outcome measures. A secondary outcome measure is estimated extraneuronal binding of 11C-methylreboxetine, based on studies of patients with iatrogenic CAF and desipraminetreated HVs.

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