Pursuant to the Section?s mission of conducting mainly patient-oriented clinical research on neurocardiologic disorders, with an emphasis on catecholamine systems, we studied patients with chronic autonomic failure (e.g., Parkinson disease with orthostatic hypotension (PD+OH)), chronic orthostatic intolerance (COI), pheochromocytoma (Pheo), and congenital inherited diseases involving abnormal catecholamine biosynthesis. Major findings and inferences: (1) We obtained neuroimaging, neurochemical, and pharmacologic evidence that PD+OH entails loss of cardiac and extra-cardiac noradrenergic nerves, providing further support for the notion that PD+OH is not only a movement disorder but also a form of dysautonomia. (2) We succeeded in using the NIH Clinical Center's High Resolution Research Tomograph to delineate central catecholaminergic innervation in patients with PD, multiple system atrophy, or pure autonomic failure and preliminarily have noted strongly positive correlations between neuroimaging and CSF neurochemical indices of central dopamine deficiency. (3) We identified another patient with autoimmune autonomic failure, from a circulating antibody to the neuronal nicotinic receptor, and under a new clinical therapeutics protocol successfully treated the patient by total plasma exchange. (4) We found that patients with postural tachycardia syndrome, a common, mysterious, controversial form of COI, had findings consistent with secondary sympathetic noradrenergic and adrenomedullary activation in response to decreased venous return to the heart, rather than a primary abnormality of catecholamine release or reuptake. (4) In a double-blind, placebo-controlled, randomized crossover study, beta-adrenoceptor blockade did not prevent sympathoadrenal imbalance or neurocardiogenic syncope. (5) We continued a project on genetics of familial COI in a large French Canadian kindred. (6) We continued a project on mutation-dependent differences in tumor cell gene expression as a basis for different phenotypes and clinical manifestations of Pheo. (7) We continued to observe that patterns of plasma catechols diagnosed Menkes disease perfectly prospectively in at-risk newborns.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Intramural Research (Z01)
Project #
1Z01NS002979-08
Application #
7324559
Study Section
(CNCS)
Project Start
Project End
Budget Start
Budget End
Support Year
8
Fiscal Year
2006
Total Cost
Indirect Cost
City
State
Country
United States
Zip Code
Goldstein, David S; Eisenhofer, Graeme; Kopin, Irwin J (2006) Clinical catecholamine neurochemistry: a legacy of Julius Axelrod. Cell Mol Neurobiol 26:695-702
Sharabi, Yehonatan; Eldadah, Basil; Li, Sheng-Ting et al. (2006) Neuropharmacologic distinction of neurogenic orthostatic hypotension syndromes. Clin Neuropharmacol 29:97-105
Gamboa, Alfredo; Gamboa, Jorge L; Holmes, Courtney et al. (2006) Plasma catecholamines and blood volume in native Andeans during hypoxia and normoxia. Clin Auton Res 16:40-5
Goldstein, David S (2006) Orthostatic hypotension as an early finding in Parkinson's disease. Clin Auton Res 16:46-54
Li, Sheng-Ting; Eldadah, Basil A; Sharabi, Yehonatan et al. (2006) Coronary vascular resistance in primary chronic autonomic failure. Clin Auton Res 16:293-5
Eldadah, Basil A; Pechnik, Sandra L; Holmes, Courtney S et al. (2006) Failure of propranolol to prevent tilt-evoked systemic vasodilatation, adrenaline release and neurocardiogenic syncope. Clin Sci (Lond) 111:209-16
Sprague, Jon E; Moze, Petra; Caden, David et al. (2005) Carvedilol reverses hyperthermia and attenuates rhabdomyolysis induced by 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) in an animal model. Crit Care Med 33:1311-6
Neumeister, Alexander; Charney, Dennis S; Belfer, Inna et al. (2005) Sympathoneural and adrenomedullary functional effects of alpha2C-adrenoreceptor gene polymorphism in healthy humans. Pharmacogenet Genomics 15:143-9
Petersson, Magnus; Friberg, Peter; Eisenhofer, Graeme et al. (2005) Long-term outcome in relation to renal sympathetic activity in patients with chronic heart failure. Eur Heart J 26:906-13
Lenders, Jacques W M; Eisenhofer, Graeme; Mannelli, Massimo et al. (2005) Phaeochromocytoma. Lancet 366:665-75

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