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. Clinical autonomic function testing and analyses of tissue and body fluid samples helped elucidate etiology, pathogenesis, pathophysiology, diagnosis, functional consequences, and treatment of these disorders. Integration of genetic techniques revealed complex genotype-phenotype relationships and suggested a common theme of imbalance between apoptosis, neurotrophism, and functions of homeostatic systems. Major findings and inferences included: (1) PD+OH features cardiac and extra-cardiac noradrenergic denervation and neurocirculatory reflex failure that are linked etiologically with the movement disorder and can occur early in the disease, potentially enabling early detection and diagnosis. (2) In PD without OH, cardiac sympathetic denervation progresses over years, by ?dying back,? providing a potentially important biomarker and model for central neurodegeneration. (3) Discovery of distinctive patterns of central and peripheral catecholaminergic lesions supported a new pathophysiologic classification of chronic autonomic failure. (4) In a collaborative gene therapy study, delivery of multiple catecholamine genes succeeded in ameliorating an animal model of PD, possibly by inducing dopamine production in non-neuronal cells. (5) Postural tachycardia syndrome, a common, mysterious, controversial form of COI, was associated with catecholaminergic and neurocirculatory abnormalities during supine rest; (6) Beta-adrenoceptor blockade did not prevent neurocardiogenic syncope in a tightly controlled study. (7) We initiated a project on genetics of familial COI in a large French Canadian kindred. (8) Plasma metanephrines sensitively detected Pheo in a sizeable prospective study; (9) 6-[18F]Fluorodopmaine scanning aids diagnostic localization of Pheo; (10) Mutation-dependent differences in tumor cell gene expression explained different phenotypes and clinical manifestations of Pheo. (11) Patterns of plasma catechols diagnosed Menkes disease perfectly in a prospective study of at-risk newborns. (12) Familial dysautonomia (FD) seems to entail loss of sympathetic nerves, by both arrested development and imbalance of neurotrophism with neurodegeneration.
Showing the most recent 10 out of 125 publications
