Website Edition: April/May 2010

Clinical Research Network for Multiple System Atrophy and Other Autonomic Disorders: The Autonomic Disorders Consortium

By: David Robertson, MD, Italo Biaggioni, MD, Roy Freeman, MD David S. Goldstein, MD, PhD, Horacio Kaufmann, MD and Phillip A. Low, MD

The Autonomic Disorders Consortium (ADC) was established as a Rare Disorders Clinical Research Consortium (RDCRC) in August 2009. The team includes physicians, scientists, nurses, patients and support groups dedicated to finding new therapies to treat and cure these diseases. Diseases the ADC plans to focus on include:

  • Multiple System Atrophy (MSA)
  • Pure Autonomic Failure (PAF)
  • Parkinsonism with Autonomic Failure
  • Lewy Body Disease
  • Autoimmune Autonomic Ganglionopathy (AAG)
  • Postural Tachycardia Syndrome (POTS)
  • Dopamine β-Hydroxylase Deficiency
  • Norepinephrine Transporter Dysfunction
  • Familial Dysautonomia
  • Baroreflex Failure
  • Neurally Mediated Syncope
  • Pheochromocytoma
  • Mastocytosis
  • Takotsubo Syndrome

The Autonomic Disorders Consortium's home institution is Vanderbilt University. The Consortium consists of five sites:

  • Vanderbilt University
  • New York University
  • Beth Israel Deaconess / Harvard
  • Mayo Clinic
  • NINDS / NIH

Mission

The mission of the ADC is to study autonomic disorders to develop novel therapies aimed not only at improving quality of life, but also altering the course of the disease. The ADC is multidisciplinary and draws strong support from our patients and their support organizations. The Consortium joins with patient support groups to harness the knowledge and energies of physicians and investigators in the major centers where these patients are cared for, so that they can discover ways to treat and to cure these diseases.

Goals for the Autonomic Disorders Consortium

We plan to meet our goals through:

  • Natural history studies
  • Therapeutic trials
  • Novel interventions which include:
    • A potentially disease arresting intervention in MSA.
    • Immunomodulatory therapy
    • Natural History of Autonomic Failure
    • A bionic baroreflex
    • A dopa-decarboxylase antagonist
  • Patient registries
  • Data / Specimen banks
  • Training physicians and scientists in the investigation and treatment of rare autonomic disorders
  • Standardizing evaluation of autonomic function
  • Learning about the long-term prognosis of the disorders

PLANNED STUDIES

1) Double-Blind, Randomized Trial of Rifampicin on Neurologic and Autonomic Function in MSA

MSA is a uniformly fatal neurodegenerative disease. Evidence from a mouse model mimicking the MSA synucleinopathy suggests that the antibiotic rifampicin inhibits development of aggregates and may disaggregate them. We propose a double-blind placebo-controlled clinical trial of rifampicin 600 mg qd x 12 months in 100 subjects with relatively early MSA. The primary endpoint is the UMSARS1 scale.

2) A Natural History of Pure Autonomic Failure

Pure Autonomic Failure (PAF) is a Lewy body disorder causing disabling orthostatic hypotension. PAF is associated with alpha-synuclein deposits (Lewy bodies) in peripheral autonomic nerves and is the only synucleinopathy without clinical signs of CNS involvement. This prospective natural history study of PAF will determine whether PAF patients have specific neuroprotective features that halt the progression of synuclein deposits in the CNS. The study also aims to identify predictive biomarkers of PAF.

3) A Double-Blind, Randomized, Placebo-Controlled Trial to Evaluate the Efficacy of Immunomodulatory Therapy in Autoimmune Autonomic Ganglionopathy.

Autoimmune Autonomic Ganglionopathy is a severe cardiovascular, gastrointestinal and genitourinary dysautonomia. It is due to antibodies against the NN nicotinic receptor. It may present as a subacute or acute dysautonomia, often very severe. There are reports of responsiveness to IVIG and plasma exchange. The goal of this study is to assess the efficacy, safety and tolerability of IVIG and rituximab.

4) Norepinephrine Transport Blockade in the Treatment of Neurogenic Orthostatic Hypotension.

This study aims to determine value of atomoxetine in the evaluation of patients with orthostatic hypotension associated with synucleinopathies. Primary autonomic failure syndromes are diagnosed when other causes of autonomic neuropathy are excluded and there is clinical and laboratory documentation of autonomic impairment. Atomoxetine blocks norepinephrine reuptake into noradrenergic nerve fibers. An increase in blood pressure, therefore, would be a pharmacological indication of the intactness of peripheral noradrenergic fibers (central autonomic disorders), whereas a lack of response would indicate efferent noradrenergic denervation (pure autonomic failure). We hypothesize that atomoxetine responders will ultimately be diagnosed as having central forms of autonomic neuropathies.

5) Assessment of a Prosthetic Baroreceptor System to Treat Neurogenic Orthostatic Hypotension and Supine Hypertension

This study proposes to develop a prosthetic barorecptor system entailing norepinephrine infusion to treat the combination of neurogenic orthostatic hypotension and supine hypertension in patients with chronic autonomic failure that is associated with baroreflex failure and sympathetic noradrenergic denervation.

6) Assessment of Epidural Cord Stimulation in Therapy of Rare Autonomic Disorders.

This study aims to test hemodynamic effects of an epidural spinal cord stimulation system to determine whether it permits rapid and predictable control of blood pressure in central autonomic dysfunction.

General Information

The Autonomic Disorders Consortium joins with patient support groups to harness the knowledge and energies of physicians and investigators in the major centers where these patients are cared for, so that they can discover ways to treat and to cure these diseases. The greater the collaboration between doctors and patients, the more we can learn about these disorders. This important first step is necessary if we are ever to find genuinely effective and curative treatments. All consortium sites (Mayo, Harvard, New York University, The National Institutes of Health and Vanderbilt) have long traditions in discovery and treatment of autonomic disorders.

For further information, please contact

David Robertson MD,
Elton Yates Professor of Medicine, Pharmacology and Neurology
AA 3228 Medical Center North
Vanderbilt University
Nashville TN 37232-2195
Tel: +1 (615) 343-6499
E-mail: David.robertson@vanderbilt.edu
Cindy A. Dorminy, Autonomic Consortium Coordinator
E-mail: Cindy.a.dorminy@vanderbilt.edu

 

David RobertsonDavid Robertson, MD is the Elton Yates Professor of Medicine, Pharmacology and Neurology at Vanderbilt University, where he is Director of the Clinical & Translational Research Center and the Center for Space and Physiology and Medicine. He established the Autonomic Dysfunction Clinic in 1978 as the first center devoted exclusively to the study of autonomic disorders. With the 5 collaborators in the current Autonomic Disorders Consortium, Dr. Robertson founded the American Autonomic Society in 1989. Dr. Robertson's Primer on the Autonomic Nervous System has gone through two English and one Japanese edition. His 2009 textbook, Clinical and Translational Science: Principles of Human Research was the first to cover the new discipline of translational research. Dr Robertson is PI of the Autonomic Disorders Consortium.

 

Italo BiaggioniItalo Biaggioni, MD is Professor of Medicine and Pharmacology. He established Vanderbilt's Clinical Trials Center in 1999 to support investigators participating in multicenter trials. He is the immediate past president of the American Autonomic Society and organizes Annual Scientific Meeting of this Society. Dr Biaggioni has 26 years experience in clinical research, with a research focus on the interaction between neural (autonomic) and metabolic (adenosine and nitric oxide) mechanisms of cardiovascular control. Dr Biaggioni is Co-PI of the Autonomic Disorders Consortium.

 

Roy FreemanRoy Freeman, MD is Director of the Center for Autonomic and Peripheral Nerve Disorders at Beth Israel Deaconess Medical Center, Harvard Medical School, a nationally recognized diagnostic and research laboratory that evaluates both common and rare autonomic and peripheral nerve disorders. Dr Freeman and his colleagues and collaborators have developed and refined techniques, including time and frequency domain measures of heart rate, blood pressure, cerebral flow, cutaneous blood flow control, baroreflex function and sudomotor function. They have harnessed these techniques to understand the pathophysiology of diabetic peripheral neuropathy, the autonomic neuropathy of HIV infection and amyloid neuropathy, MSA and PAF. Building on work carried out by the Vanderbilt Autonomic Group and in collaboration with Dr Horacio Kaufmann in projects sponsored by the FDA orphan drug program and NORD, they have carried out mechanistic and therapeutic studies with the norepinephrine precursor, droxidopa, to treat neurogenic orthostatic hypotension. This agent is now in a multicenter clinical trial.

 

David S. GoldsteinDavid S. Goldstein, MD, PhD, has been investigating brain regulation of the cardiovascular system for about 40 years. He joined the NIH as a Clinical Associate in 1978. His single-authored report on whether essential hypertension features high plasma levels of norepinephrine has been cited over 500 times. He was one of the first to validate liquid chromatography with electrical detection (LCED) for measuring levels of catecholamines in human plasma. He developed and applied approaches for estimating the rate of entry of norepinephrine into the venous drainage of the arm and later the heart. Goldstein and his group reported the first neuroimaging evidence of loss of cardiac sympathetic nerves in PD, especially PD with orthostatic hypotension, in contrast with MSA.

 

Horacio KaufmannHoracio Kaufmann, MD is the Axelrod Professor of Neurology and Medicine at New York University. He is the director of NYU's Dysautonomia Center, which specializes in research and treatment of genetic and acquired autonomic disorders. Dr. Kaufmann's research over the last 20 years has focused on the autonomic abnormalities of patients with neurodegenerative disorders. He first described Lewy body pathology in the cardiac plexus and peripheral autonomic nerves in patients with PAF. In collaboration with other consortium members, he conducted the pivotal clinical trials of midodrine and droxidopa in the U.S. He is the current Editor-in-Chief of Clinical Autonomic Research.

 

Phillip A. LowPhillip A. Low, MD was introduced to autonomic nervous system disorders about 1970. He has been a leader in the development of quantitative tests and instruments to evaluate autonomic function. He invented the quantitative sudomotor function test. He also helped develop the thermoregulatory sweat test. Additionally, he developed and validated tests of cardiovagal and adrenergic function, combining them into a composite autonomic reflex screen. These tests have been used at the Mayo Clinic to intensively evaluate the heterogeneity of POTS, its natural history and treatment options. Over ten years ago, Dr Phillip Low and his colleagues successfully launched the nation's first Autonomic Disorders Program Project which has been continuously funded by the NIH. This program is focused on elucidating the pathophysiology of autonomic failure /dysfunction and developing novel therapies. Dr Low has played a leadership role in the design and implementation of national phase 3 treatment trials of orthostatic hypotension and neuropathy, especially diabetic neuropathy.