Researchers at NYU Langone Health’s Dysautonomia Center are building on their significant advancements made in the last year to inform new approaches to the diagnosis and treatment of autonomic disorders.
Bedside Diagnostic Tool Reveals Origins of Orthostatic Hypotension
NYU Langone researchers have identified a simple calculation that can help clinicians identify a neurogenic etiology for orthostatic hypotension, a chronic and substantial drop in blood pressure upon standing, often resulting in dizziness, lightheadedness, visual blurring, or fainting.
The research was developed out of the need for clinicians to readily distinguish between neurogenic and non-neurogenic causes of orthostatic hypotension to guide patients’ prognosis and treatment.
Although the problem has a number of benign, non-neurological causes, it can also be linked to a family of serious neurodegenerative disorders known as synucleinopathies, including Parkinson’s disease, multiple system atrophy (MSA), and some types of dementia.
Orthostatic hypotension may be an early indicator of these diseases, but currently the differential diagnosis requires time-consuming, specialized autonomic testing in the laboratory. The newly developed algorithm—dividing a change in heart rate by a drop in blood pressure after a patient stands—provides a simple shortcut that allows doctors to determine whether they need to look into possible autonomic causes.
“This simple, effective bedside screen for autonomic disorders may lead us to identify patients with disorders such as Parkinson’s disease years before they suffer movement or memory difficulties—and enable intervention before severe brain damage has occurred,” says Lucy J. Norcliffe-Kaufmann, PhD, associate professor of neurology and neuroscience and physiology and lead author of the paper published in Annals of Neurology in March 2018.
Individuals with neurogenic orthostatic hypotension typically have little or no increase in heart rate after standing, while those with the non-neurogenic form have a marked increase in heart rate.
To create the analytic shortcut to distinguish between the two, the researchers identified more than 400 patients diagnosed with either type of orthostatic hypotension based on detailed autonomic testing and measured their blood pressure while on a tilt table in a supine position, as well as in the head-up position to mimic standing up.
This test indicated that when the increase in heart rate was less than half a beat per minute for each unit of drop in systolic blood pressure, the condition almost invariably had a neurogenic cause.
“For the first time, we are able to systematically show that patients whose blood pressure drops after standing up, without a specific increase in their heart rate, may have autonomic dysfunction caused by a synucleinopathy,” says Horacio Kaufmann, MD, the Felicia B. Axelrod Professor of Dysautonomia Research, professor of medicine and pediatrics, and director of the Dysautonomia Center and of the Division of Autonomic Disorders. “This research should have widespread applicability.”
Novel Application of Approved Immunosuppressant Could Target Multiple System Atrophy
A clinical trial exploring a potential new use of an FDA-approved medication could offer hope for patients with multiple system atrophy (MSA). No effective treatment to date has addressed the underlying pathology of MSA—a general breakdown of the body’s motor and autonomic nervous systems that typically strikes people in their 50s and invariably causes death, usually within 8 to 10 years.
The groundbreaking three-year NYU Langone trial, which began recruiting participants in 2018, is being led by Jose Alberto Palma Carazo, MD, PhD, assistant professor of neurology and assistant director of the Dysautonomia Research Laboratory.
Dr. Palma’s team will study the anti-MSA effects of the immune suppressant medication sirolimus, also known as rapamycin. In addition to preventing the rejection of transplanted organs, sirolimus promotes autophagy, the process by which toxic, misfolded proteins are removed from the body.
This controlled, double-blind study will enroll 56 patients with MSA, and Dr. Palma and colleagues will explore whether sirolimus can reduce levels of alpha-synuclein, the toxic protein that causes the disorder.
Of the study subjects, 75 percent will receive sirolimus and 25 percent will receive a placebo, with researchers monitoring disease progression over time with neurological examinations, regular MRI scans of the brain, and regular measurements of subjects’ retinal nerve thickness using optical coherence tomography.
Dr. Palma’s study—the first ever to employ an autophagy-stimulating drug against a neurodegenerative disorder—received funding from the National Institutes of Health through an R01 grant.
“Fortunately, sirolimus is an FDA-approved drug with a well-known safety profile to support its use in our research,” he notes. “We are building on robust evidence that sirolimus reduces alpha-synuclein accumulation and associated neurodegeneration in animal and cell models of synucleinopathies.”
Looking beyond MSA, the investigators believe that sirolimus may also hold promise as a treatment for other neurological conditions associated with the accumulation of toxic proteins, including Parkinson’s diseases and Alzheimer’s disease. “If this approach works, sirolimus could not only benefit our MSA patients but also potentially be tested as a treatment for the entire range of neurodegenerative diseases,” Dr. Palma concludes.