Synucleinopathies are a group of rare diseases associated with worsening neurological deficits and the abnormal accumulation of the protein α-synuclein in the nervous system. Onset is usually in late adulthood at age 50 or older. Usually, synucleinopathies present clinically with slowness of movement, coordination difficulties or mild cognitive impairment. Development of these features indicates that abnormal alpha-synuclein deposits have destroyed key areas of the brain involved in the control of movement or cognition. Patients with synucleinopathies and signs of CNS-deficits are frequently diagnosed with Parkinson disease (PD), dementia with Lewy bodies (DLB) or multiple system atrophy (MSA).
However, accumulation of alpha-synuclein and death of nerve cells can also begin outside the brain in the autonomic nerves. In such cases, syncucleinopathies present first with symptoms of autonomic impairment (unexplained constipation, urinary difficulties, and sexual dysfunction). In rare cases, hypotension on standing (a disorder known as orthostatic hypotension) may be the only clinical finding. This "pre-motor" autonomic stage suggests that the disease process may not yet have spread to the brain.
After a variable period of time, but usually within 5-years, most patients with abnormally low blood pressure on standing develop cognitive or motor abnormalities. This stepwise evolution indicates that the disease spreads from the body to the brain. Another indication of this spread is that acting out dreams (i.e., REM sleep behavior disorder, RBD) a problem that occurs when the lower part of the brain is affected, may also be the first noticeable sign of Parkinson disease.
The purpose of this study is to document the clinical features and biological markers of patients with synucleinopathies and better understand how these disorders evolve over time. The study will involve following patients diagnosed with a synucleinopathy (PD/DLB and MSA) and those believed to be in the "pre-motor" stage (with isolated autonomic impairment and/or RBD). Through a careful series of follow-up visits to participating Centers, we will focus on finding biological clues that predict which patients will develop motor/cognitive problems and which ones have the resilience to keep the disease at bay preventing spread to the brain. We will also define the natural history of MSA - the most aggressive of the synucleinopathies.
Both male and female patients will be included
Aged 18 or over
Referred to any of the participating consortium sites with orthostatic intolerance, defined as symptoms of dizziness or lightheadedness in the standing position that disappear when supine.
Diabetes according to the American Diabetes Association criteria
Congestive heart failure
Lupus or other collagen vascular disease
Systemic illness thought to be responsible for the orthostatic intolerance
Primary autonomic disorders are a group of diseases that usually begin in adulthood with the inability to stand because of dizziness, lightheadedness and fainting. Symptoms are the result of a dysfunction in the autonomic nerves that regulate blood pressure and heart rate, and are either related to the accumulation of abnormal protein deposits and a primary neurodegenerative process (like Parkinson's disease, pure autonomic failure, dementia with Lewy bodies and multiple system atrophy), secondary to genetic abnormalities (dopamine-beta-hydroxylase deficiency), an autoimmune process (autoimmune ganglionopathy), or because of a direct injury to the nerves involved in buffering blood pressure fluctuations (acquired baroreflex failure).
Cohort
Prospective
Not listed
To create a database of primary autonomic disorders that will serve as a phenotyping core.
We will create an enrollment database of patients with primary autonomic disorders. All patients will have standardized phenotyping evaluations that will combine clinical, physiological and biochemical strategies to characterize complex autonomic phenotypes, both known and still undiscovered.
To define the natural history of neurogenic orthostatic hypotension and identify predictive biomarkers of autonomic disorders
We will map the natural history of primary autonomic failure and test the hypothesis that pure autonomic failure (PAF) is a neurodegenerative synucleinopathy that remains confined to the autonomic nervous system. We will also identify biomarkers that can distinguish patients with PAF from those with early (i.e., "pre-motor") MSA, PD, DLB or autonomic failure as a result of another disorder.
Click on the lead sponsor to view all of their trials.
