Natural History Study of Synucleinopathies

NCT01799915 | Recruiting DMC

• 1 other identifier: 08-1408
• Study Type: observational
• Target: 800
• Locations: 4 countries
• Sites: 8

Brief Summary

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.

Conditions

Patients With Synucleinopathies; Neurogenic Orthostatic Hypotension; Pure Autonomic Failure; REM Sleep Behavior Disorder; Parkinson Disease; Dementia With Lewy Bodies; Multiple System Atrophy; Shy-Drager Disease

Outcome Measures

Primary Outcomes (1)

• 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.

  5 years

Secondary Outcomes (1)

• To define the natural history of neurogenic orthostatic hypotension and identify predictive biomarkers of autonomic disorders

  5 years

Study Arms (5)

REM sleep behavior disorder, RBD

Patients that have rapid eye movement sleep behavior disorder.

multiple system atrophy

is a neurodegenerative disorder charaterized by abnormal alpha-synuclein deposition in the cytoplasm of oligodendroglial cells in the CNS, and typically sparing peripheral autonomic nerves.

Pure Autonomic failure

A neurodegenerative disorder characterized by loss of peripheral noradrenergic fibers, with low levels of plasma norepinephine.

Parkinson disease

A degenerative disorder of the central nervous system that leads to termors, difficulty walking, movement and coordination.

Dementia with Lewy bodies

A neurodegenerative disorder similar to PAF and PD with the accumulation of Alpha-synuclein in the CNS however DLB patients develop dementia.

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

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).

You may qualify if:

• 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.

You may not qualify if:

• 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
• Drug-induced orthostatic hypotension (i.e., the use of alpha-blockers, diuretics, tricyclic antidepressants or others thought by the investigator to play an important role in the patient's orthostatic hypotension)
• Isolated vasovagal syncope
• Inability to comply with the protocol, e.g. uncooperative attitude, inability to return for follow-up visits, and unlikelihood of completing the study.

Sponsors & Collaborators

• NYU Langone Health: lead

Study Sites (8)

Beth Israel Deaconess Medical Center

Boston, Massachusetts, United States

RECRUITING

University of Michigan

Ann Arbor, Michigan, United States

RECRUITING

Mayo Clinic

Rochester, Minnesota, United States

RECRUITING

NYU Medical Center

New York, New York, 10016, United States

RECRUITING

Vanderbilt Univeristy

Nashville, Tennessee, United States

RECRUITING

FLENI - Fundación para la Lucha contras las Enfermedades Neurológicas

Buenos Aires, Argentina

RECRUITING

Seoul National University Hospital

Seoul, South Korea

RECRUITING

BioCruces Research Institute - Hospital Universitario de Cruces

Bilbao, Spain

RECRUITING

Related Publications (2)

• Palma JA, Vernetti PM, Perez MA, Krismer F, Seppi K, Fanciulli A, Singer W, Low P, Biaggioni I, Norcliffe-Kaufmann L, Pellecchia MT, Marti MJ, Kim HJ, Merello M, Stankovic I, Poewe W, Betensky R, Wenning G, Kaufmann H. Limitations of the Unified Multiple System Atrophy Rating Scale as outcome measure for clinical trials and a roadmap for improvement. Clin Auton Res. 2021 Apr;31(2):157-164. doi: 10.1007/s10286-021-00782-w. Epub 2021 Feb 7.

  PMID: 33554315 DERIVED

• Norcliffe-Kaufmann L, Kaufmann H, Palma JA, Shibao CA, Biaggioni I, Peltier AC, Singer W, Low PA, Goldstein DS, Gibbons CH, Freeman R, Robertson D; Autonomic Disorders Consortium. Orthostatic heart rate changes in patients with autonomic failure caused by neurodegenerative synucleinopathies. Ann Neurol. 2018 Mar;83(3):522-531. doi: 10.1002/ana.25170. Epub 2018 Mar 10.

  PMID: 29405350 DERIVED

Biospecimen

Retention: SAMPLES WITH DNA

Blood Sample for DNA processing

MeSH Terms

Conditions

Pure Autonomic Failure; REM Sleep Behavior Disorder; Parkinson Disease; Lewy Body Disease; Multiple System Atrophy

Condition Hierarchy (Ancestors)

Primary Dysautonomias; Autonomic Nervous System Diseases; Nervous System Diseases; REM Sleep Parasomnias; Parasomnias; Sleep Wake Disorders; Mental Disorders; Parkinsonian Disorders; Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Dementia; Neurocognitive Disorders

Study Officials

• Horacio C Kaufmann, MD

  NYU MEDICAL CENTER

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Horacio Kaufmann, MD

CONTACT

212-263-7225; horacio.kaufmann@nyulangone.org

Grace Nkrumah

CONTACT

212-263-7225; grace.nkrumah@nyulangone.org

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 25, 2013
• First Posted: February 27, 2013
• Study Start: June 1, 2011
• Primary Completion (Estimated): December 30, 2026
• Study Completion (Estimated): December 30, 2026
• Last Updated: June 11, 2025

Record last verified: 2025-06

Locations

AR (1); ES (1); US (5); KR (1)