Clinical trial NCT01799915: Natural History Study of Synucleinopathies
Official title: Natural History Study of Synucleinopathies
Study type: OBSERVATIONAL
Overall status: RECRUITING
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
Lead sponsor: NYU Langone Health
Sponsor class: OTHER
First posted: 2013-02-27
Enrollment: 800
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
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).

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.

Detailed description: α-synuclein is a small protein of 140 amino acids that is highly expressed in the brain. It's function remains poorly understood.10 Synucleinopathies are a group of neurodegenerative diseases associated with the abnormal accumulation of α-synuclein within cytoplasmic inclusions in neurons or oligodendroglia. These α-synuclein containing cytoplasmic aggregates occur throughout the brain, producing cell death and specific motor, autonomic and cognitive dysfunction in four phenotypically distinct synucleinopathies. When α-synuclein deposition occurs in neurons it aggregates into Lewy bodies, producing Parkinson disease (PD), dementia with Lewy bodies (DLB) or pure autonomic failure (PAF). Whereas in multiple system atrophy (MSA) neuronal death probably occurs as a consequence of α-synuclein aggregation in oligodendroglia.

A characteristic feature of the synucleinopathies is that they can all begin with varying degrees of autonomic dysfunction as the sole clinical feature - implying an initial diagnosis of isolated (pure) autonomic failure 11. After a variable period of time, but usually less than 5 years, only a small number of patients remain with a pure autonomic failure phenotype, but careful follow-up is lacking 11. Most patients develop cognitive or motor abnormalities (or both) and the patient is then diagnosed with PD, DLB or MSA.

This stepwise clinical progression suggests that the neurodegenerative process can in rare cases remain confined to autonomic neurons12, but more frequently spreads to affect additional areas of the central nervous system (CNS). This unique feature of the synucleinopathies poses diagnostic challenges and potential therapeutic opportunities.

The challenges are first, to determine whether PAF is a distinct disease or is always a prodromal phase of PD, DLB or MSA and second, to discover biomarkers that predict spread to motor and cognitive neurons. Such biomarkers would allow testing of disease-modifying strategies to delay or stop the neurodegenerative process in the pre-motor or pre-dementia phase. Aim 2 will focus on defining the natural history of MSA, the most aggressive of the synucleinopathies. This prospective observational study will establish disease-specific milestones for use in future clinical trials.

Obstacles to identifying biomarkers predicting further CNS involvement are that most medical centers only see patients with synucleinopathies when they already have developed motor and cognitive involvement, and that PAF and MSA are rare disorders. In this context the Autonomic Disorders Consortium (ADC) within the Rare Diseases Clinical Research Network (RDCRN) of the National Institutes of Health (NIH) was created with the objective of providing a better understanding of the variability, progression, and natural history of neurodegenerative synucleinopathies. Continuing this observational study, and increasing its power by including additional academic centers from the U.S., South America, and Europe, will allow us to define the natural history of these diseases and establish the sensitivity and specificity of the proposed biomarkers.

Eligibility criteria: Inclusion Criteria:

1. Both male and female patients will be included
2. Aged 18 or over
3. 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.

Exclusion Criteria:

1. Diabetes according to the American Diabetes Association criteria
2. Congestive heart failure
3. Lupus or other collagen vascular disease
4. Systemic illness thought to be responsible for the orthostatic intolerance
5. 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)
6. Isolated vasovagal syncope
7. Inability to comply with the protocol, e.g. uncooperative attitude, inability to return for follow-up visits, and unlikelihood of completing the study.

Primary outcomes:
measure: To create a database of primary autonomic disorders that will serve as a phenotyping core.
timeFrame: 5 years
Secondary outcomes:
measure: To define the natural history of neurogenic orthostatic hypotension and identify predictive biomarkers of autonomic disorders
timeFrame: 5 years
Other outcomes:
Locations:
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: New York
country: United States
facility: NYU Medical Center
state: New York
city: Nashville
country: United States
facility: Vanderbilt Univeristy
state: Tennessee
city: Buenos Aires
country: Argentina
facility: FLENI - Fundación para la Lucha contras las Enfermedades Neurológicas
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Bilbao
country: Spain
facility: BioCruces Research Institute - Hospital Universitario de Cruces
Study officials:
affiliation: NYU MEDICAL CENTER
name: Horacio C Kaufmann, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.