Biomarkers of Risk of Parkinson Disease
Condition: Parkinson Disease; Autonomic Nervous System Diseases; Pure Autonomic Failure
MeSH terms: Parkinson Disease; Nervous System Diseases; Pure Autonomic Failure; Autonomic Nervous System Diseases; Primary Dysautonomias
Study type: Observational

Summary: 
      This study (https://pdrisk.ninds.nih.gov) will determine if people who have risk factors for
      Parkinson disease (PD) have biomarkers (objective ways to measure a disease process) that
      show that the disease process is actually going on, and if people who have abnormal
      biomarkers go on to develop PD during several years of follow-up. Biomarkers of Parkinson
      disease (PD) might identify people who are healthy now but may develop the disease later in
      life.

      Healthy volunteers and people who have certain risk factors for developing PD who are between
      18 and 70 years of age may be eligible for this study. People with the following risk factors
      are included:

        -  Family history of PD

        -  Loss of sense of smell

        -  Fall in blood pressure when standing up

        -  REM behavior disorder (a type of sleep disturbance)

      Participants undergo the following tests and procedures:

        -  Screening examination

        -  Medical and neurological history and physical examination

        -  Tests or rating scales for movement, sense of smell, mood, attention, fatigue, pain, and
           thinking.

        -  Measurement of blood pressure and pulse rate while lying down and then standing up

        -  Blood draw for genetic testing

        -  Inpatient testing at the NIH Clinical Center for 2-3 days, including:

        -  Measurements while blowing against a resistance

        -  Measurements of blood pressure and pulse rate

        -  Blood draws for levels of various chemicals

        -  PET and MRI scanning

        -  Lumbar puncture (spinal tap)

        -  Electrocardiogram

        -  Skin electrical conduction test (test of sweat production)

        -  Skin and core temperature measurements

        -  Transcranial ultrasound (sound-wave test of the head)

        -  Follow-up testing (up to five visits in 18-month intervals) to repeat some of the tests
           listed above, excluding the genetic testing and spinal tap
    

Detailed description: 
      Objective: By the time an individual develops motor symptoms or signs of Parkinson disease
      (PD) the degeneration of nigrostriatal dopaminergic neurons that produces the movement
      disorder is already advanced. It is important to identify individuals in whom the
      pathogenetic process is in a preclinical or prodromal phase. Such individuals would be the
      best candidates for disease modification clinical trials. PD is characterized by the loss of
      neurons that use catecholamines as the neurotransmitters, both in the brain and heart. This
      study is designed to test whether, among people with multiple PD risk factors (at least 3 of
      the following: family history of PD or genetic risk, olfactory dysfunction, dream enactment
      behavior, orthostatic hypotension), those with biomarkers of central or myocardial
      catecholaminergic neurodegeneration are diagnosed with motor symptoms and signs of PD within
      7.5 years of follow-up, whereas those with the same risk factors but without biomarkers of
      catecholaminergic neurodegeneration in either the brain or heart are not diagnosed with motor
      symptoms and signs of PD during follow-up. Results so far from this study have shown that low
      cerebrospinal fluid (CSF) levels of 3,4-dihydroxyphenylacetic acid (DOPAC, the main neuronal
      metabolite of the catecholamine dopamine) and of 3,4-dihydroxyphenylanine (DOPA, the
      precursor of the catecholamines), low myocardial concentrations of 18F-dopamine-derived
      radioactivity (an index of deficiency of the catecholamine norepinephrine), and low
      putamen/occipital cortex ratios of 18F-DOPA-derived radioactivity (an index of putamen
      dopamine deficiency) distinguish at-risk participants who are diagnosed with motor symptoms
      and signs of PD within 3 years of follow-up. The study is being continued to follow
      participants with initial biomarkers data who have not yet been diagnosed with PD. In the
      follow-up phase we plan on answering the following questions: (1) What proportion of at-risk
      subjects with negative biomarkers at the time of initial testing develop symptoms of PD
      during 7.5 years of follow-up? (2) What proportion of at-risk subjects with 1 or 2 positive
      biomarkers at the time of initial testing develop the motor symptoms and signs of PD during
      7.5 years of follow-up? (3) In at-risk subjects who convert from negative to positive
      biomarkers during follow-up, what proportion develop the motor symptoms and signs of PD
      during the remaining period until 7.5 years of follow-up?

      Study Population: The subjects are individuals who may be at risk for developing PD, because
      of (a) genetic risk i.e., a family history of PD or genotypic abnormalities known to be
      associated statistically with PD; (b) olfactory dysfunction i.e., decreased ability to
      distinguish among odors; (c) symptomatic rapid eye movement (REM) sleep behavior disorder
      (RBD); or (d) orthostatic hypotension. A total of 200 at-risk subjects undergo
      catecholaminergic biomarker testing by 18F-DOPA brain and 18F-dopamine cardiac scanning.
      At-risk subjects with positive biomarkers are compared to at-risk subjects without positive
      biomarkers, in terms of development of PD during follow-up. Up to 20 control subjects are
      included, to add to a database of normal values for catecholaminergic biomarkers. As of May
      2015, accrual was completed, and participants who already have been characterized in terms of
      risk factors and biomarkers are in the follow-up phase of the study.

      Design: The study includes four phases recruitment, screening, laboratory biomarkers testing,
      and follow-up. Recruitment is by advertisement and a web site questionnaire of self-reported
      risk. A screening examination is done at the NIH Clinical Center, to confirm risk status.
      Based on the screening examination results, subjects undergo inpatient clinical laboratory
      testing, to identify central and peripheral catecholaminergic denervation. Since May 2015,
      the study has been in the follow-up phase, during which subjects are being re-tested as
      inpatients approximately every 18 months for a total of up to 5 re-evaluations (90 months, or
      7.5 years), to detect the onset of the characteristic movement disorder in PD and follow the
      status of putamen and myocardial catecholaminergic innervation.

      Outcome Measures:

      The primary outcome measure is a clinical diagnosis of PD by a Board-certified neurologist
      who is blinded to risk factor status and the results of catecholaminergic biomarkers testing;
      or else completing 7.5 years of follow-up without a diagnosis of PD. If PD diagnosed, time to
      diagnosis. Secondary outcome measures are the results of UPDRS; F-DOPA brain scanning,
      F-dopamine cardiac scanning; CSF and plasma neurochemicals; neuropsychological rating scales;
      autonomic function testing, retrospective CSF proteomics; retrospective DNA analyses.
    

Intervention name(s): 6-[18F]Fluorodopamine; 6-[18F]Fluorodopa; 13N-Ammonia
Intervention type(s): Drug; Drug; Drug
Observational model: Other
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        The subjects are individuals who may be at risk for developing PD, because of (a) genetic
        risk i.e., a family history of PD or genotypic abnormalities known to be associated
        statistically with PD; (b) olfactory dysfunction i.e., decreased ability to distinguish
        among odors; (c) symptomatic rapid eye movement (REM) sleep behavior disorder (RBD); or (d)
        orthostatic hypotension.
      
Keywords: Biomarkers; Catecholamines; 18F-Fluoro-L-dopa; Fluorodopamine; Parkinson's Disease; Natural History; Parkinson Disease; PD