Background:

Parkinson s disease is a neurologic disorder that affects movement. Its cause is unknown, and it usually begins later in life. Gene changes (PRKN and PINK1) can also cause rare types of Parkinson s disease that start at a young age. Researchers want to conduct a natural history study to learn more about how genes play a role in Parkinson s disease.

Objective:

To collect data and biological samples from people with different types of Parkinson s disease.

Eligibility:

People aged 18 to 80 years with either Parkinson s disease or PRKN- and PINK1-linked Parkinson s disease. Healthy volunteers are also needed.

Design:

Participants will have 6 clinic visits over 5 years. Each visit may take 1 to 3 days.

During each visit:

Participants will have a physical exam. The exam will be videotaped.

They will answer questions about their movement, thinking, mood, and sense of smell. The extent of any symptoms of Parkinson s disease will be evaluated: Participants movements may be assessed with a finger tapping test. They may be asked to scratch and sniff different scented strips to identify odors.

They will wear motion sensors on their arms, legs, chest, and back at the clinic. They will wear motion sensor devices on their wrists at home for 1 week.

Blood and urine samples will be collected.

Other tests are optional:

Magnetic resonance imaging (MRI) scan of the brain. Participants will lie on a table that slides into a tube.

Lumbar puncture (spinal tap). A thin needle will be inserted into their lower back to draw out a sample of the fluid around their spinal cord.

Muscle biopsy. A small sample of tissue will be taken from the leg.

Study Description:

This is a longitudinal, observational study that aims to assess progression of clinical features, imaging, and biologic markers of PD in study participants with and without manifest PD who are bi-allelic or mono-allelic carriers of pathogenic variants in the recessively inherited genes PRKN and PINK1 that represent prototypes of mitochondrial- associated PD.

Objectives:

Primary Objective: To characterize the natural history of motor symptoms in PRKN- and PINK1-linked PD.

Secondary Objectives: To comprehensively characterize other clinical features of PRKN- and PINK1-linked PD over time

Tertiary Objectives:

• To characterize structural brain changes over time
• To identify molecular signatures that differ between PRKN and PINK1-associated PD, non-manifesting mutation carriers, wildtype PD, and healthy controls.
• To generate a repository of longitudinal data and samples for future studies aimed at developing targeted therapies.
• To characterize in-home assessment of movements
• To evaluate for mitochondrial changes in the muscle

Endpoints:

Primary Endpoint: Annual change in MDS Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III

Secondary Endpoints:

• Annual change in MDS-UPDRS parts I, II, IV
• Annual change in Montreal Cognitive Assessment (MoCA)
• Annual change in Timed up and go (TUG)
• Annual change in 10-meter walk
• Annual change in 360 degree turn
• Annual change in Unified Dyskinesia Rating Scale (UDysRS)
• Annual change in University of Pennsylvania Smell Identification Test (UPSIT)
• Annual change in REM-Sleep-Behavior Disorder Screening Questionnaire (RBD-SQ)
• Annual change in Questionnaire for Impulsive-Compulsive Disorders (QUIP)
• Annual change in Epworth Sleepiness Scale (ESS)
• Annual change in Geriatric Depression Scale (GDS)
• Annual change in State-Trait Anxiety Inventory (STAI)
• Annual change in Scales for Outcomes in Parkinson s Disease - Autonomic Dysfunction (SCOPA AUT)
• Annual change in 39-item Parkinson s Disease Questionnaire (PDQ-39)- quality of life measurement
• Annual change in Schwab and England Activities of Daily Living (SE-ADL) scale
• Annual change in Hoehn and Yahr scale assessment Tertiary endpoints:
• Annual change of brain MRI measurement of overall brain, striatum and substantia nigra volumes
• Annual change of brain MRI measurement of iron deposition
• Annual change in studies from blood
• Annual change in studies from CSF
• Annual change in studies from urine
• Annual change in Wearable Accelerometry data
• Evidence of mitochondrial cytopathy on muscle biopsy

• INCLUSION CRITERIA:

To be eligible to participate in this study, an individual must meet all of the following criteria:

All participants:

• Stated willingness to comply with all study procedures and availability for the duration of the study
• Male or female between the ages of 18-80 years old
• Ability of subject to understand and the willingness to sign an informed consent document
• Ability of subject to travel to the NIH Clinical Center

Additional inclusion criteria for each cohort as below:

PD Mito - Biallelic:

• Established clinical diagnosis of Parkinson's disease
• Two Pathogenic or likely pathogenic variants in PRKN or PINK1

PD Mito - Monoallelic:

• Established clinical diagnosis of Parkinson's disease
• One Pathogenic or likely pathogenic variant in PRKN and/or PINK1

Idiopathic Parkinson's Disease (PD):

• Established clinical diagnosis of Parkinson's disease
• Etiology of PD is idiopathic/sporadic based on investigator determination

Non-manifesting mito:

• One or two pathogenic or likely pathogenic variant in PRKN and/or PINK1
• Lack of clinical diagnosis of Parkinson's disease
• Lack of current or clinically significant neurological disorder (based on investigator determination)

Healthy Volunteer

-Lack of current or clinically significant neurological disorder (based on investigator determination)

EXCLUSION CRITERIA:

An individual who meets any of the following criteria will be excluded from participation in this study:

All participants:

• Symptomatic PD syndromes due to drugs (e.g., metoclopramide, flunarizine, neuroleptics), metabolic disorders (e.g., Wilson's disease hypothyroidism), encephalitis, brain lesion, atypical parkinsonism, other monogenic forms of PD (e.g., GBA1, LRRK2, SNCA, VPS35, CHCHD2, DJ1, ATP13A2) other genetic disorders that may cause parkinsonism (e.g., spinocerebellar ataxia, X-linked dystonia parkinsonism)
• Pregnancy at time of study enrollment
• Any other reason that, in the opinion of the investigator, would render the participant unsuitable for study enrollment
• Unwilling to allow samples or data to be shared with other researchers or institutions.
• NIH staff or family members of study team members

Healthy Volunteer:

-Participants who become pregnant during the study will be withdrawn from further study procedures at the time pregnancy is identified.

Procedural Exclusions:

Subjects may still be enrolled if they cannot participate in certain procedures due to not meeting the inclusion requirements for that specific procedure. Subjects who meet exclusion criteria for procedures listed below may still undergo the procedure at a later time if the reason of exclusion is no longer present.

Brain MRI:

• Contraindications to MRI such as a contraindicated non-removable metal device (i.e., pacemaker, defibrillator, insulin pump, metal clips, non-removable jewelry)
• Pregnancy

Accelerometer:

-Non ambulatory

Lumbar puncture procedure:

• PT/PTT values that are prolonged greater than or equal to 3 seconds from the upper limit of normal (including treatment with oral and parenteral anticoagulants)
• INR greater than 1.4, thrombocytopenia (<70,000), or abnormal bleeding time or platelet dysfunction
• History of a bleeding disorder
• Use of anticoagulants or antiplatelets
• Pregnancy
• History of headache requiring blood patch after a previous LP

Needle muscle biopsy:

• PT/PTT values that are prolonged greater than or equal to 3 seconds from the upper limit of normal (including treatment with oral and parenteral anticoagulants)
• INR greater than 1.4, thrombocytopenia (<70,000), or abnormal bleeding time or platelet dysfunction
• History of a bleeding disorder
• Use of anticoagulants or antiplatelets
• Pregnancy

There will be a total of up to 50 male or female participants 18- 80 years of age and older in 5 cohorts. Target number of completers for each cohort are listed below: - PD mito-biallelic (PD participants carrying two pathogenic variants in PRKN or PINK1): up to 15 - PD mito-monoallelic (PD participants carrying one pathogenic mono-allelic variant in PRKN and/or PINK1): up to 10 - PD idiopathic: up to 5 - Non-manifesting mito (participants who carry one or two pathogenic variants in PRKN and/or PINK1 but do not have a diagnosis of PD): up to 15 - Healthy controls: up to 5