⁃ Male or female age 57 years or older at Screening visit.

⁃ Individuals taking any of the following drugs: alpha methyldopa, methylphenidate, amphetamine derivatives or modafinil, must be willing and medically able to hold the medication for at least 5 half-lives before SPECT imaging.

⁃ Confirmation that participant is eligible based on Screening SPECT imaging.

⁃ Able to provide informed consent.

⁃ Either is male, or is female and meets additional criteria below, as applicable:

∙ Female of childbearing potential who is not pregnant, lactating, or planning pregnancy during the study and has a negative pregnancy test on day of Screening SPECT imaging test prior to injection of DaTscanTM.

⁃ Male or female age 30 years or older at Screening Visit.

⁃ A diagnosis of Parkinson's disease for 2 years or less at Screening Visit.

⁃ Not expected to require PD medication within at least 6 months from Baseline.

⁃ Patients must have at least two of the following: resting tremor, bradykinesia, rigidity (must have either resting tremor or bradykinesia); OR either asymmetric resting tremor or asymmetric bradykinesia.

⁃ Hoehn and Yahr stage I or II at Baseline.

⁃ Individuals taking any of the following drugs: alpha methyldopa, methylphenidate, amphetamine derivatives or modafinil, must be willing and medically able to hold the medication for at least 5 half-lives before SPECT imaging.

⁃ Confirmation that participant is eligible based on Screening SPECT imaging.

⁃ Able to provide informed consent.

⁃ Either is male, or is female and meets additional criteria below, as applicable:

∙ Female of childbearing potential who is not pregnant, lactating, or planning pregnancy during the study and has a negative pregnancy test on day of Screening SPECT imaging test prior to injection of DaTscanTM.

⁃ Male or female age 30 years or older at Screening Visit.

⁃ A diagnosis of Parkinson's disease for 2 years or less at Screening Visit.

⁃ Patients must have at least two of the following: resting tremor, bradykinesia, rigidity (must have either resting tremor or bradykinesia); OR either asymmetric resting tremor or asymmetric bradykinesia.

⁃ Hoehn and Yahr stage I or II at Baseline.

⁃ Confirmation of causative LRRK2 or GBA (willingness to undergo genetic testing as part of genetic screening and be informed of genetic testing results, or approved documentation of prior genetic testing results).

⁃ Individuals taking any of the following drugs: alpha methyldopa, methylphenidate, amphetamine derivatives or modafinil, must be willing and medically able to hold the medication for at least 5 half-lives before SPECT imaging.

⁃ Confirmation that participant is eligible based on Screening SPECT imaging.

⁃ Able to provide informed consent.

⁃ Either is male, or is female and meets additional criteria below, as applicable:

∙ Female of childbearing potential who is not pregnant, lactating, or planning pregnancy during the study and has a negative pregnancy test on day of Screening SPECT imaging test prior to injection of DaTscanTM.

⁃ Male or female age 30 years or older at Screening Visit.

⁃ Parkinson's disease diagnosis at Screening Visit.

⁃ Patients must have at least two of the following: resting tremor, bradykinesia, rigidity (must have either resting tremor or bradykinesia); OR either asymmetric resting tremor or asymmetric bradykinesia.

⁃ Hoehn and Yahr stage I, II, or III at Baseline.

⁃ Confirmation of causative SNCA or rare genetic variant (such as Parkin or Pink1) (willingness to undergo genetic testing as part of genetic screening and be informed of genetic testing results, or approved documentation of prior genetic testing results).

⁃ Individuals taking any of the following drugs: alpha methyldopa, methylphenidate, amphetamine derivatives or modafinil, must be willing and medically able to hold the medication for at least 5 half-lives before SPECT imaging.

⁃ Confirmation that participant is eligible based on Screening SPECT imaging.

⁃ Able to provide informed consent.

⁃ Either is male, or is female and meets additional criteria below, as applicable:

∙ Female of childbearing potential who is not pregnant, lactating, or planning pregnancy during the study and has a negative pregnancy test on day of Screening SPECT imaging test prior to injection of DaTscanTM.

• For Screening:

⁃ Confirmation that participant is eligible based on centrally determined predictive criteria including the University of Pennsylvania Smell Identification Test (UPSIT).

∙ For participants in PPMI Remote, referral to the clinical site confirms predictive eligibility.

‣ For participants identified by the clinical site, predictive criteria are based on generalized risk such as first degree biologic relative, known risk of PD including RBD, or known genetic variants associated with PD risk.

⁃ Additionally, confirmation of UPSIT eligibility during the Screening visit prior to SPECT Imaging.

⁃ Male or female age 60 years or older (except age 30 years or older for SNCA, or rare genetic variants (such as Parkin or Pink1) participants).

⁃ Individuals taking any of the following drugs: alpha methyldopa, methylphenidate, amphetamine derivatives or modafinil, must be willing and medically able to hold the medication for at least 5 half-lives before SPECT imaging.

⁃ Able to provide informed consent.

⁃ Either is male, or is female and meets additional criteria below, as applicable:

⁃ • Female of childbearing potential who is not pregnant, lactating, or planning pregnancy during the study and has a negative pregnancy test on day of Screening SPECT imaging test prior to injection of DaTscanTM.

⁃ For continuation to Baseline visit and ongoing follow-up:

⁃ Confirmation that participant is eligible based on \*Screening SPECT imaging.

∙ Screening SPECT Imaging eligibility:

• Based on the results of the SPECT imaging test, Prodromal participants eligible to continue their participation in PPMI Clinical will be asked to return for their PPMI Clinical baseline visit. Neither the participant nor the site investigator will be made aware of the participant's DAT status during the study.

• It is anticipated that approximately 6,000 participants will complete a screening visit to undergo DAT imaging. Approximately 2,000 participants will be eligible to continue their participation in PPMI Clinical (those not eligible to proceed will remain in PPMI Remote, as applicable).

• All participants with DAT deficit will be eligible to continue their participation in PPMI Clinical. It is estimated that about 75% of eligible participants will have a DAT deficit (defined by a hybrid of visual assessment and quantitative striatal specific binding analysis).

• Some participants without DAT deficit will also be eligible to continue their participation in PPMI Clinical. These participants will be chosen based on DAT binding that is reduced from age expected but it not outside the normal range and/or from individuals with high-risk of PD including RBD, LRRK2, GBA, SNCA, or rare genetic variants (such as Parkin or Pink1) that do not demonstrate DAT deficit. It is estimated that about 25% of eligible participants will not have a DAT deficit.

• It is anticipated that approximately 30% of the PPMI Clinical prodromal participants with DAT deficit will phenoconvert to motor parkinsonism during a 3 to 5-year follow-up.