Inclusion Criteria:

• Able to understand the purpose and risks of the study and to provide signed and dated informed consent and authorization to use confidential health information in accordance with national and local subject privacy regulations.
• Diagnosed with PD within a maximum of 3 years prior to Screening. Subjects must have:
  • An asymmetric or bilateral presentation of one of the following:
    • resting tremor and bradykinesia;
    • bradykinesia and rigidity;
    • rigidity and resting tremor; OR
    • either asymmetric resting tremor or asymmetric bradykinesia.
  • No known or suspected cause of Parkinsonism other than neurodegenerative PD.  Subjects with drug-induced Parkinsonism (e.g., metoclopramide and flunarizine), metabolic identified neurogenetic disorders (e.g., Wilson’s  disease), encephalitis, or Parkinson Plus syndromes, other forms of atypical Parkinsonian syndromes (e.g., progressive supranuclear palsy and multiple system atrophy), or Lewy body dementia are not allowed in the study.
• Has not received any medication for the treatment of the motor symptoms of PD (including, but not limited to, levodopa and levodopa-containing products, dopamine agonists, monoamine oxidase inhibitors, centrally-acting anticholinergics, amantadine, zonisamide; see list of PD medications in the Study Reference Manual) for at least 12 weeks prior to Day 1 and, in the opinion of the Investigator, is not expected to require PD treatment for at least 6 months following Day 1. Maximum total duration of prior PD regimens should not exceed 30 days. Stable (at least 8 weeks) dosages of medications that are used to treat conditions other than PD tremor (e.g., beta-blockers, benzodiazepines, and barbiturates) are allowed. Further guidance will be provided by the study’s Medical Monitor on a case by case basis.
• Aged 40 to 80 years, inclusive, at the time of the main informed consent.
• Body mass index from 19 kg/m^2 to 35 kg/m^2.
• For Cohort A only, nonsmoker during the 6 months prior to Day 1 and willing to abstain from smoking throughout the study period.
• Score of ≤ 2.5 on the Modified Hoehn and Yahr Scale.
• Screening DaT/SPECT results demonstrating activity in the striatum is either asymmetric, absent in the putamen and/or one or both caudate nuclei, consistent with neurodegenerative Parkinsonism, as assessed with qualitative, visual assessment. DaT/SPECT images will be reviewed by a central reader to confirm eligibility.
• All women of childbearing potential and all men must practice highly effective contraception during the study and for 6 months after their last dose of study treatment.

Exclusion Criteria:

Medical History

• History of or positive test result at Screening for human immunodeficiency virus (HIV).  The requirement for testing at Screening may be omitted if it is not permitted by local regulations.
• History of, or positive test result at Screening for, hepatitis C virus antibody (HCVAb).
• Current hepatitis B infection (defined as positive for hepatitis B surface antigen [HBsAg] and/or total hepatitis B core antibody [anti-HBc]). Subjects with immunity to hepatitis B from previous natural infection (defined as negative HBsAg, positive anti-HBc, and positive hepatitis B surface antibody [anti-HBs]) or vaccination (defined as negative HBsAg, negative anti-HBc, and positive anti-HBs) are eligible to participate in the study.
• Presence of freezing of gait.
• MoCA score < 23 or other significant cognitive impairment or clinical dementia that, in the opinion of the Investigator, would interfere with study evaluation.
• Unstable psychiatric illness, including psychosis, suicidal ideation, or untreated major depression within 90 days before Screening, as determined by the Investigator.
• History or Screening MRI results showing evidence of structural abnormalities that could contribute to the subject’s clinical state, or any finding that might pose a risk to the subject, or might prevent a satisfactory MRI assessment for safety monitoring. MRI results will be reviewed by a central reader to confirm eligibility at Screening.
• History of drug or alcohol abuse within the past 5 years (as defined by the Investigator), a positive urine drug test, or an unwillingness to abstain from these substances during clinic visit days. Subjects who test positive for cannabinoids due to occasional marijuana use, as determined by the Investigator, and who agree to refrain from using marijuana for the duration of the study may be enrolled at Investigator’s discretion, after a consultation with the Sponsor.
• History of severe allergic or anaphylactic reactions, or history of hypersensitivity to BIIB054 or any of the inactive ingredients in the drug product (refer to the Investigator’s Brochure for information on the clinical formulation) or to radioligands or iodine used in the study.
• Transient ischemic attack or stroke, or any unexplained loss of consciousness within 1 year before Screening.
• History of unstable angina, myocardial infarction, chronic heart failure (New York Heart Association Class III or IV), or clinically significant conduction abnormalities (e.g., unstable atrial fibrillation) within 1 year before Screening.
• History of malignancy or carcinoma. The following exceptions may be made after discussion with the Sponsor:
  • Subjects with cancers in remission for more than 5 years prior to Screening
  • Subjects with a history of basal cell or squamous cell carcinomas of the skin that have been completely excised and are considered cured.
• History of any clinically significant endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic, dermatologic, renal, ischemic or cardiovascular, or other major diseases, as determined by the Investigator.
• History of any brain surgery for PD (e.g., pallidotomy, deep brain stimulation, or fetal tissue transplant).
• Surgery within 12 weeks before Day 1 (other than minor cosmetic surgery and minor dental surgery, as determined by the Investigator).
• Clinically significant abnormal laboratory test values at Screening, as determined by the Investigator.
• Chronic, uncontrolled hypertension (average of 3 systolic blood pressure [SBP] readings at Screening >165 mmHg or average diastolic blood pressure [DBP] ≥00 mmHg, or any documented SBP reading >180 mmHg or DBP ≥00 mmHg within the 3 months before Day 1), or orthostatic hypotension that is clinically significant as determined by the Investigator.
• Clinically significant (as determined by the Investigator) 12-lead ECG abnormalities, including confirmed demonstration of corrected QT interval using the Fridericia correction method of > 460 msec [men] and > 470 msec [women] before study treatment administration.
• Poorly controlled diabetes mellitus, as defined by having dosage adjustment of diabetic medication within 3 months before dosing (Day 1) or glycated hemoglobin value ≥ 8% at Screening.
• Screening value for hemoglobin < 12 g/dL for men or < 11 g/dL for women.
• Indication of impaired liver function as shown by an abnormal liver function profile at Screening (e.g., values of aspartate aminotransferase, or alanine aminotransferase, or total bilirubin ≥ times the upper limit of normal).
• Indication of impaired renal function at Screening (estimated glomerular filtration rate <60 mL/min).
• Screening values of coagulation parameters including platelet count, international normalized ratio (INR), prothrombin time (PT), and activated partial thromboplastin time (APTT) that are not generally within normal ranges. Subjects with nonclinically significant and stable out-of-range values may be allowed in the study at the discretion of the Investigator, and only after a consultation with the Medical Monitor.
• Currently active infection or serious infection (e.g., pneumonia, septicemia) within 8 weeks before Day 1, as determined by the Investigator.
• Presence of risk for increased or uncontrolled bleeding and/or risk of bleeding that is not managed optimally and could place a subject at an increased risk for bleeding. These could include, but are not limited to, known underlying disorders of the coagulation cascade, platelet function, or platelet count (e.g., hemophilia, Von Willebrand’s disease, liver disease).

For subjects enrolling at sites where LPs will be performed:  Subjects with the following characteristics will be excluded from participation in LP procedures:

• Any history of lumbar surgery for any reason (e.g., herniated disc) that in the opinion of the Investigator would interfere with or pose risks to the LP procedure
• Other contraindications to having a LP, including but not limited to:
  • Low platelet count (below 50,000 cells/μL), or Screening values of INR, PT, or APTT that indicate that a LP cannot be performed safely in the opinion of the Investigator;
  • Taking any antiplatelet medication (e.g., aspirin >100 mg daily, clopidogrel, or nonsteroidal anti-inflammatory drugs [NSAIDs]) within 7 days prior to the planned LP or anticipated need for antiplatelet medication within 48 hours after an LP;
  • Taking anticoagulant medication (warfarin, heparinoids, and direct coagulation factor inhibitors; e.g., apixaban, dabigatran, rivaroxaban) within 7 days prior to the planned LP or anticipated need for antiplatelet medication with 48 hours after an LP;
  • X-ray, MRI, or myelographic evidence of significant lumbar spine abnormalities or other anatomical factors at or near the LP site that might interfere with performance of LP.

Treatment History

• Participation in any passive immunotherapy study targeting α-syn , other than the BIIB054 Phase 1 study 228HV101. Subjects who participated in Study 228HV101 must meet all entry criteria for the present study, and cannot have received BIIB054 within 24 weeks before Day 1 of Study 228PD201.
• Participation in any active immunotherapy study targeting α-syn.
• Use of any of the following medications within 180 days before Day 1: typical or atypical antipsychotics (including, but not limited to, clozapine, olanzapine, flunarizine, and aripiprazole), metoclopramide, or alpha methyldopa.
• Use of any of the following medications within 90 days before Day 1: methylphenidate, cinnarizine, tetrabenazine, reserpine, amphetamine, memantine, cholinesterase inhibitors (rivastigmine, donepezil, galantamine, and tacrine), or monoamine oxidase type A inhibitors (pargyline, phenelzine, and tranylcypromine).
• Use of medicines that strongly bind to the dopamine transporter and may interfere with DaT/SPECT including amphetamine, benztropine, bupropion, cocaine, mazindol, methylphenidate, phentermine, and sertraline within 30 days before the Screening DaT/SPECT.
• Use of any glucagon-like peptide-1 (GLP-1) agonists (e.g., exenatide, liraglutide, lixisenatide, albiglutide, and dulaglutide) within 90 days before Day 1.
• Use of nilotinib within 90 days before Day 1.
• Use of allowed medications not previously specified at doses that have not been stable for at least 8 weeks before Day 1, and/or that are not expected to remain stable for the duration of the study.
• Use of selective serotonin reuptake inhibitors (SSRIs) (with the exception of sertraline, which is prohibited) or serotonin norepinephrine reuptake inhibitors (SNRIs) at doses that
• have not been stable for at least 3 months before Day 1 and/or that are not expected to
• remain stable for the duration of the study.
• Vitamins, supplements, herbal/alternative health preparations, and other over-the-counter medications at doses that are not expected to remain stable from Screening through Day 1.
• Participation or planned enrollment in any other clinical study or treatment with any investigational drug or investigational use of an approved therapy within 30 days (or 5 half-lives, whichever is longer) before Screening.

Other

• Contraindication for MRI (pacemaker, ferromagnetic objects in the body, claustrophobia, etc.).
• Presence of a ventriculoperitoneal shunt.
• Female subjects who are pregnant, currently breastfeeding, or attempting to conceive during the study.
• Blood donation (1 unit or more) within 8 weeks before Day 1 (must also refrain from donating blood for the duration of the study).
• Unwillingness or inability to comply with study requirements, including the presence of any condition (physical, mental, or social) that prevents the subject from participating in visits as scheduled.
• Other unspecified reasons that, in the opinion of the Investigator or Sponsor, make the subject unsuitable for enrollment.
• Previous registration in this study. Subjects previously enrolled in Study 228HV101 are eligible provided they meet the criteria of Study 228PD201 and were not administered BIIB054 within 24 weeks before Day 1.