Synaptic Loss in Multiple System Atrophy

Inclusion Criteria MSA group: Male or female, aged 45-80 at the time of informed consent. Meet criteria for diagnosis of probable or possible MSA (Gilman et al., 2008) (Appendix 1). A female subject is eligible to participate if she is a) of non-childbearing potential, defined as pre-menopausal females with a documented tubal ligation or hysterectomy, or postmenopausal defined as 12 months of spontaneous amenorrhea or b) of childbearing potential but not pregnant (as determined by urinary pregnancy test on screening and on each study day), is not lactating and is willing to use one of the contraception methods listed below: * Combined (estrogen and progesterone containing) hormonal contraception associated with initiation of ovulation( oral, intravaginal, or transdermal); * Progesterone-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable); * Intrauterine device; * Intrauterine hormone releasing system; * Bilateral tubal occlusion; * Vasectomized partner; * Sexual abstinence. Male subject with a female partner of child-bearing potential must use one of the following contraceptive methods for 90 days after each dose of radiotracer: * Condom plus partner use of a highly effective contraceptive (see point above) OR * Abstinence Subjects must understand the nature of the study and be able to provide signed and dated written informed consent in accordance with local regulations before the conduct of any study-related procedures. They must be able and willing to participate in all scheduled evaluations, abide by all study restrictions, and complete all required tests and procedures. Must have anticipated survival of ≥3 years (in the opinion of the Investigator). Medical treatment of MSA and co-morbid medical conditions must be stable for at least 30 days prior to screening and between screening and baseline PET scan. Intermittently administered treatment may be considered stable if the dose and dosing frequency have been unchanged for the greater of 30 days or three dosing inbiomartervals (e.g. a treatment given once a month must be at a stable dose and dosing frequency for 3 months). For inclusion in optional CSF sampling, written informed consent must be provided, either by separate signed and dated written informed consent or by specific written acknowledgement on the main study informed consent form, according to local procedure. Failure to participate in optional CSF sampling will have no influence on the subject's ability to participate in the main study. In the opinion of the investigator, the subject must be considered likely to comply with the study protocol and to have high probability of completing the study. PSP Group: Male or female, aged 45-80 at the time of informed consent. Meet criteria for diagnosis of suggestive, probable or possible PSP - with preference for PSP-RS, PSP-OM, PSP-PI, PSP with gait freezing, and PSP-SL and PSP-P subtypes (Höglinger et al., 2017 (Appendix 2). A female subject is eligible to participate if she is a) of non-childbearing potential, defined as pre-menopausal females with a documented tubal ligation or hysterectomy, or postmenopausal defined as 12 months of spontaneous amenorrhea or b) of childbearing potential but not pregnant (as determined by urinary pregnancy test on screening and on each study day), is not lactating and is willing to use one of the contraception methods listed below: * Combined (estrogen and progesterone containing) hormonal contraception associated with initiation of ovulation( oral, intravaginal, or transdermal); * Progesterone-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable); * Intrauterine device; * Intrauterine hormone releasing system; * Bilateral tubal occlusion; * Vasectomized partner; Sexual abstinence. Male subject with a female partner of child-bearing potential must use one of the following contraceptive methods for 90 days after each dose of radiotracer: • Condom plus partner use of a highly effective contraceptive (see point above) OR Abstinence Subjects must understand the nature of the study and be able to provide signed and dated written informed consent in accordance with local regulations before the conduct of any study-related procedures. They must be able and willing to participate in all scheduled evaluations, abide by all study restrictions, and complete all required tests and procedures. Exclusion criteria: MSA group: History of other neurological disorders or intracranial co-morbidities, such as stroke, haemorrhage, space-occupying lesions. Presence of supranuclear gaze palsy. Presence of any clinically significant medical condition (including cardiovascular, respiratory, cerebrovascular, hematological, hepatic, renal, gastrointestinal, or other disease) that, based on the judgement of the investigator, is clinically unstable, is likely to deteriorate during the course of the study, could put the patient at risk because of participation in the study, could affect the subject's ability to complete the study, or could influence the study results. Severe-to-complete dependence on caregivers (score \>3 on UMSARS Part IV, Global Disability), severe impairment of swallowing (score ≥3 on UMSARS Part I, Question 2), or frequent falls (score ≥3 on UMSARS Part I, Question 8) at Screening. Presence of any of the following MRI contraindications: pacemaker; cardiac defibrillator; spinal cord or vagus nerve stimulator; aneurysm clip; artificial heart valve; recent coronary or carotid stent; ear implant; CSF shunt; other implanted medical device (e.g. Swan-Ganz catheter, insulin pump); or metal fragments or foreign objects in the eyes, skin, or body. If the principal investigator considers the presence of any of the above not to be a contraindication to MRI in a given subject, the investigator may obtain approval from the MR operators based on a discussion of the case.Negative modified Allen test in both hands. History of claustrophobia or back pain that makes prolonged laying on the MRI or PET scanner intolerable. Pregnancy, lactation, or, if female of childbearing potential, positive urine β-hCG at screening or prior to PET scan. Use of drugs acting on SV2A such as antiepileptics (e.g. levetiracetam or brivaracetam). History of brain surgery for parkinsonism or stem cell treatment. Clinically significant blood clotting or bleeding disorder, including clinically significant abnormal findings in laboratory assessments of coagulation or hematology. Current or recent history of alcohol or drug abuse / dependence (except nicotine dependence). History of cancer within the last 5 years, with the exception of nonmetastatic basal cell carcinoma of the skin. Hemoglobin A1c (HbA1c) ≥ 6.5% at screening. Uncontrolled/poorly controlled diabetes mellitus. For subjects participating in optional CSF sampling: * Any spinal malformation or other aspects (e.g. tattoos) / clinical findings (e.g. papilledema) that may complicate or contraindicate lumbar puncture, as judged by the investigator. * Neoplasm or other space-occupying intracranial lesion on MRI. Any clinically important abnormality, as determined by the investigator, on physical examination or vital signs, ECG, or clinical laboratory test results other than abnormality due to a stable, well-controlled medical condition; or any abnormality that could be detrimental to the subject or could compromise the study. PSP group: History of other neurological disorders or intracranial co-morbidities, such as stroke, haemorrhage, space-occupying lesions. Inclusion in any clinical trial with investigational drugs targeting tau. Presence of any clinically significant medical condition (including cardiovascular, respiratory, cerebrovascular, hematological, hepatic, renal, gastrointestinal, or other disease) that, based on the judgement of the investigator, is clinically unstable, is likely to deteriorate during the course of the study, could put the patient at risk because of participation in the study, could affect the subject's ability to complete the study, or could influence the study results. Presence of any of the following MRI contraindications: pacemaker; cardiac defibrillator; spinal cord or vagus nerve stimulator; aneurysm clip; artificial heart valve; recent coronary or carotid stent; ear implant; CSF shunt; other implanted medical device (e.g. Swan-Ganz catheter, insulin pump); or metal fragments or foreign objects in the eyes, skin, or body. If the principal investigator considers the presence of any of the above not to be a contraindication to MRI in a given subject, the investigator may obtain approval from the MR operators based on a discussion of the case. Abnormal modified Allen test in both hands. History of claustrophobia or back pain that makes prolonged laying on the MRI or PET scanner intolerable. Pregnancy, lactation, or, if female of childbearing potential, positive urine β-hCG at screening or prior to PET scan. History of brain surgery for parkinsonism or stem cell treatment. Clinically significant blood clotting or bleeding disorder, including clinically significant abnormal findings in laboratory assessments of coagulation or hematology. Current or recent history of alcohol or drug abuse / dependence (except nicotine dependence). History of cancer within the last 5 years, with the exception of nonmetastatic basal cell carcinoma of the skin. For subjects participating in optional CSF sampling: • Any spinal malformation or other aspects (e.g. tattoos) / clinical findings (e.g. papilledema) that may complicate or contraindicate lumbar puncture, as judged by the investigator. Neoplasm or other space-occupying intracranial lesion on MRI. Any clinically important abnormality, as determined by the investigator, on physical examination or vital signs, ECG, or clinical laboratory test results other than abnormality due to a stable, well-controlled medical condition; or any abnormality that could be detrimental to the subject or could compromise the study.