Molecular Imaging of Inflammation in Parkinson's Disease Using LPS and TSPO-PET/MR

Inclusion Criteria (all): * 50-85 years of age, male or female * Able to give informed consent * Adequate visual and auditory acuity to complete the neuropsychological testing * No presence or history of significant neurological or psychiatric disorders * BDI ≥ 20, moderate depression * No presence or history of inflammatory or autoimmune disorders * Negative family history for neurodegenerative diseases * Cognitively healthy (i.e., education-adjusted MoCA total score ≥ 26 points at screening) * Female subjects must either be documented by medical records or physician's note to be either surgically sterile (by means of hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) or post-menopausal for at least 1 year (no menses for 12 months without an alternative medical cause) or if they are of childbearing potential, they must commit to use of a highly effective contraceptive measure for the duration of the study and a minimum of six months following the PET scan (including combined \[estrogen and progestogen containing\] hormonal contraception associated with inhibition of ovulation \[oral, intravaginal, or transdermal\], progestogen-only hormonal contraception associated with inhibition of ovulation \[oral, injectable, or implantable\], intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomised partner or sexual abstinence). * Male subjects and their partners of childbearing potential must commit to the use of a highly effective method of contraception during the study and for a minimum of three months following each PET scan (including, for female partners of childbearing potential, combined \[estrogen and progestogen containing\] hormonal contraception associated with inhibition of ovulation \[oral, intravaginal, or transdermal\], progestogen-only hormonal contraception associated with inhibition of ovulation \[oral, injectable, or implantable\], intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, male subjects with vasectomy or sexual abstinence). * Male subjects must commit to not donate sperm during the study and for a minimum of three months after the last PET scan. * Individuals must commit to refrain from drinking alcohol for 48 hours before each visit, refrain from drinking any caffeinated substance for 12 hours before the PET-MR visits, and to refrain from smoking or using any nicotine-containing products on the day of the PET-MR scans. * Individuals must commit to not donating blood up to three months after the last PET scan. * Individuals must commit to come to the screening and Day 1 visits in a fasting state (i.e., minimum of 8 hours since last meal/food intake). * Individuals must commit to not to take any over-the-counter non-steroidal anti-inflammatory drugs or drink alcohol for 48h before screening visit. Inclusion Criteria (Parkinson's disease patients): * 50-85 years of age, male or female * Able to give informed consent * Adequate visual and auditory acuity to complete the neuropsychological testing * No presence or history of other significant neurological or psychiatric disorders * Diagnosis of PD according to the Movement Disorder Society Clinical Diagnostic Criteria (Postuma et al., Mov Disord 2015) * Drug-naïve participants with PD must have a diagnosis of PD but must be therapy-free at the time of enrolment * For participants with PD-MCI: diagnosis of MCI according the diagnostic criteria for MCI-PD (Level I; Litvan et al., Mov Disord 2012) and/or MoCA \< 23 * For participants with PD taking dopaminergic therapy: must be in stable therapy (i.e. not have changed therapy in the last 60 days) * Female subjects must either be documented by medical records or physician's note to be either surgically sterile (by means of hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) or post-menopausal for at least 1 year (no menses for 12 months without an alternative medical cause) or if they are of childbearing potential, they must commit to use of a highly effective contraceptive measure for the duration of the study and a minimum of six months following the PET scan (including combined \[estrogen and progestogen containing\] hormonal contraception associated with inhibition of ovulation \[oral, intravaginal, or transdermal\], progestogen-only hormonal contraception associated with inhibition of ovulation \[oral, injectable, or implantable\], intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomised partner or sexual abstinence). * Male subjects and their partners of childbearing potential must commit to the use of a highly effective method of contraception during the study and for a minimum of three months following each PET scan (including, for female partners of childbearing potential, combined \[estrogen and progestogen containing\] hormonal contraception associated with inhibition of ovulation \[oral, intravaginal, or transdermal\], progestogen-only hormonal contraception associated with inhibition of ovulation \[oral, injectable, or implantable\], intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, male subjects with vasectomy or sexual abstinence). * Male subjects must commit to not donate sperm during the study and for a minimum of three months after the last PET scan. * Individuals must commit to refrain from drinking alcohol for 48 hours before each visit, refrain from drinking any caffeinated substance for 12 hours before the PET-MR visits, and to refrain from smoking or using any nicotine-containing products on the day of the PET-MR scans. * Individuals must commit to not donating blood up to three months after the last PET scan. * Individuals must commit to come to the screening and Day 1 visits in a fasting state (i.e., minimum of 8 hours since last meal/food intake). * Individuals must commit to not to take any over-the-counter non-steroidal anti-inflammatory drugs or drink alcohol for 48h before screening visit. For participants with iRBD: Inclusion criteria: * 40-85 years of age, male or female * Able to give informed consent * Adequate visual and auditory acuity to complete the neuropsychological testing * No presence or history of significant neurological or psychiatric disorders * BDI-II ≥ 20, moderate depression * No presence or history of inflammatory or autoimmune disorders * Negative family history for neurodegenerative diseases * Cognitively healthy (i.e., education-adjusted MoCA total score ≥ 26 points at screening) * Female subjects must either be documented by medical records or physician's note to be either surgically sterile (by means of hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) or post-menopausal for at least 1 year (no menses for 12 months without an alternative medical cause) or if they are of childbearing potential, they must commit to use of a highly effective contraceptive measure for the duration of the study and a minimum of six months following the PET scan (including combined \[estrogen and progestogen containing\] hormonal contraception associated with inhibition of ovulation \[oral, intravaginal, or transdermal\], progestogen-only hormonal contraception associated with inhibition of ovulation \[oral, injectable, or implantable\], intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomised partner or sexual abstinence). * Male subjects and their partners of childbearing potential must commit to the use of a highly effective method of contraception during the study and for a minimum of three months following each PET scan (including, for female partners of childbearing potential, combined \[estrogen and progestogen containing\] hormonal contraception associated with inhibition of ovulation \[oral, intravaginal, or transdermal\], progestogen-only hormonal contraception associated with inhibition of ovulation \[oral, injectable, or implantable\], intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, male subjects with vasectomy or sexual abstinence). * Male subjects must commit to not donate sperm during the study and for a minimum of three months after the last PET scan. * Individuals must commit to refrain from drinking alcohol for 48 hours before each visit, refrain from drinking any caffeinated substance for 12 hours before the PET-MR visits, and to refrain from smoking or using any nicotine-containing products on the day of the PET-MR scans. * Individuals must commit to not donating blood up to three months after the last PET scan. * Individuals must commit to come to the screening and Day 1 visits in a fasting state (i.e., minimum of 8 hours since last meal/food intake). * Individuals must commit to not to take any over-the-counter non-steroidal anti-inflammatory drugs or drink alcohol for 48h before screening visit. Exclusion Criteria (all): * Unwilling and/or unable to cooperate with study procedures * Current or a recent (\<12 months) history of drug or alcohol abuse/dependence * BDI ≥ 20, moderate depression * Presence of clinically significant (as deemed by the study physician) alterations on safety laboratory blood and urine testing * Presence of comorbidities or concomitant medications incompatible with the assessment or imaging procedures as deemed by the study physician * Recent (less than 30 days) use of antipsychotics and corticosteroids * Recent (less than 2 days) use of NSAIDs. * Use of any long-acting benzodiazepines (e.g., diazepam) or use of slow or medium acting benzodiazepines with doses ≥ 30 mg within 30 days prior to the first imaging scan. * Presence of rs6971 genotype of low-affinity binders that hinders the measure of microglial activation with \[11C\]PBR28 PET * Presence of neurological disorders and known intracranial co-morbidities such as stroke, haemorrhage, space-occupying lesions, signs of inflammation of the CNS * Presence of serology compatible with HIV, syphilis, SARS-CoV2, or viral hepatitis * History of autonomic dysfunction, previous vasovagal syncope or a positive tilt-test, and with bradycardia or use of medications causing bradycardia (e.g. beta-blockers) * Pregnancy or breastfeeding * Contraindication to MRI, such as presence of metal devises or implants, metal deposited in the body, or metal grains in the eyes * History of cancer within the last 5 years, except for appropriately treated, non-melanoma skin carcinoma, non-metastatic prostate cancer, treated carcinoma in situ of the cervix or Stage I uterine cancer. * Claustrophobia or history of back pain that makes prolonged laying on the PET or MRI scanner intolerable * Contraindication to arterial cannulation, such as history of bleedings, haemorrhage, etc. * Negative Allen's test (i.e. absence of collateral flow on hands on the test) * Recent (less than 30 days) infection or vaccination (e.g. flu, SARS-CoV2 etc.) * Concurrent participation to any clinical trial testing investigational drugs Exclusion Criteria (Parkinson's disease patients): * Unwilling and/or unable to cooperate with study procedures * Current or recent history of drug or alcohol abuse/dependence * BDI ≥ 20, moderate depression * Presence of clinically significant (as deemed by the study physician) alterations on safety laboratory blood or urine testing * Presence of comorbidities or concomitant medications incompatible with the assessment or imaging procedures as deemed by the study physician * Recent (less than 30 days) use of antipsychotics and corticosteroids. * Recent (less than 2 days) use of NSAIDs. * Use of any long-acting benzodiazepines (e.g., diazepam) or use of slow or medium acting benzodiazepines with doses ≥ 30 mg within 30 days prior to the first imaging scan. * Presence of rs6971 genotype of low-affinity binders that hinders the measure of microglial activation with \[11C\]PBR28 PET * Presence of other neurological disorders and known intracranial co-morbidities such as stroke, haemorrhage, space-occupying lesions, signs of inflammation of the CNS * History of autonomic dysfunction, previous vasovagal syncope or a positive tilt-test, and with bradycardia or use of medications causing bradycardia (e.g. beta-blockers) * Presence of serology compatible with HIV, syphilis, SARS-CoV2, or viral hepatitis * Pregnancy or breastfeeding * Contraindication to MRI, such as presence of metal devises or implants, metal deposited in the body, or metal grains in the eyes * History of cancer within the last 5 years, except for appropriately treated, non-melanoma skin carcinoma, non-metastatic prostate cancer, treated carcinoma in situ of the cervix or Stage I uterine cancer. * Claustrophobia or history of back pain that makes prolonged laying on the PET or MRI scanner intolerable * Contraindication to arterial cannulation, such as history of bleedings, haemorrhage, etc. * Negative Allen's test (i.e. absence of collateral flow on hands on the test) * Recent (less than 30 days) infection or vaccination (e.g. flu, SARS-CoV2 etc.) * Concurrent participation to any clinical trial testing investigational drugs Exclusion criteria (for participants with iRBD): * Unwilling and/or unable to cooperate with study procedures * Current or a recent (\<12 months) history of drug or alcohol abuse/dependence * BDI-II ≥ 20, moderate depression * Presence of clinically significant (as deemed by the study physician) alterations on safety laboratory blood and urine testing * Presence of comorbidities or concomitant medications incompatible with the assessment or imaging procedures as deemed by the study physician * Recent (less than 30 days) use of antipsychotics and corticosteroids * Recent (less than 2 days) use of NSAIDs. * Use of any long-acting benzodiazepines (e.g., diazepam) or use of slow or medium acting benzodiazepines with doses ≥ 30 mg within 30 days prior to the first imaging scan. * Use of any of the following drugs that might interfere with dopamine transporter SPECT imaging: Ephedrine, ketamine, isoflurane, cocaine, methylphenidate, amphetamine of any amphetamine derivatives, mazindol, modafinil, benztropine, fentanyl, derivatives, buproprion, phentermine neuroleptics, metoclopramide, alpha methyldopa, , reserpine, . * Presence of rs6971 genotype of low-affinity binders that hinders the measure of microglial activation with \[11C\]PBR28 PET * Presence of neurological disorders and known intracranial co-morbidities such as stroke, haemorrhage, space-occupying lesions, signs of inflammation of the CNS * Presence of serology compatible with HIV, syphilis, or viral hepatitis * History of autonomic dysfunction, previous vasovagal syncope or a positive tilt-test, and with bradycardia or use of medications causing bradycardia (e.g. beta-blockers) * Pregnancy or breastfeeding * Contraindication to MRI, such as presence of metal devises or implants, metal deposited in the body, or metal grains in the eyes * History of cancer within the last 5 years, except for appropriately treated, non-melanoma skin carcinoma, non-metastatic prostate cancer, treated carcinoma in situ of the cervix or Stage I uterine cancer. * Claustrophobia or history of back pain that makes prolonged laying on the PET or MRI scanner intolerable * Contraindication to arterial cannulation, such as history of bleedings, haemorrhage, etc. * Negative Allen's test (i.e. absence of collateral flow on hands on the test) * Recent (less than 30 days) infection or vaccination (e.g. flu, SARS-CoV2 etc.) * Evidence of presynaptic dopaminergic denervation on \[123I\]FP-CIT SPECT * Concurrent participation to any clinical trial testing investigational drugs