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.

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