PBR28 Brain Positron Emission Tomography Imaging With Lipopolysaccharide (LPS) Challenge for the Study of Microglia Function in Alzheimer's Disease
Overview
- Phase
- Early Phase 1
- Intervention
- LPS
- Conditions
- Alzheimer Disease
- Sponsor
- Yale University
- Enrollment
- 18
- Locations
- 1
- Primary Endpoint
- Microglial Activation Reserve Index (MARI)
- Status
- Completed
- Last Updated
- 2 years ago
Overview
Brief Summary
To examine the differences in the capacity to activate microglia in patients with Alzheimer's Disease (AD) compared to age-comparable cognitively normal subjects and younger healthy controls.
Detailed Description
The primary outcome is Microglia Activation Reserve Index (MARI) (calculated in the parietal region of interest (ROIs)) in AD patients compared to elderly controls. The researchers will recruit up to 20 participants. The investigators will use 7 AD and 7 comparably aged cognitively normal successfully scanned subjects to calculate the microglial activation reserve index. The expectations are significant differences between the two groups suggesting altered reactivity of the microglia in AD. The result would be an exciting one suggesting at least one mechanism by which some patients with significant amyloid load have progressive dementia while comparable others are either cognitively normal or have stable Mild Cognitive Impairment (MCI). It will also suggest avenues for intervention in amyloid positive MCIs to prevent progression to Alzheimer's dementia. The exploratory analysis will include: 1. Effects of aging on MARI: The researchers will evaluate the effects of aging on MARI. Comparisons will be made for MARI between cognitively normal elderly and the 8 healthy individuals to whom the investigators applied this protocol in an earlier study. The reactivity of microglia is reported to change with age and so the investigators expect MARI to change in the cognitively normal elderly. However, the expectation is that the differences between the young and elderly cognitively normal subjects to be small relative to the comparison of AD and elderly normal controls. 2. Effects of amyloid on MARI: The researchers will look at the relationship of regional and global amyloid load to MARI. The presence of a relationship suggests that one of the reasons for altered microglial reactivity might be interactions of microglia with pathologic amyloid. 3. Effects of MARI on cognition: The researchers will explore whether MARI would correlate with the measure of disease stage, with higher MARIs associated with worse neuropsychological score and more severe disease. The researchers will look for correlations between MARI and the individual neuropsychological scores. This would determine if disease severity is correlated with microglial activation reserve.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Mild AD Subjects:
- •National Institute on Aging (NIA)-Alzheimer's Association core clinical criteria for probable AD
- •Age between 55 and 90 (inclusive)
- •Score on the Montreal Cognitive Assessment (MOCA) greater than or equal to 17
- •Presence of a responsible caregiver who will accompany AD subjects to all procedures.
- •Biomarker evidence of Alzheimer's disease via an amyloid PET scan or cerebrospinal fluid (CSF) amyloid Beta measurement.
- •The patient should have the capacity to consent.
- •Clinical Dementia Rating (CDR) global score greater than
- •Cognitively normal elderly Subjects:
- •Absence of National Institute on Aging-Alzheimer's Association core clinical criteria for probable AD
Exclusion Criteria
- •Any significant neurologic disease (other than probable AD in the AD Subjects group), such as stroke, Parkinson's disease, brain tumor, seizure disorder, multiple sclerosis, or history of significant head trauma followed by persistent neurologic deficits.
- •Any significant systemic disease including hepatic failure, heart failure, renal failure, chronic obstructive pulmonary disease (COPD), active infection and autoimmune disease.
- •Screening/baseline MRI scan with evidence of infection, infarction, or other focal lesions. Subjects with multiple lacunes or lacunes in a critical memory structure are excluded.
- •Any significant systemic illness or unstable medical condition, including uncontrolled or insulin- dependent diabetes mellitus, uncorrected hypothyroidism or hyperthyroidism, or systemic cancer.
- •Current or regular use of over-the-counter medication that may affect the immune system (e.g., ibuprofen), including corticosteroids or immunosuppressant drugs; no use in 3 weeks prior to the PET scan
- •Investigational agents are prohibited 4 weeks prior to entry and for the duration of the study.
- •Previous treatment with an investigational small molecule with anti-amyloid properties or passive immunization against amyloid within 1 year of study entry.
- •Previous treatment with an active immunization against amyloid.
- •History of schizophrenia or other major psychiatric disorder (DSM IV criteria).
- •History of alcohol or substance abuse or dependence (DSM IV criteria) within the past 2 years.
Arms & Interventions
Patients receiving endotoxin
The 20 enrolled subjects will have LPS (0.4 ng/kg) administered intravenously
Intervention: LPS
Outcomes
Primary Outcomes
Microglial Activation Reserve Index (MARI)
Time Frame: 180 minutes post intervention
Participants will undergo \[11C\]PBR PET scanning both before and then after LPS injection. Parametric images of volume of distribution (VT)were generated for each using multilinear analysis (MA1) and MARI was calculated in the parietal cortex using the equation \[(VT post LPS - VT pre LPS)/VT post LPS\] x 100%. Higher values of MARI are thought to represent higher levels of microglial activation. There are no clinically relevant thresholds for this measure.
Secondary Outcomes
- Effects of MARI on Cognition(180 minutes post intervention)