Alzheimer Disease
Conditions
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.
Interventions
DRUGLPS
LPS (0.4 ng/kg)
Sponsors
National Institute on Aging (NIA)
Yale University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
DIAGNOSTIC
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
55 Years to 90 Years
Healthy volunteers
Yes
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 0. * Cognitively normal elderly Subjects: * Absence of National Institute on Aging-Alzheimer's Association core clinical criteria for probable AD * Objective memory scores within the normal range for age (do not meet MCI Subjects criterion 2) * Age between 55 and 90 (inclusive) * Clinical Dementia Rating (CDR) global score of 0.0
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. * Clinically significant abnormalities on screening laboratory tests (B12, Thyroid function tests, hematology, chemistry, urinalysis, ECG). * Pregnancy, as determined by screening pregnancy tests for pre-menopausal females * Impairment of visual or auditory acuity sufficient to interfere with study procedures. * Education level \< 6 years. * Evidence of current depression as defined by a score of ≥ 5 on the Geriatric Depression Scale. * Presence of pacemakers, aneurysm clips, artificial heart valves, ear implants, metal fragments or foreign objects in the eyes, skin or body. The presence of claustrophobia, precluding MRI. * Current or recent participation in any procedures involving radioactive agents such that the total radiation dose exposure to the subject in any given year would exceed the limits of annual and total dose commitment set forth in the US Code of Federal Regulations (CFR) Title 21 Section 361.1. * Vaccination in the last month. * Drink more than 5 alcoholic drinks per week or any heavy drinking days in the last 30 days. * BMI \> 35 or \< 19 * Women who are pregnant or nursing, or fail to use one of the following methods of birth control unless she or partner is surgically sterile or she is postmenopausal (hormone contraceptives \[oral, implant, injection, patch, or ring\], contraceptive sponge, double barrier \[diaphragm or condom plus spermicide\], or Intrauterine Device (IUD) * Individuals who are classified as low binders for the rs6971 polymorphism (\<10% of the population) * Patients on antiplatelet and anticoagulant medications will be excluded. * Any patient without the capacity to consent will be excluded. * Unstable hypertension. If blood pressure is greater than 160/100, the investigators will contact the subject's primary care physician to manage their blood pressure. If their blood pressure is not reduced to be consistently below 160/100 by the scanning day the subject will be excluded from the protocol. * Patients with contraindications for lumbar puncture procedure can be still involved and will be excluded from the optional portion of the study with the lumbar puncture. These include existing intracranial space-occupying lesion with mass effect, posterior fossa mass, risk of cerebral herniation by increased CSF pressure or Arnold chiari malformation, as well as anticoagulant medication, coagulopathies and uncorrected bleeding diathesis, congenital spine abnormalities, and local skin infection at the puncture site.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Microglial Activation Reserve Index (MARI) | 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
| Measure | Time frame | Description |
|---|---|---|
| Effects of MARI on Cognition | 180 minutes post intervention | The Pearson's correlation between MARI and performance on the Montreal Cognitive Assessment (MOCA) will be calculated. The MOCA is a global assessment of cognitive function ranging from 0 to 30 where higher scores represent better cognitive performance. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Patients Receiving Endotoxin The enrolled subjects, both with AD and cognitively normal, will have LPS (0.4 ng/kg) administered intravenously
LPS: LPS (0.4 ng/kg) | 12 |
| Total | 12 |
Baseline characteristics
| Characteristic | Patients Receiving Endotoxin |
|---|---|
| Age, Continuous Alzheimer's Disease | 75.3 years STANDARD_DEVIATION 2.3 |
| Age, Continuous Cognitively Normal | 67.2 years STANDARD_DEVIATION 6.5 |
| Global Clinical Dementia Rating Global Score (CDR) Alzheimer's Disease | 0.75 score on a scale STANDARD_DEVIATION 0.27 |
| Global Clinical Dementia Rating Global Score (CDR) Cognitively Normal | 0 score on a scale STANDARD_DEVIATION 0 |
| Montreal Cognitive Assessment (MOCA) Alzheimer's Disease | 21.5 score on a scale STANDARD_DEVIATION 3.8 |
| Montreal Cognitive Assessment (MOCA) Cognitively Normal | 26.7 score on a scale STANDARD_DEVIATION 2.4 |
| Number of participants with one of two rs6971 polymorphism Alzheimer's Disease high affinity binder (HAB) | 6 Participants |
| Number of participants with one of two rs6971 polymorphism Alzheimer's Disease mixed affinity binder (MAB) | 0 Participants |
| Number of participants with one of two rs6971 polymorphism Cognitively Normal high affinity binder (HAB) | 3 Participants |
| Number of participants with one of two rs6971 polymorphism Cognitively Normal mixed affinity binder (MAB) | 3 Participants |
| Race/Ethnicity, Customized Alzheimer's Disease Black | 0 Participants |
| Race/Ethnicity, Customized Alzheimer's Disease White | 6 Participants |
| Race/Ethnicity, Customized Cognitively Normal Black | 1 Participants |
| Race/Ethnicity, Customized Cognitively Normal White | 5 Participants |
| Region of Enrollment United States | 12 participants |
| Sex: Female, Male Alzheimer's Disease Female | 1 Participants |
| Sex: Female, Male Alzheimer's Disease Male | 5 Participants |
| Sex: Female, Male Cognitively Normal Female | 3 Participants |
| Sex: Female, Male Cognitively Normal Male | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 12 |
| other Total, other adverse events | 0 / 12 |
| serious Total, serious adverse events | 0 / 12 |
Outcome results
Primary
Microglial Activation Reserve Index (MARI)
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.
Time frame: 180 minutes post intervention
Population: One participant from the cognitively normal group was excluded from this analysis since blood input function data for the baseline scan was inadequate for pharmacokinetic modeling.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Patients Receiving Endotoxin | Microglial Activation Reserve Index (MARI) | Alzheimer's Disease | 17.7 percentage of MARI | Standard Deviation 0.1 |
| Patients Receiving Endotoxin | Microglial Activation Reserve Index (MARI) | Cognitively Normal | 30.1 percentage of MARI | Standard Deviation 0.1 |
p-value: 0.14unpaired t-tests (continuous variables)
Secondary
Effects of MARI on Cognition
The Pearson's correlation between MARI and performance on the Montreal Cognitive Assessment (MOCA) will be calculated. The MOCA is a global assessment of cognitive function ranging from 0 to 30 where higher scores represent better cognitive performance.
Time frame: 180 minutes post intervention
Population: Data are from correlation between parietal cortex MARI and MOCA scores for participants with AD
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Patients Receiving Endotoxin | Effects of MARI on Cognition | -0.12 Pearson r |
p-value: 0.82univariate linear regression analysis