Multi-Center Development of a Novel Diagnostic Test for Alzheimer's Disease

Study Overview
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Brief Summary
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In this multi-center study, the investigators plan to develop a simple blood-based test for early detection of Alzheimer's disease (AD). The test is based on a single injection of Pramlintide, an amylin analogue and FDA-approved drug currently used for treatment of diabetes. The investigative team has provided evidence in humans with full-blown AD and AD-relevant mouse models that a single injection of Pramlintide transiently renders the blood brain barrier (BBB) more permeable to Amyloidbeta (Aß) peptides, allowing their efflux from the brain compartment into the blood. This Aß efflux causes a corresponding transient elevation of blood levels of Aß, the magnitude of which the applicants believe is proportional to the brain amyloid load as determined by AV-45 PET. The measured difference in the level of plasma Aß taken just before and a short time after injection should reveal the magnitude of the transient increase in blood Aß levels. Supportive preliminary data comes from later stage (full-blown) AD patients with more in-depth background studies in Tg2576 and 5X Familial Alzheimer's Disease (FAD) mouse models. If successful for use as an early AD (i.e., at the Mild Cognitive Impairment [MCI] stage) biomarker, this could be a game-changer for both early AD diagnostics and clinical trials aimed at identifying and testing the efficacy of drugs useful for treatment of AD at early stages. If Pramlintide is effective in releasing mobile pools of Aß from the brain into the blood, this could also have some therapeutic potential, with the goal of reducing brain amyloid load. Three groups of particpants will be studied: 1) amnestic MCI with or without positive AD imaging pathology, 2) probable AD with positive imaging AD pathology, and 3) controls who have normal cognition and do not have memory complaints.

Official Title
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Multi-Center Development of a Novel Diagnostic Test for Alzheimer's Disease

Conditions
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Alzheimer Disease, Mild Cognitive Impairment

Intervention / Treatment
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* Drug: Pramlintide challenge test


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Current research subjects at the BU ADC, VA BHS, or IU ADC A consensus diagnosis of probable AD, amnestic MCI, or control BMI of 20-35 Probable AD subjects must be confirmed for positive AD pathology in the CNS Probable AD subjects must have a designated research proxy signed before they became demented. Exclusion Criteria: Diabetes mellitus Gastroparesis Use of insulin, pramlintide, other injectable anti-hyperglycemic agents, such as glucagon like peptide-1 (GLP-1), or oral anti-diabetic products Unexplained hypoglycemia (glucose ≤ 60 mg/dL) or hyperglycemia (glucose ≥ 126 mg/dL) pre-injection History of stroke Seizures or use of anti-seizure medications History of brain injury and loss of consciousness Diagnosed cerebral amyloid angiopathy (CAA) Infection within 1 month

Ages Eligible for Study
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Minimum Age: 60 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Probable AD<br>Participants with probable AD with positive imaging AD pathology will receive the pramlintide challenge test. | Drug: Pramlintide challenge test<br>* Enrolled subjects will have a pre-trial blood draw (3 ml) and will be placed with an IV needle for future blood draws. Pramlintide will be subcutaneously injected in the abdominal area. For each arm the participants will be randomized so that half will be given a dose of 0.8 mcg/kg and the other half of the arm a dose of 1.6 mcg/kg. Blood will be drawn before and at 5, 30, 60, and 180 min after injection. Vital signs and blood glucose will also be checked at these time points. Thirty minutes after the injection, subjects will be offered a standard meal. Subjects will have a final check of vital signs and blood glucose approximately 15 min before discharge.<br>* Other names: Symlin;|
| Active Comparator: Amnestic MCI<br>Participants with amnestic MCI with or without positive AD imaging pathology will receive the pramlintide challenge test. | Drug: Pramlintide challenge test<br>* Enrolled subjects will have a pre-trial blood draw (3 ml) and will be placed with an IV needle for future blood draws. Pramlintide will be subcutaneously injected in the abdominal area. For each arm the participants will be randomized so that half will be given a dose of 0.8 mcg/kg and the other half of the arm a dose of 1.6 mcg/kg. Blood will be drawn before and at 5, 30, 60, and 180 min after injection. Vital signs and blood glucose will also be checked at these time points. Thirty minutes after the injection, subjects will be offered a standard meal. Subjects will have a final check of vital signs and blood glucose approximately 15 min before discharge.<br>* Other names: Symlin;|
| Active Comparator: Control- Normal Cognition<br>Participants with normal cognition without any memory complaints will receive the pramlintide challenge test. | Drug: Pramlintide challenge test<br>* Enrolled subjects will have a pre-trial blood draw (3 ml) and will be placed with an IV needle for future blood draws. Pramlintide will be subcutaneously injected in the abdominal area. For each arm the participants will be randomized so that half will be given a dose of 0.8 mcg/kg and the other half of the arm a dose of 1.6 mcg/kg. Blood will be drawn before and at 5, 30, 60, and 180 min after injection. Vital signs and blood glucose will also be checked at these time points. Thirty minutes after the injection, subjects will be offered a standard meal. Subjects will have a final check of vital signs and blood glucose approximately 15 min before discharge.<br>* Other names: Symlin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Aβ and t-tau changes | Plasma Aβ1-40 and Aβ1-42 data will be analyzed. For each peptide, the mean ± SD, median, 25%, 75%, and range | 5, 30, 60, and 180 min after challenge test | 
| Plasma inflammatory changes | Changes in proinflammatory-related biomarkers: particularly the IL-1β/IL-1Ra pathway, as well as GM-CSF, G-CSF, Trem2, CD36, and CD163, CD68 will be measured applying high-density multiplex ELISA assays (RayBiotech, Norcross, GA) | 5, 30, 60, and 180 min after challenge test | 
| Plasma metabolic changes in blood | Changes in 2. Metabolism biomarkers associated with amylin: leptin, GLP-1, RBP4, Insulin R, ApoE, and ApoJwill be measured applying high-density multiplex ELISA assays (RayBiotech, Norcross, GA) | 5, 30, 60, and 180 min after a pramlintide challenge test | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in MMSE | MMSE range is from 1-30, we expect a positive challenge test will have a decrease of MMSE | baseline, 12 and 24 months post challenge | 
| Change in CDR | CDR range is from 0-3, we expect a positive challenge test for increased CDR score | baseline, 12 and 24 months post challenge | 
| Change in NAB | We expect NAB to be decreased | baseline, 12 and 24 months post challenge | 
| Change in WMS-III Logical Memory | WMS-III range is from 0-25, we expect a decrease in WMS-III Logical memory | baseline, 12 and 24 months post challenge | 
| Change in CLOX paradigm | CLOX paradigm range is from 0-3, we expect a decrease in this paradigm | baseline, 12 and 24 months post challenge | 
| Change in Trailmaking Test Part B | Trailmaking Test Part B range is from 0-300 seconds, we expect an increase in this test | baseline, 12 and 24 months post challenge | 
| Change in Controlled Oral Word Association Test | Controlled Oral Word Association Test has no range, we expect this to be decreased | baseline, 12 and 24 months post challenge | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Early AD diagnosis, Pramlintide challenge test, Amyloid, Amyloid PET imaging, CSF Aβ, CSF pTau, Cognitive evaluation