DTAD: Multi-Center Development of a Novel Diagnostic Test for Alzheimer's Disease
Study Details
Study Description
Brief Summary
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Early Phase 1 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Probable AD Participants with probable AD with positive imaging AD pathology will receive the pramlintide challenge test. |
Drug: Pramlintide challenge test
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.
Other Names:
|
| Active Comparator: Amnestic MCI Participants with amnestic MCI with or without positive AD imaging pathology will receive the pramlintide challenge test. |
Drug: Pramlintide challenge test
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.
Other Names:
|
| Active Comparator: Control- Normal Cognition Participants with normal cognition without any memory complaints will receive the pramlintide challenge test. |
Drug: Pramlintide challenge test
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.
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Plasma Aβ and t-tau changes [5, 30, 60, and 180 min after challenge test]
Plasma Aβ1-40 and Aβ1-42 data will be analyzed. For each peptide, the mean ± SD, median, 25%, 75%, and range
- Plasma inflammatory changes [5, 30, 60, and 180 min after challenge test]
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)
- Plasma metabolic changes in blood [5, 30, 60, and 180 min after a pramlintide challenge test]
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)
Secondary Outcome Measures
- Change in MMSE [baseline, 12 and 24 months post challenge]
MMSE range is from 1-30, we expect a positive challenge test will have a decrease of MMSE
- Change in CDR [baseline, 12 and 24 months post challenge]
CDR range is from 0-3, we expect a positive challenge test for increased CDR score
- Change in NAB [baseline, 12 and 24 months post challenge]
We expect NAB to be decreased
- Change in WMS-III Logical Memory [baseline, 12 and 24 months post challenge]
WMS-III range is from 0-25, we expect a decrease in WMS-III Logical memory
- Change in CLOX paradigm [baseline, 12 and 24 months post challenge]
CLOX paradigm range is from 0-3, we expect a decrease in this paradigm
- Change in Trailmaking Test Part B [baseline, 12 and 24 months post challenge]
Trailmaking Test Part B range is from 0-300 seconds, we expect an increase in this test
- Change in Controlled Oral Word Association Test [baseline, 12 and 24 months post challenge]
Controlled Oral Word Association Test has no range, we expect this to be decreased
Eligibility Criteria
Criteria
Inclusion Criteria:
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Current research subjects at the BU ADC, VA BHS, or IU ADC
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A consensus diagnosis of probable AD, amnestic MCI, or control
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BMI of 20-35
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Probable AD subjects must be confirmed for positive AD pathology in the CNS
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Probable AD subjects must have a designated research proxy signed before they became demented.
Exclusion Criteria:
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Diabetes mellitus
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Gastroparesis
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Use of insulin, pramlintide, other injectable anti-hyperglycemic agents, such as glucagon like peptide-1 (GLP-1), or oral anti-diabetic products
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Unexplained hypoglycemia (glucose ≤ 60 mg/dL) or hyperglycemia (glucose ≥ 126 mg/dL) pre-injection
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History of stroke
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Seizures or use of anti-seizure medications
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History of brain injury and loss of consciousness
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Diagnosed cerebral amyloid angiopathy (CAA)
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Infection within 1 month
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Indiana University Alzheimer Disease Center | Indianapolis | Indiana | United States | 46202 |
| 2 | BU Alzheimer Disease Center | Boston | Massachusetts | United States | 02118 |
| 3 | Memory Center VA Boston Healthcare | Jamaica Plain | Massachusetts | United States | 02130 |
Sponsors and Collaborators
- Boston University
- National Institute on Aging (NIA)
Investigators
- Principal Investigator: Wendy Qiu, MD PhD, Boston Medical Center and BUSM
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- H-37432
- 1R01AG059424-01