Biomarker Exploration in Aging, Cognition and Neurodegeneration

Study Overview
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Brief Summary
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The purpose of this research study is to understand the factors that underlie changes in thinking and memory with increasing age. The investigators will test the usefulness of MRI, PET, and cognitive testing in detecting subtle changes in the brain that precede cognitive decline. An addendum to this study includes additional PET scans to examine the relationship between tau protein in the brain and cognitive decline. Tau is a protein that is known to form tangles in the areas of the brain important for memory, and these tau tangles are a hallmark of Alzheimer's disease. This sub-study research aims to look at the tau accumulation in the brain using an investigational drug called MK-6240, which is a radio tracer that gets injected prior to a positron emission tomography (PET) scan.

Detailed Description
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This study investigates the relationship between Alzheimer's disease (AD) pathology, brain structure and function, as well as cognition in non-demented older adults. The goal is to develop a more complete understanding of the factors that lead to cognitive decline in the elderly and progression to AD. The investigators will enroll 200 cognitively intact adults between the ages of 60-85 years old from the UCI Alzheimer's Disease Research Center or directly from the local community. Study procedures will include: 1) PET amyloid scans with Amyvid™ radiotracer (florbetapir-F18) and PET tau scans with [18F]MK6240 radiotracer; 2) High-resolution structural, functional, and diffusion MRI; and 3) Cognitive examinations. The investigators will track cognitive outcomes through longitudinal monitoring. Amyloid imaging will only be conducted once in the study at baseline, and MRI and tau PET imaging will be at baseline and Year 1. The investigators aim to identify the best combination of tests for predicting longitudinal cognitive/clinical decline. The proposed study will significantly inform the understanding of cognitive decline in the aging brain and allow investigators to better define preclinical AD and make recommendations for future intervention trials.

Official Title
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The BEACoN Study- Biomarker Exploration in Aging, Cognition and Neurodegeneration

Conditions
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Alzheimer Disease, Cognitive Impairment, Cognitive Decline

Intervention / Treatment
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* Radiation: Amyloid PET scan
* Drug: Tau PET scan using MK-6240
* Behavioral: Neurocognitive testing
* Other: MRI


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged 60 or older; Speaks fluent English or Spanish; Visual and auditory acuity adequate for neuropsychological and computerized testing; Good general health with no disease(s) expected to interfere with the study; Willing and able to participate for the duration of the study and in all study procedures including MRI and PET; Normal cognition defined as a Clinical Dementia Rating of 0 and a Mini-Mental State Examination score of 25 or higher. FAST Stage 1 or 2. Subjective memory or other cognitive complaints will be included. Exclusion Criteria: Significant co-morbid neurologic disease such as Parkinson's disease, multiple sclerosis, brain cyst, tumor or aneurysm; Major health conditions, except for Type II diabetes mellitus, hypercholesterolemia, and hypertension, which are NOT exclusionary for this study given their high prevalence in our target populations; Significant psychiatric disorders such as schizophrenia, bipolar disorder, or attention-deficit hyperactivity disorder, except for depression and anxiety, which are NOT exclusionary for this study given their high prevalence in our target populations; Existing diagnosis of dementia or mild cognitive impairment; Alcohol or substance abuse or dependence within the past 2 years (DSM-IV criteria); MRI contraindications, e.g. pacemakers, aneurysm clips, artificial heart valves, ear implants, metal fragments or foreign objects in the eyes, skin or body. Females who are pregnant or trying to get pregnant are also excluded; PET contraindications, e.g. significant prior radiation exposure and pregnancy.

Ages Eligible for Study
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Minimum Age: 60 Years
Maximum Age: 105 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Health Services Research
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: All participants will complete the same study procedures, including the tau PET scans with investigational radio tracer 18F-MK6240. The arms define the age range and APOE status of the participants, with each having their own enrollment target.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Age 60-65 ApoE e4+<br>Participants in this cohort are between the ages of 60-65 and are ApoE e4 carriers. All participants in this cohort will complete the Amyloid PET scan, Tau PET scan using MK-6240, MRI scans, and neurocognitive testing. | Radiation: Amyloid PET scan<br>* Amyloid Positron Emission Tomography scan using radio tracer florbetapir-F18<br>Drug: Tau PET scan using MK-6240<br>* Tau Positron Emission Tomography scan using radio tracer MK-6240<br>* Other names: tau PET;Behavioral: Neurocognitive testing<br>* A battery of clinical neuropsychological assessments and computerized cognitive tasks will be used to test participants' memory and cognitive abilities.<br>Other: MRI<br>* High-resolution structural, functional, and diffusion Magnetic Resonance Imaging scans will be collected during the study.<br>|
| Experimental: Age 66-70 ApoE e4-<br>Participants in this cohort are between the ages of 66-70 and are not ApoE e4 carriers. All participants in this cohort will complete the Amyloid PET scan, Tau PET scan using MK-6240, MRI scans, and neurocognitive testing. | Radiation: Amyloid PET scan<br>* Amyloid Positron Emission Tomography scan using radio tracer florbetapir-F18<br>Drug: Tau PET scan using MK-6240<br>* Tau Positron Emission Tomography scan using radio tracer MK-6240<br>* Other names: tau PET;Behavioral: Neurocognitive testing<br>* A battery of clinical neuropsychological assessments and computerized cognitive tasks will be used to test participants' memory and cognitive abilities.<br>Other: MRI<br>* High-resolution structural, functional, and diffusion Magnetic Resonance Imaging scans will be collected during the study.<br>|
| Experimental: Age 66-70 ApoE e4+<br>Participants in this cohort are between the ages of 66-70 and are ApoE e4 carriers. All participants in this cohort will complete the Amyloid PET scan, Tau PET scan using MK-6240, MRI scans, and neurocognitive testing. | Radiation: Amyloid PET scan<br>* Amyloid Positron Emission Tomography scan using radio tracer florbetapir-F18<br>Drug: Tau PET scan using MK-6240<br>* Tau Positron Emission Tomography scan using radio tracer MK-6240<br>* Other names: tau PET;Behavioral: Neurocognitive testing<br>* A battery of clinical neuropsychological assessments and computerized cognitive tasks will be used to test participants' memory and cognitive abilities.<br>Other: MRI<br>* High-resolution structural, functional, and diffusion Magnetic Resonance Imaging scans will be collected during the study.<br>|
| Experimental: Age 71-75 ApoE e4-<br>Participants in this cohort are between the ages of 71-75 and are not ApoE e4 carriers. All participants in this cohort will complete the Amyloid PET scan, Tau PET scan using MK-6240, MRI scans, and neurocognitive testing. | Radiation: Amyloid PET scan<br>* Amyloid Positron Emission Tomography scan using radio tracer florbetapir-F18<br>Drug: Tau PET scan using MK-6240<br>* Tau Positron Emission Tomography scan using radio tracer MK-6240<br>* Other names: tau PET;Behavioral: Neurocognitive testing<br>* A battery of clinical neuropsychological assessments and computerized cognitive tasks will be used to test participants' memory and cognitive abilities.<br>Other: MRI<br>* High-resolution structural, functional, and diffusion Magnetic Resonance Imaging scans will be collected during the study.<br>|
| Experimental: Age 71-75 ApoE e4+<br>Participants in this cohort are between the ages of 71-75 and are ApoE e4 carriers. All participants in this cohort will complete the Amyloid PET scan, Tau PET scan using MK-6240, MRI scans, and neurocognitive testing. | Radiation: Amyloid PET scan<br>* Amyloid Positron Emission Tomography scan using radio tracer florbetapir-F18<br>Drug: Tau PET scan using MK-6240<br>* Tau Positron Emission Tomography scan using radio tracer MK-6240<br>* Other names: tau PET;Behavioral: Neurocognitive testing<br>* A battery of clinical neuropsychological assessments and computerized cognitive tasks will be used to test participants' memory and cognitive abilities.<br>Other: MRI<br>* High-resolution structural, functional, and diffusion Magnetic Resonance Imaging scans will be collected during the study.<br>|
| Experimental: Age 76-80 ApoE e4-<br>Participants in this cohort are between the ages of 76-80 and are not ApoE e4 carriers. All participants in this cohort will complete the Amyloid PET scan, Tau PET scan using MK-6240, MRI scans, and neurocognitive testing. | Radiation: Amyloid PET scan<br>* Amyloid Positron Emission Tomography scan using radio tracer florbetapir-F18<br>Drug: Tau PET scan using MK-6240<br>* Tau Positron Emission Tomography scan using radio tracer MK-6240<br>* Other names: tau PET;Behavioral: Neurocognitive testing<br>* A battery of clinical neuropsychological assessments and computerized cognitive tasks will be used to test participants' memory and cognitive abilities.<br>Other: MRI<br>* High-resolution structural, functional, and diffusion Magnetic Resonance Imaging scans will be collected during the study.<br>|
| Experimental: Age 76-80 ApoE e4+<br>Participants in this cohort are between the ages of 76-80 and are ApoE e4 carriers. All participants in this cohort will complete the Amyloid PET scan, Tau PET scan using MK-6240, MRI scans, and neurocognitive testing. | Radiation: Amyloid PET scan<br>* Amyloid Positron Emission Tomography scan using radio tracer florbetapir-F18<br>Drug: Tau PET scan using MK-6240<br>* Tau Positron Emission Tomography scan using radio tracer MK-6240<br>* Other names: tau PET;Behavioral: Neurocognitive testing<br>* A battery of clinical neuropsychological assessments and computerized cognitive tasks will be used to test participants' memory and cognitive abilities.<br>Other: MRI<br>* High-resolution structural, functional, and diffusion Magnetic Resonance Imaging scans will be collected during the study.<br>|
| Experimental: Age 81+ ApoE e4-<br>Participants in this cohort are between the ages of 81-85 and are not ApoE e4 carriers. All participants in this cohort will complete the Amyloid PET scan, Tau PET scan using MK-6240, MRI scans, and neurocognitive testing. | Radiation: Amyloid PET scan<br>* Amyloid Positron Emission Tomography scan using radio tracer florbetapir-F18<br>Drug: Tau PET scan using MK-6240<br>* Tau Positron Emission Tomography scan using radio tracer MK-6240<br>* Other names: tau PET;Behavioral: Neurocognitive testing<br>* A battery of clinical neuropsychological assessments and computerized cognitive tasks will be used to test participants' memory and cognitive abilities.<br>Other: MRI<br>* High-resolution structural, functional, and diffusion Magnetic Resonance Imaging scans will be collected during the study.<br>|
| Experimental: Age 81+ ApoE e4+<br>Participants in this cohort are between the ages of 81-85 and are ApoE e4 carriers. All participants in this cohort will complete the Amyloid PET scan, Tau PET scan using MK-6240, MRI scans, and neurocognitive testing. | Radiation: Amyloid PET scan<br>* Amyloid Positron Emission Tomography scan using radio tracer florbetapir-F18<br>Drug: Tau PET scan using MK-6240<br>* Tau Positron Emission Tomography scan using radio tracer MK-6240<br>* Other names: tau PET;Behavioral: Neurocognitive testing<br>* A battery of clinical neuropsychological assessments and computerized cognitive tasks will be used to test participants' memory and cognitive abilities.<br>Other: MRI<br>* High-resolution structural, functional, and diffusion Magnetic Resonance Imaging scans will be collected during the study.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Clinical Dementia Rating - Sum of Box Score | A measure of cognitive/clinical decline | Years 4 and 5 of the grant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in lure discrimination index - objects | Key measure of performance on the object pattern separation task | Years 4 and 5 of the grant | 
| Change in lure discrimination index - spatial | Key measure of performance on the spatial pattern separation task | Years 4 and 5 of the grant | 
| Change in lure discrimination index - temporal | Key measure of performance on the temporal pattern separation task | Years 4 and 5 of the grant | 
| Change in entorhinal cortical thickness | Key measure of structural decline on MRI scans | Years 4 and 5 of the grant | 
| Change in perforant path integrity | Key measure of structural connectivity decline on MRI scans | Years 4 and 5 of the grant | 
| Change in tau spatial distribution - advancing Braak stage | Key measure of tau spatial spread on tau PET scans | Years 4 and 5 of the grant | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Alzheimer disease, cognitive impairment, mild cognitive impairment, biomarker, MRI, PET