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Discovery and Validation of Genetic Variants Affecting Microglial Activation in Alzheimer's Disease

Primary Purpose

Alzheimer Disease

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
11C-ER176
18F-florbetaben
Sponsored by
Columbia University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional diagnostic trial for Alzheimer Disease focused on measuring PET scan, Inflammation, Genetic testing, Cognitive Impairment

Eligibility Criteria

50 Years - undefined (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion criteria:

  1. Age 50 and older at time of study entry.
  2. Meet criteria for either a) amnestic mild cognitive impairment (single or mixed domain) or Alzheimer's disease, or b) have no cognitive impairment, based on history, exam, and neuropsychological testing.
  3. Patients must have Clinical Dementia Rating Scale score of 0.5 or 1 at enrollment. Controls must have Clinical Dementia Rating scale score of 0 at enrollment.
  4. Subjects must have AD biomarker previously obtained for research or clinical purposes or undergo a 18F-florbetaben PET scan during the screening process. Patients must have positive amyloid PET scan or CSF results consistent with AD. Controls must have a negative amyloid PET scan or CSF results not consistent with AD.
  5. Self-identify as white, non-Hispanic or Latino
  6. Subjects must be ableto provide informed consent
  7. Written and oral fluency in English
  8. Able to participate in all scheduled evaluations and to complete all required tests and procedures.
  9. In the opinion of the investigator, the subject must be considered likely to comply with the study protocol and to have a high probability of completing the study.

Exclusion Criteria:

  1. Past or present history of certain brain disorders other than MCI or AD.
  2. Certain significant medical conditions, which make study procedures of the current study unsafe. Such serious medical conditions include uncontrolled epilepsy and multiple serious injuries.
  3. Contraindication to MRI scanning
  4. Conditions precluding entry into the scanners (e.g. morbid obesity, claustrophobia, etc.).
  5. Exposure to research related radiation in the past year that, when combined with this study, would place subjects above the allowable limits.
  6. Participation in the last year in a clinical trial for a disease modifying drug for AD.
  7. Inability to have a catheter in subject's vein for the injection of radioligand.
  8. Inability to have blood drawn from subject's veins.
  9. Taking anticoagulant (e.g., warfarin) or immunosuppressive/immunomodulatory medication. Nonsteroidal anti-inflammatory drugs (NSAIDs) are not exclusionary. Use of steroids in the 30 days preceding the PET scan.
  10. Having a diagnosis of a chronic inflammatory disease (for example, multiple sclerosis, inflammatory bowel disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus) or a chronic infectious disease such as H.I.V.

Sites / Locations

  • Columbia University Irving Medical CenterRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Cognitive Impairment

No Cognitive Impairment

Arm Description

Subjects diagnosed with Alzheimer's disease (AD) or mild cognitive impairment (MCI) will have one PET scan with 11C-ER176, with arterial sampling. If the subject lacks known AD-biomarkers, they may undergo a 18F-florbetaben PET scan prior to the 11C-ER176 PET scan. Genome-wide genetic analysis will be performed. Participants will undergo an annual clinical evaluation and blood sample collection for 5 years to establish the trajectory of AD-related serum biomarkers and syndromic diagnoses.

Healthy volunteers who are cognitively normal will have one PET scan with 11C-ER176, with arterial sampling. If the subject lacks known AD-biomarkers, they may undergo an 18F-florbetaben PET scan prior to the 11C-ER176 PET scan. Genome-wide genetic analysis will be performed. Participants will undergo an annual clinical evaluation and blood sample collection for 5 years to establish the trajectory of AD-related serum biomarkers and syndromic diagnoses.

Outcomes

Primary Outcome Measures

Correlation between the chromosome 1 variant (rs2997325) and TSPO binding
The measure will be in vivo validation of GWAS and assessment of clinical relevance by performing TSPO PET imaging using 11C-ER176 to measure microglial activation. PET images will be analyzed using 1) the two-tissue kinetic model to calculate total distribution volume, corrected for free fraction of radioligand in plasma (VT/fP). Analysis will be a meta-analysis of the association of rs2997325 with 11C-ER176 binding (total distribution volume, VT).
Number of variants discovered in genome-wide association study (GWAS) that influence TSPO binding
11C-ER176 data will be used to perform a discovery GWAS for additional variants that influence TSPO binding and to define the genetic architecture of the PAM trait. Using PLINK and all imputed high quality genotypes (imputation r2 >0.8), adjusted for sex, age, and technical variables, the investigators will perform a GWAS for TSPO binding.

Secondary Outcome Measures

Full Information

First Posted
April 8, 2021
Last Updated
July 26, 2023
Sponsor
Columbia University
Collaborators
National Institute on Aging (NIA)
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1. Study Identification

Unique Protocol Identification Number
NCT04840979
Brief Title
Discovery and Validation of Genetic Variants Affecting Microglial Activation in Alzheimer's Disease
Official Title
Discovery and Validation of Genetic Variants Affecting Microglial Activation in Alzheimer's Disease With 11C-ER176
Study Type
Interventional

2. Study Status

Record Verification Date
July 2023
Overall Recruitment Status
Recruiting
Study Start Date
May 11, 2021 (Actual)
Primary Completion Date
December 2026 (Anticipated)
Study Completion Date
December 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Columbia University
Collaborators
National Institute on Aging (NIA)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The primary objectives are to validate that a previously identified gene variant influences the proportion of activated microglia (PAM) and the amount of TSPO binding on PET imaging, to identify novel loci that influence PAM and TSPO PET, and to understand the functional consequences of gene variants that drive microglial activation in Alzheimer's disease.
Detailed Description
While activated microglia have been observed in the vicinity of neuritic amyloid plaques in Alzheimer's disease (AD), there have been no large-scale assessments of microglial activation in aging and neurodegenerative disease. The investigators seek to understand the genetic underpinning of microglial responses-particularly the proportion of microglia in a morphologically-defined state of activation-that increase susceptibility to AD, so the investigators can develop more targeted forms of immune-based therapies to prevent cognitive decline and progression to dementia. The objective is to refine the genetic architecture of microglial activation to validate a previously identified gene variant -- and to identify novel loci -- that influence the proportion of activated microglia. The investigators also seek to understand the functional consequences of variants driving microglial activation in AD. The central hypothesis is that identifiable gene variants influence microglial activation and susceptibility to AD. The investigators will test this hypothesis by conducting genome-wide analysis and identifying associations between gene variants and microglial activation. Microglial activation will be measured in human autopsy tissue (ex vivo), living human brain using PET imaging (in vivo), and in monocyte-derived microglia-like cells (in situ and in vitro). This genetic study is designed to validate a finding that was discovered in participants with self-reported European-Caucasian ancestry. Therefore, the study seeks to enroll participants who self-report as white, not Hispanic or Latino. However, if this study is successful, the investigators plan to use the methods in this protocol in a future study to identify new genetic variants associated with changes on TSPO PET in a more diverse participant population. The investigators intend to use the results from this study to eventually benefit individuals of all racial and ethnic groups.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Alzheimer Disease
Keywords
PET scan, Inflammation, Genetic testing, Cognitive Impairment

7. Study Design

Primary Purpose
Diagnostic
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
250 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Cognitive Impairment
Arm Type
Experimental
Arm Description
Subjects diagnosed with Alzheimer's disease (AD) or mild cognitive impairment (MCI) will have one PET scan with 11C-ER176, with arterial sampling. If the subject lacks known AD-biomarkers, they may undergo a 18F-florbetaben PET scan prior to the 11C-ER176 PET scan. Genome-wide genetic analysis will be performed. Participants will undergo an annual clinical evaluation and blood sample collection for 5 years to establish the trajectory of AD-related serum biomarkers and syndromic diagnoses.
Arm Title
No Cognitive Impairment
Arm Type
Active Comparator
Arm Description
Healthy volunteers who are cognitively normal will have one PET scan with 11C-ER176, with arterial sampling. If the subject lacks known AD-biomarkers, they may undergo an 18F-florbetaben PET scan prior to the 11C-ER176 PET scan. Genome-wide genetic analysis will be performed. Participants will undergo an annual clinical evaluation and blood sample collection for 5 years to establish the trajectory of AD-related serum biomarkers and syndromic diagnoses.
Intervention Type
Drug
Intervention Name(s)
11C-ER176
Other Intervention Name(s)
[11C]ER176
Intervention Description
11C-ER176 is a novel TSPO radioligand that was developed because of its relative insensitivity to the rs6971 polymorphism. Increased TSPO signal on PET is associated with activation of microglia in the brain. The radioligand will be administered in tracer doses at activity of up to 20 mCi (740 MBq), IV, total of one injection. A single dose of radioligand will be injected over 1 minute.
Intervention Type
Drug
Intervention Name(s)
18F-florbetaben
Other Intervention Name(s)
[18F] Florbetaben
Intervention Description
Florbetaben has been approved by the FDA to help diagnose Alzheimer's disease. Florbetaben measures amyloid in the brain.
Primary Outcome Measure Information:
Title
Correlation between the chromosome 1 variant (rs2997325) and TSPO binding
Description
The measure will be in vivo validation of GWAS and assessment of clinical relevance by performing TSPO PET imaging using 11C-ER176 to measure microglial activation. PET images will be analyzed using 1) the two-tissue kinetic model to calculate total distribution volume, corrected for free fraction of radioligand in plasma (VT/fP). Analysis will be a meta-analysis of the association of rs2997325 with 11C-ER176 binding (total distribution volume, VT).
Time Frame
Up to 1 year
Title
Number of variants discovered in genome-wide association study (GWAS) that influence TSPO binding
Description
11C-ER176 data will be used to perform a discovery GWAS for additional variants that influence TSPO binding and to define the genetic architecture of the PAM trait. Using PLINK and all imputed high quality genotypes (imputation r2 >0.8), adjusted for sex, age, and technical variables, the investigators will perform a GWAS for TSPO binding.
Time Frame
Up to 1 year

10. Eligibility

Sex
All
Minimum Age & Unit of Time
50 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion criteria: Age 50 and older at time of study entry. Meet criteria for either a) amnestic mild cognitive impairment (single or mixed domain) or Alzheimer's disease, or b) have no cognitive impairment, based on history, exam, and neuropsychological testing. Patients must have Clinical Dementia Rating Scale score of 0.5 or 1 at enrollment. Controls must have Clinical Dementia Rating scale score of 0 at enrollment. Subjects must have AD biomarker previously obtained for research or clinical purposes or undergo a 18F-florbetaben PET scan during the screening process. Patients must have positive amyloid PET scan or CSF results consistent with AD. Controls must have a negative amyloid PET scan or CSF results not consistent with AD. Self-identify as white, non-Hispanic or Latino Subjects must be ableto provide informed consent Written and oral fluency in English Able to participate in all scheduled evaluations and to complete all required tests and procedures. In the opinion of the investigator, the subject must be considered likely to comply with the study protocol and to have a high probability of completing the study. Exclusion Criteria: Past or present history of certain brain disorders other than MCI or AD. Certain significant medical conditions, which make study procedures of the current study unsafe. Such serious medical conditions include uncontrolled epilepsy and multiple serious injuries. Contraindication to MRI scanning Conditions precluding entry into the scanners (e.g. morbid obesity, claustrophobia, etc.). Exposure to research related radiation in the past year that, when combined with this study, would place subjects above the allowable limits. Participation in the last year in a clinical trial for a disease modifying drug for AD. Inability to have a catheter in subject's vein for the injection of radioligand. Inability to have blood drawn from subject's veins. Taking anticoagulant (e.g., warfarin) or immunosuppressive/immunomodulatory medication. Nonsteroidal anti-inflammatory drugs (NSAIDs) are not exclusionary. Use of steroids in the 30 days preceding the PET scan. Having a diagnosis of a chronic inflammatory disease (for example, multiple sclerosis, inflammatory bowel disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus) or a chronic infectious disease such as H.I.V.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Galen Ziaggi
Phone
212-305-9079
Email
gfz2102@cumc.columbia.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Elena Golub
Phone
212-305-9079
Email
eg2972@cumc.columbia.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Philip De Jager, MD
Organizational Affiliation
Columbia University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Columbia University Irving Medical Center
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Galen Ziaggi
Phone
212-305-9079
Email
gfz2102@cumc.columbia.edu
First Name & Middle Initial & Last Name & Degree
Philip De Jager, MD

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
Individual participant data will be available upon reasonable request from a qualified investigator.
IPD Sharing Time Frame
Up to two weeks after review and approval of request.
IPD Sharing Access Criteria
Investigator qualifications and previous work will be reviewed by PI. Subsequent email correspondence will relay technical criteria needed for access.

Learn more about this trial

Discovery and Validation of Genetic Variants Affecting Microglial Activation in Alzheimer's Disease

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