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

Discovery and Validation of Genetic Variants Affecting Microglial Activation in Alzheimer's Disease With 11C-ER176

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.

Study Overview

• Status: Recruiting
• Conditions: Alzheimer Disease
• Intervention / Treatment: Drug: 11C-ER176; Drug: 18F-florbetaben

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.

• Study Type: Interventional
• Enrollment (Estimated): 250
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Galen Ziaggi; Phone Number: 212-305-9079; Email: gfz2102@cumc.columbia.edu
• Study Contact Backup: Name: Elena Golub; Phone Number: 212-305-9079; Email: eg2972@cumc.columbia.edu

Study Locations

• United States
  • New York
    • New York, New York, United States, 10032
      • Recruiting
      • Columbia University Irving Medical Center
      • Contact: Galen Ziaggi; Phone Number: 212-305-9079; Email: gfz2102@cumc.columbia.edu
      • Principal Investigator: Philip De Jager, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cognitive Impairment; 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.	Drug: 11C-ER176; 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.; Other Names: [11C]ER176; Drug: 18F-florbetaben; Florbetaben has been approved by the FDA to help diagnose Alzheimer's disease. Florbetaben measures amyloid in the brain.; Other Names: [18F] Florbetaben
Active Comparator: No Cognitive Impairment; 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.	Drug: 11C-ER176; 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.; Other Names: [11C]ER176; Drug: 18F-florbetaben; Florbetaben has been approved by the FDA to help diagnose Alzheimer's disease. Florbetaben measures amyloid in the brain.; Other Names: [18F] Florbetaben

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	Up to 1 year
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.	Up to 1 year

Collaborators and Investigators

• Sponsor: Columbia University
• Collaborators: National Institute on Aging (NIA)
• Investigators: Principal Investigator: Philip De Jager, MD, Columbia University

Study record dates

Study Major Dates

• Study Start (Actual): May 11, 2021
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: April 8, 2021
• First Submitted That Met QC Criteria: April 8, 2021
• First Posted (Actual): April 12, 2021

Study Record Updates

• Last Update Posted (Actual): July 28, 2023
• Last Update Submitted That Met QC Criteria: July 26, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: Inflammation; PET scan; Cognitive Impairment; Genetic testing
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Neurodegenerative Diseases; Dementia; Tauopathies; Alzheimer Disease
• Other Study ID Numbers: AAAT2774; RF1AG070438 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD 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.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No