11C-Acetate PET/CT Imaging As a Biomarker of Amyloid-Induced Neuroinflammation

11C-Acetate Position Emission Tomography/Computerized Tomography (PET/CT) Imaging As a Biomarker of Amyloid-Induced Neuroinflammation

The proposed study aims to use 11C-acetate position emission tomography/computed tomography (PET/CT) to preliminarily test and validate methods for imaging astrocyte activation as an early indicator of neuroinflammation in Alzheimer's disease (AD). 11C-Acetate PET/CT has been shown to quantify astrocyte activation in vivo, but no reports have evaluated its potential in AD. The investigators propose to test 11C-Acetate PET/CT as a marker for astrocyte activation associated with pathologic amyloid deposition in AD. The investigators will compare binding between subjects with early stage AD and healthy controls. Further, the investigators will investigate the correlation between amyloid and acetate binding. If the investigators find increased astrocyte activation in response to cerebral amyloid by showing a group difference in brain acetate uptake between disease and controls or a strong correlation between acetate and amyloid PET/CT binding. Validating neuroinflammation markers in AD ultimately may guide therapeutic modulation of beneficial and damaging neuroinflammation to slow disease progression, as well as providing new insights into AD pathophysiology.

Study Overview

• Status: Terminated
• Conditions: Mild Cognitive Impairment
• Intervention / Treatment: Drug: 11C-acetate

• Study Type: Interventional
• Enrollment (Actual): 11
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 63 years and older (Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria for amnestic MCI cohort:

1. Participants will be at least 65 years of age
2. Positive brain amyloid PET/CT scan within 6 months of study screening
3. Mini-mental status examination (MMSE) score ≥ 24 at screening visit
4. A brain MRI is required. If a brain MRI has been performed within 6 months of 11C-Acetate PET/CT and of adequate quality that scan may be used for the study analysis, subjects who do not have a brain MRI will undergo a brain MRI as a part of this study
5. Participants must identify a study partner who is willing to accompany the patient to study visits
6. Participants must be informed of the investigational nature of this study and provide written informed consent in accordance with institutional and federal guidelines prior to study-specific procedures. If the patient is unable to provide informed consent, the patient's legal representative may consent on behalf of the patient but the patient will be asked to confirm assent.

Inclusion Criteria for Control cohort:

1. Participants will be at least 65 years of age
2. History of negative brain amyloid PET/CT scan within 6 months of study screening OR negative cerebrospinal fluid (CSF) analysis for AD biomarkers within 6 months of study screening
3. Mini-mental status examination (MMSE) > 27 at screening visit
4. A brain MRI is required. If a brain MRI has been performed within 6 months of enrollment to this study and of adequate quality that scan may be used for the study analysis, subjects who do not have a brain MRI will undergo a brain MRI as a part of this study
5. Participants must be informed of the investigational nature of this study and provide written informed consent in accordance with institutional and federal guidelines prior to study-specific procedures.

Exclusion Criteria for both cohorts:

1. Inability to tolerate or contraindication to imaging procedures (PET/CT or MRI) in the opinion of an investigator or treating physician
2. History of stroke or other neurological disease that in the opinion of the investigator might interfere with evaluation of the 11C-Acetate scan
3. Any medical or psychological conditions that, in the opinion of the investigator, would compromise the subject's safety or successful participation in the study.

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: Amnestic MCI cohort; Patients with Mild Cognitive Impairment (MCI) (up to 14) will be recruited primarily from the Penn Memory Center (PMC). Clinical diagnostic criteria (described in further detail in Study Procedures section) will be used to identify subjects who are meet criteria for amnestic MCI. Participants will receive injection of radioactive tracer 11C-acetate and complete a PET/CT scan.	Drug: 11C-acetate; Participants will receive injection of radioactive tracer 11C-acetate and complete a PET/CT scan.
Other: Control cohort; Normal control subjects in the same age range (up to 6) will be recruited from a current ongoing study investigating neuroinflammation in late life depression and healthy controls, from the control group in which all subjects receive MRI and lumbar puncture (LP) and from the PMC research cohort. Participants will receive injection of radioactive tracer 11C-acetate and complete a PET/CT scan.	Drug: 11C-acetate; Participants will receive injection of radioactive tracer 11C-acetate and complete a PET/CT scan.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
11C-acetate Uptake in Amyloid Positive Mild Cognitive Impairment (MCI) Subjects Versus Amyloid Negative Healthy Controls	We compare the whole brain 11C-acetate uptake standardized uptake value ratio (SUVR) between the amnestic MCI and control cohorts. Static summed images from 40-60 minutes after tracer injection were generated from raw dynamic PET data. This timeframe was selected to preferentially capture 11C-acetate trapped in biosynthetic pathways in activated astrocytes, rather than what was catabolized to 11C-CO2 .Mean tracer binding, expressed as standardized uptake values (SUV) in the whole cerebral cortex and other regions is measured from these summed images using PMOD software (PMOD technologies). SUVR is generated by dividing the mean whole cortex SUV by the mean cerebellar gray matter SUV; SUVR is a unitless measure. For this tracer, higher values are worse, indicating more astrocyte activation and inflammation.	6 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Correlate 11C-acetate uptake to areas of greater amyloid plaque burden quantified on Amyloid PET/CT	7 days
Compare 11C-acetate in areas of mildly elevated PET SUVR to areas with high or sub-threshold amyloid burden	7 days
Correlate 11C-acetate uptake to levels of inflammatory markers in CSF	7 days

Collaborators and Investigators

• Sponsor: University of Pennsylvania
• Investigators: Principal Investigator: Ilya Nasrallah, MD, University of Pennsylvania

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2017
• Primary Completion (Actual): February 28, 2022
• Study Completion (Actual): February 28, 2022

Study Registration Dates

• First Submitted: June 20, 2016
• First Submitted That Met QC Criteria: June 20, 2016
• First Posted (Estimated): June 23, 2016

Study Record Updates

• Last Update Posted (Actual): January 11, 2024
• Last Update Submitted That Met QC Criteria: January 10, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Nervous System Diseases; Inflammation; Neurocognitive Disorders; Cognition Disorders; Cognitive Dysfunction; Neuroinflammatory Diseases
• Other Study ID Numbers: 824822

Plan for Individual participant data (IPD)

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