The Synapse Project

NCT04871074 | Completed Phase 2 Results FDA Drug

• 5 other identifiers: 2018-1283A534255SMPH/MEDICINE/GER-AD DEVProtocol Version 3/7/2024R01AG062285
• Study Type: interventional
• Target: 100
• Locations: 1 country
• Sites: 1

Brief Summary

The overarching goal of this project is to use \[C-11\]UCB-J to obtain spatial information on neuronal synapse abundance and inform Alzheimer's disease (AD) progression. The investigators propose to collect longitudinal amyloid, tau, and Synaptic vesicle glycoprotein 2A (SV2A) positron emission tomography (PET) in participants in the Wisconsin Alzheimer's Disease Research Center (ADRC) and Wisconsin Registry for Alzheimer's Prevention (WRAP) across the clinical stages of AD, including cognitively unimpaired biomarker negative, unimpaired biomarker positive, mild cognitive impairment (MCI), and dementia due to AD.

Conditions

Alzheimer Disease

Outcome Measures

Primary Outcomes (7)

• ROC AUCs (MCI/AD vs Cognitively Unimpaired (CU)) for Medial Temporal Lobe (MTL) UCB-J Distribution Volume Ratio (DVR) and Hippocampal Volume

  DeLong's method will test whether the MTL UCB-J receiver-operator characteristic (ROC) area under the curve (AUC) has better mild cognitive impairment/probable AD dementia (MCI/AD) prediction accuracy than the hippocampal volume ROC AUC. ROC AUC is a measure of the correctness of group (where group is MCI/AD and cognitively unimpaired) classification using a continuous predictor, in this case, the medial temporal lobe UCB-J uptake (11C-UCB-J is a PET tracer for imaging the synaptic vesicle glycoprotein 2A in the human brain. It is considered a measure of synaptic density). This ROC AUC was compared to that of the comparator continuous predictor, hippocampal volume.

  Baseline

• ROC AUCs (MCI/AD vs CU) for MTL UCB-J and Hippocampal Cingulum Neurite Density Index

  DeLong's method will test whether the MTL UCB-J ROC AUC has better MCI/AD prediction accuracy than the hippocampal cingulum neurite density index ROC AUC. ROC AUC is a measure of the correctness of group (where group is MCI/AD and cognitively unimpaired) classification using a continuous predictor, in this case, the medial temporal lobe UCB-J uptake (11C-UCB-J is a PET tracer for imaging the synaptic vesicle glycoprotein 2A in the human brain. It is considered a measure of synaptic density). This ROC AUC was compared to that of the comparator continuous predictor, hippocampal cingulum neurite density index.

  Baseline

• Annual Rate of Change in UCB-J DVR

  Linear mixed effects regression will model UCB-J distribution volume ratio (DVR) as a function of time since baseline. 11C-UCB-J is a PET tracer for imaging the synaptic vesicle glycoprotein 2A in the human brain. It is considered a measure of synaptic density. Participants' synaptic density was examined as a change per year. A positive number would mean an increase in synaptic density, a negative number means a decrease.

  Baseline and 2 years

• Baseline Diagnosis Group Differences in Annual Rate of Change in UCB-J DVR

  Baseline diagnosis (CU vs MCI/probable AD dementia) group differences in rate of UCB-J DVR change will be estimated via group x time interaction term in a linear mixed effects model. Participants' synaptic density was examined as a change per year. The difference in the rate of change in the two groups was estimated. A negative number means that impaired participants decreased in synaptic density more quickly and a positive number would mean that the impaired participants decreased less quickly.

  baseline and 2 years

• Amyloid Positivity Status Differences in Annual Rate of Change in UCB-J DVR

  Amyloid positivity status differences in rate of UCB-J DVR change will be estimated via group x time interaction term in a linear mixed effects model. Amyloid positivity status will be determined from amyloid PET. Participants' synaptic density was examined in a change per year. The difference in the rate of change in the two groups was estimated. A negative number means that amyloid positive participants decreased in synaptic density more quickly and a positive number would mean that the amyloid positive participants decreased less quickly.

  baseline and 2 years

• Tau Positivity Status Differences in Annual Rate of Change in UCB-J DVR

  Tau positivity status differences in rate of UCB-J DVR change will be estimated via group x time interaction term in a linear mixed effects model. Tau positivity status will be determined from tau PET. Participants' synaptic density was examined as a change per year. The difference in the rate of change in the two groups was estimated. A negative number means that tau positive participants decreased in synaptic density more quickly and a positive number would mean that the tau positive participants decreased less quickly.

  baseline and 2 years

• MTL UCB-J DVR Baseline Differences in a Cognitive Performance Age Slope in Non-demented Participants

  Linear mixed effects will be used to model cognitively unimpaired participants' memory performance as a function of their age and synaptic density. Specifically, investigators will test whether those with higher synaptic density had less deterioration over time. Memory performance will be assessed using Rey Auditory Verbal Learning Test Delayed Recall. An interaction was tested, and a negative number means that those with higher synaptic density decreased faster over time, and a positive number means that they decreased slower over time.

  baseline and 2 years

Secondary Outcomes (6)

• Difference Between ROC AUCs (MCI/AD vs CU) for Medial Temporal Lobe (MTL) UCB-J Distribution Volume Ratio (DVR) and Cerebrospinal Fluid (CSF) Neurofilament Light Chain Protein (NfL)

  baseline

• Difference Between ROC AUCs (MCI/AD vs CU) for MTL UCB-J DVR and Cerebrospinal Fluid (CSF) T-tau

  baseline

• Difference Between ROC AUCs (MCI/AD vs CU) for MTL UCB-J and CSF Neurogranin

  baseline

• Sex Differences in Annual Rate of Change in UCB-J DVR

  baseline and 2 years

• Age Differences in Annual Rate of Change in UCB-J DVR

  baseline and 2 years

Study Arms (1)

Cognitively Impaired plus Cognitive Unimpaired Participants

EXPERIMENTAL

Participants include both cognitively impaired and unimpaired populations to populate a single model to examine variables within the group as a whole. * Cognitively impaired participants have abnormal cognitive status of MCI or dementia as judged by consensus or expert review using National Institute of Aging and Alzheimer's Association (NIA-AA) 2018 criteria. * Cognitively unimpaired participants: results of most recent testing with the source cohort indicate the participant is cognitively unimpaired as judged by consensus or expert review.

Drug: UCB-J; Device: MRI Scan; Device: PET Scan

Interventions

UCB-J DRUG

PET imaging with UCB-J

Cognitively Impaired plus Cognitive Unimpaired Participants

MRI Scan DEVICE

MRI exams will be performed using a 3T MRI scanner, scan duration is typically 60 minutes

Also known as: Magnetic Resonance Imaging

Cognitively Impaired plus Cognitive Unimpaired Participants

PET Scan DEVICE

PET imaging may be collected using either a PET scanner or a PET/Computed Tomography (CT) scanner, a PET scan will be initiated with the injection of radiotracer

Also known as: Positron Emission Tomography

Cognitively Impaired plus Cognitive Unimpaired Participants

Eligibility Criteria

• Age: 55 Years - 89 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Cognitively unimpaired adults-
• Aged 55 - 89
• Normal cognition (results of most recent testing with the source cohort indicate the participant is cognitively unimpaired as judged by consensus or expert review)
• In good general health with no conditions/medications affecting cognition or imaging
• Willing to undergo \[C-11\]UCB-J, \[C-11\]PiB, and \[F-18\]MK6240 PET scans
• An adequate MRI exam within 12 months prior to baseline. An MRI will be performed if not already available.
• Mild dementia and amnestic Mild Cognitive Impairment-
• Aged 50 years or older
• Abnormal cognitive status of MCI or dementia as judged by consensus or expert review using NIA-AA 2018 criteria
• MCI's must be affected in the memory domain but may also have other affected domains
• Willing to undergo \[C-11\]UCB-J, \[C-11\]PiB, and \[F-18\]MK6240 PET scans
• An adequate MRI exam within 12 months prior to baseline. This MRI exam will come from ADRC/WRAP studies. Clinical MRI's (ones obtained outside of the research program) will not be adequate. An MRI will be performed if not already available from within the research program.

You may not qualify if:

• For women, pregnant, lactating or breastfeeding, or intention to become pregnant
• Evidence of unstable or untreated clinically significant gastrointestinal, cardiovascular, hepatic, renal, hematological, neoplastic, endocrine, alternative neurological, immunodeficiency, pulmonary, or other disorder or disease.
• Stable, treated chronic medical conditions like hypertension, hypercholesterolemia, diabetes mellitus, non-metastatic dermatologic or prostatic cancer, etc. are acceptable as long as they do not, in the study investigator's opinion, contribute to cognitive dysfunction or limit participation in study procedures.
• Any illness or other consideration that makes it unlikely that the subject will be able to complete the 24-month study.
• Current or prior history (within past 5 years) of significant alcohol or substance abuse as determined by the investigator.
• Psychiatric disorders that may interfere with the study including current major Axis I DSM-V disorders including but not limited to severe Major depression, current or history of bipolar I disorder, or schizophrenia.
• Current use of the anti-seizure medication Levetiracetam, also known as Keppra, Spritam or Roweepra
• MRI-incompatible implants or devices such as certain cardiac pacemakers or defibrillators, insulin pumps, cochlear implants, metallic ocular foreign body, implanted neural stimulators, CNS aneurysm clips and other medical implants that have not been certified for MRI, or history of claustrophobia in MRI that prevents completion of MRI protocol.
• Lack of decisional capacity at the time of informed consent

Sponsors & Collaborators

• University of Wisconsin, Madison: lead
• National Institute on Aging (NIA): collaborator

Study Sites (1)

University of Wisconsin

Madison, Wisconsin, 53792, United States

Location

MeSH Terms

Conditions

Alzheimer Disease

Interventions

Magnetic Resonance Imaging; Positron-Emission Tomography

Condition Hierarchy (Ancestors)

Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Tomography; Diagnostic Imaging; Diagnostic Techniques and Procedures; Diagnosis; Tomography, Emission-Computed; Image Interpretation, Computer-Assisted; Image Enhancement; Photography; Radionuclide Imaging; Diagnostic Techniques, Radioisotope

Results Point of Contact

• Title: Barbara Bendlin, PhD, MA
• Organization: UW School of Medicine and Public Health

bbb@medicine.wisc.edu

(608) 265-2483

Study Officials

• Barbara Bendlin, PhD

  University of Wisconsin, Madison

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: DIAGNOSTIC
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 28, 2021
• First Posted: May 4, 2021
• Study Start: November 18, 2018
• Primary Completion: October 17, 2023
• Study Completion: May 1, 2025
• Last Updated: August 12, 2025
• Results First Posted: August 12, 2025

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)