Brain Inflammation Imaging for Alzheimer's Disease

(ADVISe Trial)

Overseen By Diana S. Guzman

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Patrick Lao

Disqualifiers: Brain disorders, Uncontrolled epilepsy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 1

100 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to understand the connection between brain inflammation and the progression of Alzheimer's disease and its early symptoms. Researchers use various imaging techniques and procedures, such as lumbar puncture (to collect cerebrospinal fluid), to explore these connections. Individuals with different forms of Alzheimer's, including memory, vision, or language difficulties, as well as healthy older adults, are invited to participate. Suitable participants may have mild cognitive issues or be completely symptom-free. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, allowing participants to contribute to important early-stage findings.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. The decision on medication exclusions is up to the study's principal investigator and medical liaison.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that the treatments in this study are generally well-tolerated. The first treatment, 11C-ER176, remains under investigation. Although data specifically for Alzheimer's patients is limited, other studies suggest it has manageable side effects.

For 18F-Florbetaben, the safety profile is more established. Studies involving over 1,000 participants found it generally safe, with no major adverse effects reported. This compound is already approved for diagnosing Alzheimer's, supporting its safety.

Regarding 18F-MK6240, research indicates it is well-tolerated and presents no significant safety concerns. This tracer has been tested in both Alzheimer's patients and healthy individuals without major issues.

Lastly, the lumbar puncture (spinal tap) is a common procedure used to collect spinal fluid. Some people may experience mild headaches or backaches afterward, but it is considered safe for older adults, even those with cognitive problems.

Overall, these treatments have a reassuring safety profile, making them viable options for participation in clinical trials. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about this trial because it offers a new way to visualize brain inflammation, which is crucial for understanding Alzheimer's disease. Unlike traditional methods that primarily focus on managing symptoms or slowing disease progression, this trial uses advanced imaging agents like 11C-ER176, 18F-Florbetaben, and 18F-MK6240 to provide detailed insights into the brain's inflammatory processes. These imaging agents have the potential to identify specific patterns of brain inflammation associated with different forms of Alzheimer's, such as mild cognitive impairment and amnestic Alzheimer's disease. By improving our understanding of these patterns, the trial could lead to more targeted and effective treatments in the future.

What evidence suggests that this trial's treatments could be effective for Alzheimer's disease?

In this trial, participants will undergo imaging with different agents to study brain changes related to Alzheimer's disease. Research has shown that 11C-ER176, one of the imaging agents used in this trial, effectively captures images of brain inflammation, which is linked to the progression of Alzheimer's disease. Measuring this inflammation is important because it plays a key role in the disease.

Another imaging agent in this trial, 18F-Florbetaben, has been shown in studies to effectively detect amyloid plaques. These plaques are clumps of protein associated with Alzheimer's, aiding in diagnosing and monitoring the disease.

Additionally, 18F-MK6240, also used in this trial, has been shown to track the build-up of tau proteins over time. Tau proteins form tangles in the brain, another sign of Alzheimer's, and this tracer helps make them visible.

Each of these imaging agents provides important insights into brain changes related to Alzheimer's, aiding in understanding and diagnosing the disease. ^{1 2 4 6 7}

Who Is on the Research Team?

Patrick J. Lao, PhD

Principal Investigator

Columbia University

Are You a Good Fit for This Trial?

This trial is for adults over 50 with or without Alzheimer's disease (AD), including those with vision or language difficulties, and typical memory issues. Participants must be fluent in English, able to give consent (or have a surrogate decision maker), and likely to follow the study plan. People with serious medical conditions, recent excessive research-related radiation exposure, immune system-suppressing medication use, other brain disorders besides AD, or MRI contraindications cannot join.

Inclusion Criteria

In the opinion of the PI, the subject must be considered likely to comply with the study protocol and to have a high probability of completing the study

I do not have cognitive impairment or specific Alzheimer's disease.

I am 50 years old or older.

Exclusion Criteria

You have been in a clinical trial for a drug that changes how a disease affects your body in the past year.

I am currently taking medication that suppresses my immune system.

Serious medical conditions, which make study procedures of the current study unsafe

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Baseline Assessment

Initial PET scans, MRI, and lumbar puncture to measure inflammation and protein levels

1-2 weeks

1 visit (in-person)

Longitudinal Monitoring

Participants undergo repeated PET scans, MRI, and lumbar puncture to assess changes over time

24 months

Multiple visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after the main assessments

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• 11C-ER176
• 18F-Florbetaben
• 18F-MK6240
• Lumbar Puncture

Trial Overview The study aims to understand how brain inflammation relates to Alzheimer's progression and symptoms by using imaging agents like 11C-ER176 and 18F-MK6240 PET scans along with an amyloid plaque detector called 18F-Florbetaben. It also involves a lumbar puncture procedure to examine spinal fluid.

How Is the Trial Designed?

Group I: Cognitive impairment Experimental Treatment 4 Interventions

* Mild Cognitive Impairment * Posterior cortical atrophy - a version of Alzheimer's disease with vision difficulties * Logopenic variant primary progressive aphasia - a version of Alzheimer's disease with language difficulties * Amnestic Alzheimer's disease - a "typical" version of Alzheimer's disease with memory difficulties

Group II: No cognitive impairment Active Control 4 Interventions

Healthy controls

Who Is Running the Clinical Trial?

Patrick Lao

Lead Sponsor

Trials

2

Recruited

160+

William Charles Kreisl

Lead Sponsor

Trials

7

Recruited

520+

James M Noble, MD, MS, CPH, FAAN

Lead Sponsor

Trials

3

Recruited

240+

National Institute on Aging (NIA)

Collaborator

Trials

1,841

Recruited

28,150,000+

Published Research Related to This Trial

In the ongoing phase 1b PRIME study involving patients with prodromal or mild Alzheimer's disease, aducanumab treatment led to significant reductions in amyloid PET SUVR, indicating a decrease in amyloid plaque burden over time and with higher doses.

The choice of reference regions for calculating SUVR significantly influenced effect sizes, with subcortical white matter and the pons yielding the largest effect sizes, while using the anterior cingulate cortex as a target ROI provided better results than a composite cortex approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of Reference and Target Region Selection on Amyloid PET SUV Ratios in the Phase 1b PRIME Study of Aducanumab. Chiao, P., Bedell, BJ., Avants, B., et al.[2019]

Florbetapir F 18 shows a wide effective dose range, as both 111 MBq (3 mCi) and 370 MBq (10 mCi) doses produced similar results in visual assessments and standardized uptake value ratios (SUVrs) for detecting β-amyloid in Alzheimer's disease patients and healthy controls.

The test-retest reliability of florbetapir F 18 is very high, with a correlation coefficient of 0.99 for SUVrs and a κ-statistic of 0.89 for Aβ classification, indicating consistent and reliable imaging results over time.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Performance characteristics of amyloid PET with florbetapir F 18 in patients with alzheimer's disease and cognitively normal subjects. Joshi, AD., Pontecorvo, MJ., Clark, CM., et al.[2022]

The use of [11C](R)-PK11195 PET imaging allows for the detection of neuroinflammatory changes in the brain, which can be crucial for understanding various brain diseases and their progression.

This method focuses on measuring the activity of microglia, the brain's immune cells, rather than just assessing neuronal damage, highlighting its potential as a marker for disease activity in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vivo imaging of neuroinflammation. Cagnin, A., Gerhard, A., Banati, RB.[2019]

[(18)F]florbetaben is a highly accurate PET imaging agent that effectively detects β-amyloid plaques in the brain, demonstrating high sensitivity and specificity in identifying Alzheimer's disease and other cognitive impairments based on a phase III study.

The agent is generally well tolerated, with only mild to moderate adverse reactions reported, primarily related to the injection site, and no serious adverse events associated with its use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[(18)F]Florbetaben: a review in β-amyloid PET imaging in cognitive impairment. Syed, YY., Deeks, E.[2022]

In a study involving healthy controls, mild cognitive impairment, and Alzheimer's disease patients, florbetapir-F18 PET imaging showed significant correlations with cerebrospinal fluid biomarkers like amyloid beta and tau, indicating its potential in assessing Alzheimer's disease.

Logistic regression analysis revealed that both amyloid beta and tau levels effectively differentiate between healthy individuals and those with Alzheimer's, suggesting that these biomarkers, along with FBP PET, can enhance diagnostic accuracy for Alzheimer's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Florbetapir positron emission tomography and cerebrospinal fluid biomarkers. Hake, A., Trzepacz, PT., Wang, S., et al.[2018]

Florbetapir (18F) is a promising PET tracer that effectively binds to amyloid-β plaques, allowing for the differentiation of Alzheimer's disease patients from healthy individuals, as demonstrated in phase I and II clinical trials with clear imaging results.

The tracer shows fast kinetics, with optimal imaging quality achieved within 5 to 10 minutes post-injection, and has a strong correlation with postmortem assessments of amyloid deposition, indicating its potential for early detection of Alzheimer's disease without serious adverse events reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Florbetapir (18F), a PET imaging agent that binds to amyloid plaques for the potential detection of Alzheimer's disease. Okamura, N., Yanai, K.[2016]

New diagnostic criteria for Alzheimer's disease (AD) focus on biomarkers related to synaptic dysfunction and neurodegeneration, enhancing clinical detection methods.

Advanced imaging techniques like MRI and PET scans can effectively identify key indicators of AD, such as medial-temporal atrophy and amyloid protein retention, aiding in diagnosis and monitoring treatment progress.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Brain imaging of Alzheimer' disease: state of the art and perspectives for clinicians]. Trombella, S., Assal, F., Zekry, D., et al.[2016]

In a pilot study of nine patients with suspected cardiac amyloidosis, 18F-florbetaben PET/MRI effectively visualized systemic amyloid deposition, showing high uptake in the left ventricle in five patients, which correlated with amyloid presence.

The imaging technique revealed abnormal 18F-florbetaben accumulation in various organs, including the bone marrow and stomach, suggesting its potential to provide critical information for diagnosis and treatment evaluation in amyloidosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

18F-florbetaben whole-body PET/MRI for evaluation of systemic amyloid deposition. Baratto, L., Park, SY., Hatami, N., et al.[2023]

The use of 18 F-PBR06 PET imaging revealed increased glial activation in specific brain regions of a 69-year-old woman diagnosed with Alzheimer's disease, indicating a potential biomarker for disease progression.

Over a 6-year follow-up, the patient's cognitive impairment worsened from mild to moderate, highlighting the progressive nature of Alzheimer's disease and the importance of monitoring brain changes over time.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessment of Microglial Activation in Alzheimer Disease Using 18 F-PBR06 PET. Carter, K., Cicero, S., Rissanen, E., et al.[2023]

The PET tracer 18F-PI-2620 effectively detects tau pathology in Alzheimer's disease patients, showing significantly higher binding in brain regions associated with tau deposition compared to healthy controls, indicating its potential as a diagnostic tool.

The administration of 18F-PI-2620 was found to be safe and well tolerated, with imaging results demonstrating a strong correlation between tau uptake and cognitive impairment, suggesting its utility in assessing disease severity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tau PET imaging with 18F-PI-2620 in Patients with Alzheimer Disease and Healthy Controls: A First-in-Humans Study. Mueller, A., Bullich, S., Barret, O., et al.[2022]

PET imaging with (18)F-AV-45 (florbetapir) effectively differentiates between patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI) from healthy controls, showing significant differences in amyloid load, particularly in the overall cortex.

The quantitative assessment of PET scans demonstrated high sensitivity (92.3%) and specificity (90.5%) for identifying AD, indicating that florbetapir is a promising and safe biomarker for routine clinical use, although visual assessments need improvement for better specificity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Using PET with 18F-AV-45 (florbetapir) to quantify brain amyloid load in a clinical environment. Camus, V., Payoux, P., Barré, L., et al.[2022]

Florbetaben, an 18F-labeled PET tracer, has shown promising results in diagnosing Alzheimer's disease, with a sensitivity of 80% and specificity of 91% in distinguishing patients with probable AD from healthy controls in a recent multi-center trial.

Current research is focused on validating florbetaben's effectiveness by correlating PET imaging results with post-mortem evaluations and assessing its ability to predict progression to Alzheimer's in individuals with mild cognitive impairment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Florbetaben to trace amyloid-β in the Alzheimer brain by means of PET. Barthel, H., Sabri, O.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5288742/

11C-ER176, a Radioligand for 18-kDa Translocator Protein ... This study sought, first, to determine whether the sensitivity of 11C-ER176 in humans is similar to the low sensitivity measured in vitro and, ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40187909/

[11C]ER176 images brain inflammation across TSPO ... Accurately measuring brain inflammation in Alzheimer's disease (AD) is crucial due to the role of inflammatory processes in neurodegeneration.

3. withpower.com withpower.com/trial/phase-3-alzheimer-disease-2-2021-0235f

Neuroinflammation Imaging for Alzheimer's Disease What data supports the effectiveness of the drug C-11 ER-176 for Alzheimer's disease? The research highlights the importance of imaging neuroinflammation in ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S0925443911002559

PET amyloid-beta imaging in preclinical Alzheimer's disease To date, the most widely studied and best validated biomarkers include cerebrospinal fluid (CSF) assays of Aβ and tau, and amyloid imaging with N-methyl-[11C]2 ...

5. link.springer.com link.springer.com/article/10.1007/s00259-022-05999-z

PET molecular imaging for pathophysiological visualization ... Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by gradual memory loss and cognitive decline [1]. It is the ...

6. sciencedirect.com sciencedirect.com/science/article/pii/S2274580724001997

Neuroinflammation Biomarkers in the AT(N) Framework ... The [11C]ER176 presents favorable kinetics (118), high signal-to-noise ratio, and volume of distribution stability (119), however, no data with AD patients is ...

7. mdpi.com mdpi.com/2075-4418/13/6/1029

PET Imaging of Neuro-Inflammation with Tracers Targeting ... The aim of this study is to review the current PET radiotracers targeting TSPO, a transmembrane protein that is overexpressed by microglia.