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

Trial Summary

What is the purpose of this trial?

The purpose of this study is to determine how inflammation is related to other changes in the brain that occur during the progression of Alzheimer's disease. The investigators are also studying how inflammation is related to the symptoms that first occur in patients with Alzheimer's disease (AD). For this reason, the investigators are asking people with different versions of Alzheimer's disease and/or other related dementias to participate. This includes patients with: * 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 * The investigators are also enrolling older adults with normal visual, language, and memory function.

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.

What data supports the effectiveness of the drug 11C-ER176 and related treatments for Alzheimer's disease?

Research shows that PET imaging with tracers like 18F-Florbetaben and Florbetapir (18F) is effective in detecting amyloid-β plaques, which are associated with Alzheimer's disease. These tracers have demonstrated high sensitivity and specificity in distinguishing Alzheimer's patients from healthy individuals, suggesting their potential utility in diagnosing and monitoring the disease. ^{1 2 3 4 5}

Is 18F-Florbetaben safe for use in humans?

18F-Florbetaben, used for brain imaging in Alzheimer's patients, was generally well tolerated in clinical trials. Most side effects were mild, like redness or pain at the injection site, and there were no serious adverse reactions reported. ^{6 7 8 9 10}

How does this treatment differ from other treatments for Alzheimer's disease?

This treatment uses PET imaging with the ligand [11C](R)-PK11195 to detect brain inflammation by targeting activated microglia, which is different from other treatments that focus on amyloid or tau protein detection. It provides a unique way to monitor neuroinflammation as a marker of disease activity, rather than just measuring amyloid or tau deposits. ^{1 2 5 11 12}

Research Team

Patrick J. Lao, PhD

Principal Investigator

Columbia University

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

[(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]

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 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]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

In vivo imaging of neuroinflammation. [2019]

2. England pubmed.ncbi.nlm.nih.gov

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

3. Switzerland pubmed.ncbi.nlm.nih.gov

[Brain imaging of Alzheimer' disease: state of the art and perspectives for clinicians]. [2016]

4. United States pubmed.ncbi.nlm.nih.gov

Assessment of Microglial Activation in Alzheimer Disease Using 18 F-PBR06 PET. [2023]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Florbetaben to trace amyloid-β in the Alzheimer brain by means of PET. [2022]

6. Germany pubmed.ncbi.nlm.nih.gov

18F-florbetaben whole-body PET/MRI for evaluation of systemic amyloid deposition. [2023]

7. New Zealand pubmed.ncbi.nlm.nih.gov

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

8. United States pubmed.ncbi.nlm.nih.gov

Florbetapir positron emission tomography and cerebrospinal fluid biomarkers. [2018]

9. United States 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. [2019]

10. United States pubmed.ncbi.nlm.nih.gov

Performance characteristics of amyloid PET with florbetapir F 18 in patients with alzheimer's disease and cognitively normal subjects. [2022]

11. United States 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. [2022]

12. Germany pubmed.ncbi.nlm.nih.gov

Using PET with 18F-AV-45 (florbetapir) to quantify brain amyloid load in a clinical environment. [2022]