[18F]-FEOBV PET Scan for Cognitive Function in Down Syndrome

Overseen By Amy Boegel, Ph.D.

Age: 18 - 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Vanderbilt University Medical Center

Disqualifiers: Dementia, Unstable cardiac, Renal failure, 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: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how brain function changes in adults with Down syndrome (DS) as they age, focusing on brain cells that affect memory and learning. Researchers aim to identify markers that could predict who might respond well to future treatments targeting these brain cells. Participants will undergo brain imaging scans, including the [18F]-FEOBV PET Scan, and other tests to gather data. Adults with Down syndrome, who do not have dementia and are generally healthy, may be eligible to join. As a Phase 2 trial, this research measures how well the treatment works in an initial, smaller group, offering participants a chance to contribute to important findings.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you must stop taking your current medications. However, CNS-active medications are allowed if the dose is stable for at least 4 weeks. If you start new medications, the medical team will review your case to decide on the timing of baseline cognitive testing.

What prior data suggests that the [18F]-FEOBV PET Scan is safe for assessing cognitive function in Down Syndrome?

Research has shown that the [18F]-FEOBV PET Scan is generally easy for people to handle. This scan uses a radiotracer ([18F]-FEOBV) to detect changes in the brain. Studies with adults who have Down syndrome indicate that this radiotracer can reveal varying levels of activity in different brain regions. However, the available research does not detail specific safety information for [18F]-FEOBV in people with Down syndrome.

The trial's Phase 2 status indicates that earlier studies have already assessed its safety in humans. By this stage, treatments are usually considered safe enough for people, although researchers continue to monitor for any possible side effects. The scan itself is non-invasive, similar to other medical imaging tests, and is primarily used to study brain function. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about the [18F]-FEOBV PET scan for cognitive function in Down syndrome because it offers a new way to visualize brain activity using a radiotracer that targets the vesicular acetylcholine transporter. Unlike current methods that primarily focus on symptom management, this technique could provide deeper insights into the neurological changes in Down syndrome. By highlighting specific brain functions, it may help tailor more effective treatments in the future. Additionally, combining this scan with EEG recordings offers a comprehensive approach to understanding brain function, which is not available with standard imaging techniques.

What evidence suggests that this trial's treatments could be effective for cognitive function in Down Syndrome?

Research has shown that [18F]-FEOBV PET scans can detect changes in the brain's cholinergic system, crucial for memory and attention. Studies have found that reduced activity in this system, as seen in these scans, often correlates with memory and thinking problems in individuals with mild memory issues. In adults with Down syndrome participating in this trial, these scans revealed increased activity, suggesting changes in brain function that might relate to cognitive challenges. These findings indicate that the scan might help identify early signs of brain changes, which could be useful for developing future treatments to improve cognitive function. ^{1 6 7 8 9}

Who Is on the Research Team?

Paul A Newhouse, M.D.

Principal Investigator

Vanderbilt University Medical Center

Alexander C Conley, Ph.D.

Principal Investigator

Vanderbilt University Medical Center

Are You a Good Fit for This Trial?

Adults aged 18-55 with Down syndrome, including mosaic DS or partial trisomy 21, who are in good health without dementia and have a mental age of at least 4 years. Participants must not be pregnant, able to complete MRI and PET scans, and should not have significant medical conditions that could affect testing or contraindications for MRI.

Inclusion Criteria

My mental age is 4 years or older according to the Kaufman test.

I am a woman who can still have children and I have a negative pregnancy test.

English is my first language.

Exclusion Criteria

I haven't had cancer in the last 5 years, except for certain skin or early stage cancers.

I do not have a blood clotting disorder or abnormal bleeding, and I am not on strong blood thinners like warfarin.

I cannot undergo MRI and PET scans.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Biomarker Assessment

Assessment of cholinergic integrity using molecular, functional, and structural biomarkers including EEG, MRI, and PET scans

Approximately 3 years

Multiple visits for imaging and assessments

Follow-up

Participants are monitored for safety and effectiveness after biomarker assessments

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• [18F]-FEOBV PET Scan
• [18F]-FEOBV Radiotracer
• EEG recording
• Optional MRI Scan

Trial Overview The trial is studying the integrity of cholinergic neurons in adults with Down syndrome using [18F]-FEOBV Radiotracer. It aims to understand how these neurons' condition correlates with cognitive deficits related to aging and Alzheimer's Disease pathology.

How Is the Trial Designed?

Group I: Down Syndrome Experimental Treatment 1 Intervention

Adults between 18-55 with Down Syndrome.

Who Is Running the Clinical Trial?

Vanderbilt University Medical Center

Lead Sponsor

Trials

922

Recruited

939,000+

Vanderbilt Kennedy Center

Collaborator

Trials

3

Recruited

160+

Published Research Related to This Trial

A small dose of donepezil (2.5 mg daily) significantly improved cognitive function in patients with amnestic mild cognitive impairment (aMCI), as evidenced by better scores in memory IQ tests and the mini-mental state examination after 3 months of treatment.

Magnetic resonance spectroscopy (MRS) results suggest that donepezil may enhance memory by activating astrocytes and stabilizing neurons, despite no significant changes in certain metabolite ratios in the hippocampus.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[An interventional study on amnestic mild cognitive impairment with small dose donepezil]. Wang, LN., Wang, W., Zhang, XH., et al.[2018]

In a study of 118 non-demented adults with Down syndrome over 1.5 to 8 years, amyloid beta (Aβ) levels were linked to declines in cognitive performance across various domains, including episodic memory and executive functioning.

The Cued Recall Test was identified as a potential early indicator for the transition from preclinical to prodromal Alzheimer's disease, highlighting its importance in monitoring cognitive changes in this at-risk population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cognitive indicators of transition to preclinical and prodromal stages of Alzheimer's disease in Down syndrome. Hartley, SL., Handen, BL., Devenny, D., et al.[2022]

In a 12-week study involving 468 patients with mild to moderately severe Alzheimer disease, donepezil hydrochloride significantly improved cognitive function and clinical outcomes compared to placebo, with notable improvements in ADAS-cog and CIBIC plus scores.

Donepezil was well-tolerated, with a similar incidence of side effects compared to placebo, and did not show the hepatotoxic effects seen with other cholinesterase inhibitors, making it a safe option for treating Alzheimer's symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Donepezil improves cognition and global function in Alzheimer disease: a 15-week, double-blind, placebo-controlled study. Donepezil Study Group. Rogers, SL., Doody, RS., Mohs, RC., et al.[2022]

In a study involving 18 older adults (9 with mild cognitive impairment and 9 healthy controls), donepezil treatment led to increased frontal brain activity during cognitive tasks, which correlated with improved task performance and baseline hippocampal volume.

Short-term use of donepezil not only stabilized or improved cognitive function in patients with mild cognitive impairment but also highlighted the potential of functional MRI to monitor treatment effects and understand the mechanisms of cognition-enhancing medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cholinergic enhancement of frontal lobe activity in mild cognitive impairment. Saykin, AJ., Wishart, HA., Rabin, LA., et al.[2018]

In a study comparing brain activity among 17 middle-aged adults with Down syndrome (DS), 10 with moderate Alzheimer's disease (AD), and 24 controls, both DS and AD groups showed decreased brain glucose metabolism in the posterior cingulate compared to controls, indicating early signs of potential dementia.

Interestingly, individuals with DS exhibited higher glucose metabolism in the inferior temporal/entorhinal cortex compared to controls, suggesting a possible compensatory mechanism that may precede the onset of dementia, which could eventually lead to neurodegeneration as these compensatory responses fail.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temporal cortex hypermetabolism in Down syndrome prior to the onset of dementia. Haier, RJ., Alkire, MT., White, NS., et al.[2019]

In a 10-week study involving 129 children with Down syndrome, donepezil did not show significant benefits over placebo in improving cognitive function, as measured by the Vineland-II Adaptive Behavior Scales.

Despite the lack of efficacy, donepezil was well tolerated by participants, indicating it may be safe for use in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Donepezil for treatment of cognitive dysfunction in children with Down syndrome aged 10-17. Kishnani, PS., Heller, JH., Spiridigliozzi, GA., et al.[2020]

In a 24-week study involving 30 adults with Down syndrome and mild to moderate Alzheimer's disease, donepezil was found to be generally safe and well-tolerated, with no life-threatening side effects reported.

While the results showed some potential efficacy, with 50% of donepezil patients improving in dementia scores compared to 31% on placebo, the small sample size limited the statistical significance of these findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Down syndrome and Alzheimer's disease--pilot study. Prasher, VP., Huxley, A., Haque, MS.[2019]

Florbetapir PET imaging effectively detected high levels of fibrillar amyloid-β (Aβ) in a 55-year-old Down syndrome patient with Alzheimer disease, correlating well with post-mortem neuropathological findings, indicating its potential utility in diagnosing Aβ pathology in this population.

The study highlights that while florbetapir PET can identify significant Aβ burden in various brain regions, it may not detect all forms of amyloid pathology, such as diffuse plaques and amyloid angiopathy in the cerebellum, suggesting limitations in its diagnostic capabilities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Positron emission tomography and neuropathologic estimates of fibrillar amyloid-β in a patient with Down syndrome and Alzheimer disease. Sabbagh, MN., Fleisher, A., Chen, K., et al.[2021]

Donepezil is rapidly absorbed after oral administration, with most of the drug remaining unchanged in the brain, indicating that it effectively crosses the blood-brain barrier while its metabolites do not.

The drug is primarily excreted through feces, with extensive metabolism occurring in the body, but no significant accumulation of its metabolites in the brain or other tissues, suggesting a low risk of toxicity from these byproducts.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Absorption, distribution, metabolism, and excretion of donepezil (Aricept) after a single oral administration to Rat. Matsui, K., Mishima, M., Nagai, Y., et al.[2018]

Donepezil, a medication commonly used for Alzheimer's disease, shows potential for enhancing cognition in various conditions such as autism, ADHD, and traumatic brain injury, although human studies outside of Alzheimer's are limited.

Current research suggests that while donepezil may improve attention and memory, these cognitive functions are likely influenced by more than just the cholinergic system, indicating a need for further studies to explore its efficacy in autism specifically.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Relevance of donepezil in enhancing learning and memory in special populations: a review of the literature. Yoo, JH., Valdovinos, MG., Williams, DC.[2019]

In a study of 14 young patients with Down's syndrome, brain SPECT imaging revealed significant unilateral perfusion defects in the temporal-parietal-occipital region, indicating abnormal regional cerebral blood flow.

The patterns observed in these patients were similar to those typically seen in Alzheimer's disease, suggesting a potential link between Down's syndrome and Alzheimer's disease in terms of brain function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regional cerebral blood flow of Alzheimer's disease-like pattern in young patients with Down's syndrome detected by 99Tcm-HMPAO brain SPECT. Kao, CH., Wang, PY., Wang, SJ., et al.[2019]

The study used the PET tracer [18F]FEOBV to map the cholinergic system in the brains of 20 healthy elderly participants, revealing the highest binding in areas like the striatum and basal forebrain, which are crucial for cholinergic signaling.

The distribution of [18F]FEOBV correlated well with post-mortem histological data and gene expression levels of the VAChT coding gene, supporting its use as a reliable tool for in vivo imaging of cholinergic activity in the human brain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Distribution of cholinergic nerve terminals in the aged human brain measured with [18F]FEOBV PET and its correlation with histological data. Okkels, N., Horsager, J., Labrador-Espinosa, MA., et al.[2023]

In a study of 11 patients with Down's syndrome, brain CT scans revealed that enlargement of the suprasellar cistern is an early indicator of Alzheimer-type dementia, which was not observed in non-demented individuals with Down's syndrome.

The progression of brain atrophy was linked to the severity of dementia, with CT scans showing changes from the medial temporal lobe to the frontal lobe and generalized cerebral cortices, suggesting that measuring the suprasellar cistern size could aid in early diagnosis of dementia in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Correlative study of the brain CT and clinical features of patients with Down's syndrome in three clinical stages of Alzheimer type dementia]. Maruyama, K., Ikeda, S., Yanagisawa, N.[2016]

Citations

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Age-Related Changes in the Cholinergic System in Adults ... ... S. (2022). Reduced cortical cholinergic innervation measured using [18F]-FEOBV PET imaging correlates with cognitive decline in mild cognitive impairment.

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FEOBV PET imaging correlates with cognitive decline in ... Reduced cortical cholinergic innervation measured using [18F]-FEOBV PET imaging correlates with cognitive decline in mild cognitive impairment.

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[18F]-FEOBV PET Scan for Cognitive Function in Down ... Trial Overview The trial is studying the integrity of cholinergic neurons in adults with Down syndrome using [18F]-FEOBV Radiotracer. It aims to understand how ...

4. alz-journals.onlinelibrary.wiley.com alz-journals.onlinelibrary.wiley.com/doi/am-pdf/10.1002/alz.70134

Brain cholinergic terminal density utilizing [18F] We have recently demonstrated that non-demented adults with DS display increased [18F]-FEOBV uptake in a range of cortical and sub- cortical ...

5. researchgate.net researchgate.net/publication/359464365_Reduced_cortical_cholinergic_innervation_measured_using_18F-FEOBV_PET_imaging_correlates_with_cognitive_decline_in_mild_cognitive_impairment

FEOBV PET imaging correlates with cognitive decline in ... Reduced cortical cholinergic innervation measured using [18F]-FEOBV PET imaging correlates with cognitive decline in mild cognitive impairment. March 2022 ...

6. sciencedirect.com sciencedirect.com/science/article/pii/S019745802500020X

Differences in cholinergic terminal density in adults with ... [18F]-FEOBV uptake shows a steeper age-associated decline in adults with DS than controls. Abstract. Adults with Down syndrome are genetically predisposed to ...

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39574852/

Age-Related Changes in the Cholinergic System in Adults ... Adults with Down syndrome displayed significantly increased [18F]-fluoroethoxybenzovesamicol uptake in the cerebellum, brainstem, thalamus, and ...

8. researchgate.net researchgate.net/publication/385485540_Age-Related_Changes_in_the_Cholinergic_System_in_Adults_with_Down_Syndrome_Assessed_Using_18_F-Fluoroethoxybenzovesamicol_Positron_Emission_Tomography_Imaging

Age-Related Changes in the Cholinergic System in Adults ... Adults with Down syndrome displayed significantly increased [ ¹⁸ F]-fluoroethoxybenzovesamicol uptake in the cerebellum, brainstem, thalamus, ...

9. pubs.acs.org pubs.acs.org/doi/10.1021/acs.molpharmaceut.1c00961

No Dopamine Agonist Modulation of Brain [ 18 F]FEOBV ... We examined associations of regional brain [ 18 F]FEOBV PET binding in Parkinson's disease (PD) subjects without versus with dopamine D2-like receptor agonist ...