[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

20 Participants Needed

Trial Summary

What is the purpose of this trial?

Progressive age-related cognitive deficits occurring in both AD and DS have been connected to the degeneration of several neuronal populations, but mechanisms are not fully elucidated. The most consistent neuronal losses throughout the progression of AD are seen in cholinergic neurons where these losses negatively affect cognition, particularly in attention, learning, and memory formation. Evidence of reduced cholinergic integrity in DS is largely limited to animal models and post-mortem human data. The investigators propose to use molecular, functional, and structural biomarkers to assess the cholinergic integrity in adults with DS. The investigators anticipate using the data gathered in this pilot study to inform future study designs to determine AD risk stratification in DS by identifying individuals who show an accelerated decline in cholinergic integrity that correlates with cognitive and neurobehavioral changes. Also, our cholinergic biomarkers may identify whether individuals with DS are likely to respond to pro-cholinergic interventions, including the novel cholinergic modulators that are being developed to enhance cholinergic-sensitive cognitive functioning. The investigators anticipate using the data gathered here to inform future treatment studies in TRC-DS and beyond where novel cholinergic treatments may offer opportunities for early intervention in DS and be complementary to disease-modifying approaches such as anti-amyloid treatments.

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 data supports the idea that [18F]-FEOBV PET Scan for Cognitive Function in Down Syndrome is an effective treatment?

The available research shows that Donepezil Hydrochloride (Aricept), a drug related to the [18F]-FEOBV PET Scan, has been studied for its effects on cognitive function in individuals with Down syndrome. In a 10-week study, children with Down syndrome who took Donepezil showed improvements in adaptive behavior, communication, daily living skills, and socialization compared to those who took a placebo. This suggests that Donepezil, which is similar to the [18F]-FEOBV PET Scan in its purpose, can be effective in enhancing cognitive function in Down syndrome. However, specific data on the [18F]-FEOBV PET Scan itself is not provided in the available research. ^{1 2 3 4 5}

What safety data exists for the [18F]-FEOBV PET Scan and Donepezil in Down Syndrome treatment?

The safety of Donepezil Hydrochloride (Aricept) has been evaluated in several studies, including a 24-week, double-blind, placebo-controlled trial in Down syndrome patients with Alzheimer's disease, and a 15-week, double-blind, placebo-controlled study in Alzheimer's patients. These studies confirm its safety and efficacy in treating cognitive impairments. For [18F]-FEOBV, it is used as a PET tracer to study cholinergic nerve terminals in the brain, but specific safety data for Down syndrome patients is not detailed in the provided research. ^{1 2 6 7 8}

Is the [18F]-FEOBV PET Scan a promising treatment for cognitive function in Down syndrome?

The [18F]-FEOBV PET Scan is a promising treatment because it helps detect early brain changes linked to Alzheimer's disease in people with Down syndrome. This early detection can be crucial for managing and potentially slowing down cognitive decline. ^{9 10 11 12 13}

Research Team

Paul A Newhouse, M.D.

Principal Investigator

Vanderbilt University Medical Center

Alexander C Conley, Ph.D.

Principal Investigator

Vanderbilt University Medical Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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 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]

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]

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 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]

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]

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]

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 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]

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]

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]

References

1. England 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. [2019]

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

Cholinergic enhancement of frontal lobe activity in mild cognitive impairment. [2018]

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

Relevance of donepezil in enhancing learning and memory in special populations: a review of the literature. [2019]

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

Donepezil for treatment of cognitive dysfunction in children with Down syndrome aged 10-17. [2020]

5. China pubmed.ncbi.nlm.nih.gov

[An interventional study on amnestic mild cognitive impairment with small dose donepezil]. [2018]

6. United States 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. [2023]

7. United States 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. [2022]

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

Absorption, distribution, metabolism, and excretion of donepezil (Aricept) after a single oral administration to Rat. [2018]

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

Positron emission tomography and neuropathologic estimates of fibrillar amyloid-β in a patient with Down syndrome and Alzheimer disease. [2021]

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

Temporal cortex hypermetabolism in Down syndrome prior to the onset of dementia. [2019]

11. Japan 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]. [2016]

12. England 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. [2019]

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

Cognitive indicators of transition to preclinical and prodromal stages of Alzheimer's disease in Down syndrome. [2022]