Dementia, Hippocampal Overactivity
Conditions
Brief summary
This randomized, crossover, placebo controlled clinical study will assess the efficacy and safety of a slow release form of levetiracetam (AGB101) in the treatment of cognitively normal adults by measuring change in several imaging measures over the course of a two week treatment period.
Detailed description
In clinical studies, the magnitude of hippocampal over-activity longitudinally predicts subsequent cognitive decline/conversion to dementia, and hippocampal over-activity in subjects with mild cognitive impairment (MCI) due to Alzheimer's disease (AD) is significantly correlated with the extent of neuronal injury affecting AD-specific regions of the brain. A previous study reported a significant correlation between greater hippocampal activation (fMRI) and more pronounced medial temporal lobe (MTL) atrophy (cortical thinning) indicative of AD-related neurodegeneration in subjects with MCI due to AD with a Clinical Dementia Rating (CDR) score of 0.5 selected by Alzheimer's Disease Neuroimaging Initiative (ADNI)-1 criteria. This supports a therapeutic rationale to reduce over-activity in order to slow or prevent neuronal injury. Modest hippocampal over-activity has also been observed in preclinical (asymptomatic) conditions in older adults. In previous studies, older adults showed increased hippocampal activation compared to young adults in the context of cognitive performance within the normal range for the participant's age. These findings suggest that hippocampal over-activity may be an opportunity for early intervention examining whether treatment of hippocampal over-activity early in the progression confers benefit to older adults at risk for AD dementia. The current study aims to test this hypothesis in cognitively normal subjects between the ages of 50 and 80.
Interventions
DRUGAGB101
low-dose levetiracetam, 220 mg, extended release tablet
DRUGPlacebo
placebo capsule
Sponsors
Johns Hopkins University
AgeneBio
National Institute on Aging (NIA)
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
50 Years to 80 Years
Healthy volunteers
Yes
Inclusion criteria
Subjects must meet all of the following inclusion criteria at screening: 1. Subjects between 50 and 80 years old (inclusive) in good general health: 1. Willing and able to consent and participate for the duration of the study. 2. Have eighth-grade education or good work history sufficient to exclude mental retardation. 3. Have visual and auditory acuity adequate for neuropsychological testing. 4. Have proficient fluency of the native local language to participate in all the neuropsychological test assessments. 2. Have a study partner who has sufficient contact (≥ 2 hours per week) with the subject and can provide assessments of any changes and an independent evaluation of the subject's functioning. 3. Have normal cognition as defined by the following criteria: 1. Mini-Mental State Examination (MMSE) scores between 27 and 30 (inclusive; exceptions may be made for subjects with \< 12 years of education at the discretion of the investigator) 2. No memory complaint reported by the subject or his/her study partner. 3. Evidence of normal memory function documented by a normal score on the Buschke Selective Reminding Test Immediate and Delayed Recall or equivalent test. 4. A Clinical Dementia Rating Scale (CDR) global score of 0 with a memory box score of 0. 4. Antidepressants must be at a stable dose for 1 month prior to screening and expected to remain stable throughout the study. 5. Willing and able to undergo repeated MRI scans (3 Tesla) with no contraindications to MRI. 6. Willing to allow collection of blood for apolipoprotein E (ApoE) genotyping and banking. 7. If female participant or partner/spouse is of childbearing age, participant and/or partner must be willing to use an effective contraception for duration of the study and for 4 days after it. For women, effective contraception may be hormonal; for men, a condom.
Exclusion criteria
* Subjects must not meet any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in hippocampal overactivity as measured by fMRI (functional Magnetic Resonance Imaging) | Week 2, Week 8 | The primary efficacy evaluation is confirmation of target engagement demonstrated by reduction in hippocampal overactivity comparing the end of the active treatment period compared to the end of the placebo treatment condition as measured by task-based functional magnetic resonance imaging. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in functional connectivity measures as measured by fMRI (functional Magnetic Resonance Imaging) | Week 2, Week 8 | Functional connectivity measures comparing the end of the active treatment period to the end of the placebo treatment condition as measured by resting state fMRI (functional Magnetic Resonance Imaging). |
Countries
United States
Contacts
STUDY_DIRECTORArnold Bakker, Ph.D.
Johns Hopkins University
PRINCIPAL_INVESTIGATORMarilyn Albert, PhD
Johns Hopkins University
Outcome results
None listed