Mild Cognitive Impairment (MCI)
Conditions
Keywords
Mild Cognitive Impairment, Amnestic Mild Cognitive Impairment, Functional Magnetic Resonance Imaging, Levetiracetam, Keppra, Medial Temporal Lobe, Memory Impairment, Alzheimer's Disease, AD
Brief summary
This research is being done to find out if daily use of the drug levetiracetam can improve memory function in individuals with memory problems like those associated with Mild Cognitive Impairment (MCI) and Alzheimer's disease (AD).
Detailed description
Increasing research is focused on conditions that precede the clinical diagnosis of Alzheimer's disease (AD) in order to detect patients at risk for early intervention. One such condition is mild cognitive impairment (MCI). Functional magnetic resonance imaging (fMRI) studies in this group of patients have reported increased activation in the Medial Temporal Lobe (MTL) during performance of memory tasks. The functional significance of increased activation is unclear. One possibility is that greater activity reflects the increased effort needed in order to maintain performance, and as such would be a compensatory response. An alternative possibility is that increased activation reflects aberrant physiology related to the disease process itself and as such would be a sign of greater underlying disease severity and would interfere with brain function. Data in animal models suggest the possibility that low dose levetiracetam (well-tolerated anti-convulsant) treatment may reduce the observed hyperactivity and improve memory performance among individuals with MCI. The investigators are therefore conducting a within-subjects trial of 8 weeks duration, involving 144 subjects and low dose treatment with levetiracetam. During the course of the study, each subject may receive both drug and placebo for two weeks, with the order of administering those treatments counterbalanced. Cognitive testing and fMRI imaging will be obtained after 2-weeks on drug/placebo. The overall goal of the study is to determine if treatment of MCI subjects with low dose levetiracetam reduces hyperactivity within the MTL and improves memory performance.
Interventions
DRUGLevetiracetam 62.5mg
62.5mg twice daily (2 weeks)
DRUGLevetiracetam 125mg
125mg twice daily (2 weeks)
250mg twice daily (2 weeks)
DRUGPlacebo
placebo capsule twice daily (2 weeks)
Sponsors
National Institute on Aging (NIA)
Johns Hopkins University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
50 Years to 85 Years
Healthy volunteers
Yes
Inclusion criteria
* All: English as a first language; right handed; able to complete written informed consent. * MCI subjects: In addition to above, must meet criteria for amnestic Mild Cognitive Impairment (MCI). This includes a memory complaint corroborated by an informant; impaired memory function for age and educational level; preserved general cognitive function; intact abilities of daily living; no clinical dementia. * Age matched Controls: Must have memory and cognitive status that is normal for their age.
Exclusion criteria
* Familial Alzheimer's Disease (AD) due to known genetic mutations * AD with Parkinsonian features; major psychiatric or behavioral disorders (e.g. depression, agitation, psychosis, manic-depressive disorder) * Primary or metastatic intracranial neoplasm * History of severe head trauma * Intra-cerebral hemorrhage * Seizure disorder * Hemispheric stroke * Presence of a progressive central nervous system disease * Presence of lacunar infarcts * Medical contraindications to MRI including cardiac pacemaker, presence of intraocular or intracranial metallic objects * Any known allergy to levetiracetam or behavioral problems that are a contraindication to taking Levetiracetam (e.g. agitation) * Prescribed use of anti-seizure medications.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Brain Activity in the Dentate Gyrus / CA3 Subregion of the Hippocampus Measured With Blood Oxygenation Level Dependent (BOLD) Functional MRI | 2 weeks | Measurement of average brain activity in the dentate gyrus / CA3 subregion of the hippocampus measured with BOLD functional MRI in patients with mild cognitive impairment on placebo and on drug compared to average brain activity in this brain area in control subjects. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Behavioral Performance as Assessed in the Functional Magnetic Resonance Imaging (fMRI) Memory Task | 2 weeks | Mnemonic similarity task which assesses long term memory function. Scale ranges from 0-100 with higher scores indicating better memory performance. |
Countries
United States
Participant flow
Pre-assignment details
Data for the 125mg BID treatment cohort was collected first. Analysis showed no effects of treatment order. As a result, data was collapsed and analyzed irrespective of order across all doses. All subsequent data analyses are thus provided collapsed across treatment orders in all reporting on this study, including the results reported here.
Participants by arm
| Arm | Count |
|---|---|
| aMCI_62.5mg Drug First, Then Placebo Amnestic MCI:
62.5mg levetiracetam twice daily (two weeks), washout (4 weeks), and placebo capsule twice daily (two weeks) | 8 |
| aMCI_Placebo First, Then 62.5mg Drug Amnestic MCI:
Placebo capsule twice daily (two weeks), washout (4 weeks), and 62.5mg levetiracetam twice daily (two weeks) | 12 |
| aMCI_125mg Drug First, Then Placebo Amnestic MCI:
125mg levetiracetam twice daily (two weeks), washout (4 weeks), and placebo capsule twice daily (two weeks) | 7 |
| aMCI_Placebo First, Then 125mg Drug Amnestic MCI:
Placebo capsule twice daily (two weeks), washout (4 weeks), and 125mg levetiracetam twice daily (two weeks) | 10 |
| aMCI_250mg Drug First, Then Placebo Amnestic MCI:
250mg levetiracetam twice daily (two weeks), washout (4 weeks), and placebo capsule twice daily (two weeks) | 9 |
| aMCI_Placebo First, Then 250mg Drug Amnestic MCI:
Placebo capsule twice daily (two weeks), washout (4 weeks), and 250mg levetiracetam twice daily (two weeks) | 8 |
| Control_Placebo First, Then Placebo Healthy control
placebo capsule twice daily (two weeks), washout (4 weeks), and placebo capsule twice daily (two weeks) | 17 |
| Total | 71 |
Baseline characteristics
| Characteristic | aMCI_62.5mg Drug First, Then Placebo | aMCI_Placebo First, Then 62.5mg Drug | aMCI_125mg Drug First, Then Placebo | aMCI_Placebo First, Then 125mg Drug | aMCI_250mg Drug First, Then Placebo | aMCI_Placebo First, Then 250mg Drug | Control_Placebo First, Then Placebo | Total |
|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 8 Participants | 10 Participants | 5 Participants | 10 Participants | 8 Participants | 7 Participants | 16 Participants | 64 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 2 Participants | 2 Participants | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 7 Participants |
| Region of Enrollment United States | 8 participants | 12 participants | 7 participants | 10 participants | 9 participants | 8 participants | 17 participants | 71 participants |
| Sex: Female, Male Female | 5 Participants | 6 Participants | 6 Participants | 5 Participants | 5 Participants | 6 Participants | 8 Participants | 41 Participants |
| Sex: Female, Male Male | 3 Participants | 6 Participants | 1 Participants | 5 Participants | 4 Participants | 2 Participants | 9 Participants | 30 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 24 | 0 / 24 | 0 / 23 | 0 / 23 | 0 / 22 | 0 / 22 | 0 / 27 |
| other Total, other adverse events | 5 / 24 | 0 / 24 | 3 / 23 | 0 / 23 | 5 / 22 | 7 / 22 | 3 / 27 |
| serious Total, serious adverse events | 0 / 24 | 0 / 24 | 0 / 23 | 0 / 23 | 0 / 22 | 0 / 22 | 0 / 27 |
Outcome results
Primary
Brain Activity in the Dentate Gyrus / CA3 Subregion of the Hippocampus Measured With Blood Oxygenation Level Dependent (BOLD) Functional MRI
Measurement of average brain activity in the dentate gyrus / CA3 subregion of the hippocampus measured with BOLD functional MRI in patients with mild cognitive impairment on placebo and on drug compared to average brain activity in this brain area in control subjects.
Time frame: 2 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| aMCI_62.5 | Brain Activity in the Dentate Gyrus / CA3 Subregion of the Hippocampus Measured With Blood Oxygenation Level Dependent (BOLD) Functional MRI | -0.1203 mean beta coefficient | Standard Error 0.3475 |
| aMCI_62.5 Placebo | Brain Activity in the Dentate Gyrus / CA3 Subregion of the Hippocampus Measured With Blood Oxygenation Level Dependent (BOLD) Functional MRI | 0.4353 mean beta coefficient | Standard Error 0.2215 |
| aMCI_125 | Brain Activity in the Dentate Gyrus / CA3 Subregion of the Hippocampus Measured With Blood Oxygenation Level Dependent (BOLD) Functional MRI | -0.2238 mean beta coefficient | Standard Error 0.1747 |
| aMCI_125 Placebo | Brain Activity in the Dentate Gyrus / CA3 Subregion of the Hippocampus Measured With Blood Oxygenation Level Dependent (BOLD) Functional MRI | 0.8814 mean beta coefficient | Standard Error 0.3798 |
| aMCI_250 | Brain Activity in the Dentate Gyrus / CA3 Subregion of the Hippocampus Measured With Blood Oxygenation Level Dependent (BOLD) Functional MRI | 0.3928 mean beta coefficient | Standard Error 0.2366 |
| aMCI_250 Placebo | Brain Activity in the Dentate Gyrus / CA3 Subregion of the Hippocampus Measured With Blood Oxygenation Level Dependent (BOLD) Functional MRI | 0.4825 mean beta coefficient | Standard Error 0.1954 |
| Age Matched Control | Brain Activity in the Dentate Gyrus / CA3 Subregion of the Hippocampus Measured With Blood Oxygenation Level Dependent (BOLD) Functional MRI | -.02507 mean beta coefficient | Standard Error 0.2238 |
Secondary
Behavioral Performance as Assessed in the Functional Magnetic Resonance Imaging (fMRI) Memory Task
Mnemonic similarity task which assesses long term memory function. Scale ranges from 0-100 with higher scores indicating better memory performance.
Time frame: 2 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| aMCI_62.5 | Behavioral Performance as Assessed in the Functional Magnetic Resonance Imaging (fMRI) Memory Task | 38 percent correct recalled | Standard Error 4 |
| aMCI_62.5 Placebo | Behavioral Performance as Assessed in the Functional Magnetic Resonance Imaging (fMRI) Memory Task | 33 percent correct recalled | Standard Error 5 |
| aMCI_125 | Behavioral Performance as Assessed in the Functional Magnetic Resonance Imaging (fMRI) Memory Task | 33 percent correct recalled | Standard Error 5 |
| aMCI_125 Placebo | Behavioral Performance as Assessed in the Functional Magnetic Resonance Imaging (fMRI) Memory Task | 28 percent correct recalled | Standard Error 4 |
| aMCI_250 | Behavioral Performance as Assessed in the Functional Magnetic Resonance Imaging (fMRI) Memory Task | 34 percent correct recalled | Standard Error 4 |
| aMCI_250 Placebo | Behavioral Performance as Assessed in the Functional Magnetic Resonance Imaging (fMRI) Memory Task | 31 percent correct recalled | Standard Error 3 |
| Age Matched Control | Behavioral Performance as Assessed in the Functional Magnetic Resonance Imaging (fMRI) Memory Task | 44 percent correct recalled | Standard Error 4 |