Alzheimer's Disease
Conditions
Keywords
Alzheimer's disease, AD, Early-onset AD, EOAD, Early-onset Alzheimer's, Early-onset Alzheimer's disease
Brief summary
Patients with Alzheimer's disease (AD) can have seizures in addition to losing their memory and other mental functions (referred to as cognitive functions). The seizures, and other examples of overactive electrical activity in the brain that is not noticeable, contribute to the loss of cognitive function. Studies in animal models of AD suggest that a drug that prevents seizures called levetiracetam may reduce neuronal over-excitation and improve cognition. Based on this evidence, the investigators propose to determine if levetiracetam can be used to treat patients with AD. The investigators developed novel instruments for this population that will also be used in future large-scale clinical trials. The current study will last for 12 weeks and will involve people with AD. Participants will be initially examined with an overnight brain wave study to assess for silent epileptic (seizure-like) activity. Presence of epileptic activity on the screening exam is not required to enter the trial. Participants will then be assigned to groups in a randomized manner. One group will receive levetiracetam for 4 weeks, then no drug for 4 weeks, and then placebo for 4 weeks. For another group, the order of treatments will be reversed. The cognitive abilities of participants will be retested every 4 weeks and compared to those at the beginning. The cognitive tests include a virtual-reality navigation test of memory and computerized tests of mental flexibility and problem solving. The participants will be monitored with a magnetoencephalogram (MEG) with simultaneous EEG (M/EEG) at each visit. M/EEG is a highly effective non-invasive method for identifying brain regions of epileptic activity. The investigators will need to recruit 36 randomized participants to test the study hypotheses. This study will take place at the University of California, San Francisco (UCSF) and the University of Minnesota.
Detailed description
For a more detailed explanation of the study and what our results were, please read our publication at https://jamanetwork.com/journals/jamaneurology/fullarticle/2784539
Interventions
DRUGlevetiracetam
Sponsors
University of Minnesota
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
45 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
To be included in the trial all of the following inclusion criteria must be met: Ability to obtain written informed consent from the patient or caregiver as a surrogate; Meets National Institute on Aging-Alzheimer's Association Workgroups criteria for probable AD dementia (McKhann et al. 2011); Age ≤ 80 years at time of screening; Willing and able caregiver who has daily contact with the subject; Mini-Mental State Examination (MMSE) score ≥ 18 and/or Clinical Dementia Rating (CDR) \< 2 at the initial screening assessment; Subjects and caregivers must be able to comply with prescribed regime of study treatment throughout the course of the study, and meet the required time commitment of four days of in-person visits; Any concurrent treatment for AD approved by the Food and Drug Administration (FDA), such as donepezil, galantamine, or rivastigmine, and memantine, must be stable for at least 30 days prior to screening and at least 60 days prior to study day 1. Other medications (except those listed under
Exclusion criteria
) are allowed as long as the dose is stable for 30 days prior to screening. The following criteria are considered grounds for exclusion: Any conditions which could account for cognitive deficits in addition to AD, including but not limited to Vitamin B12 or folate deficiency, abnormal thyroid function, posttraumatic conditions, syphilis, multiple sclerosis or another neuroinflammatory disorder, Parkinson's disease, vascular or multi-infarct dementia, Huntington's disease, normal pressure hydrocephalus, central nervous system (CNS) tumor, progressive supranuclear palsy, subdural hematoma, etc.; Previous history of a seizure disorder, excepting cases where the first seizure or detection of epileptiform activity was within 5 years of screening and the patient is not prescribed an anticonvulsant; Significant systemic medical illnesses; Use of medications likely to affect CNS functions (e.g., benzodiazepines, narcotics); Severe renal dysfunction with creatine clearance \< 30 ml/min, which would affect serum LEV levels; Participation in another AD clinical trial within 3 months of Screening, or any AD clinical trial, such as a vaccine, that has potential long-term effects; Treatment with another study drug or investigational drug within 30 days of Screening; Pregnant or lactating; Any other medical condition which is determined by the investigators to potentially create an undue risk for an adverse effect; Biomarker evidence unsupportive of a diagnosis of AD.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Executive Function as Measured by the NIH EXAMINER Computer Battery | Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment) | Changes in executive function were measured using the NIH EXAMINER, a 1-hour computer-based battery of various executive function tasks. The subject's performance after the study treatment will be compared with results from a baseline assessment done before the study treatment, using statistical tests to assess whether there was any significant change. The Examiner assessment consists of the following scales: antisaccade , set shifting , flanker task, dot counting, spatial 1-back, category fluency, and letter fluency. Scores for this task have an indefinite range. Higher scores however do indicate better performance. Scores for this scale were generated using item response theory. For this study, scores with SEs greater than 0.55 were classified as unreliable and excluded from analysis. Composite scores from 2 participants were excluded on this basis.The EXAMINER ranges for the participants in the study were -2.59 to 1.33. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes in ADAS-cog | Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment) | Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-cog) - The ADAS-cog rating instrument (Rosen et al. 1984) will be used to evaluate the global cognitive functioning. The ADAS-cog is a 70-point scale that includes an assessment of verbal memory, language, orientation, reasoning, and praxis.The score is derived from adding point values from each of its subsections. The higher your score on the ADAS-cog, the better you do. |
| Clinical Dementia Rating Sum of Boxes (CDR-SOB) | Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment) | Clinical Dementia Rating Sum of Boxes (CDR-SOB) - The CDR will be used as a global measure of dementia severity (Morris 1993). The CDR consists of questions addressed to the caregiver/informant. The lowest score one can receive is a 0 and the highest is a 3. Score is measured by getting the mean of the individual scores in each category. Lower scores equate to less dementia severity. |
| Changes in Behavior and Level of Disability - ADCS-ADL | Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment) | Alzheimer's Disease Cooperative Study Activities of Daily Living Scale (ADCS-ADL) - The ADCS-ADL rating instrument (Galasko et al. 1997) will be used to evaluate functional capacity. The ADCS-ADL is a caregiver rated questionnaire. Scores on the 24-item ADCS-ADL range from 0 to 78. A higher score indicates less severity while a lower score indicates greater severity. |
| Changes in Stroop Interference Naming | Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment) | Stroop Test - The Stroop Test (Stroop 1935) will be used to assess executive functions including selective attention, cognitive flexibility and processing speed. Subtasks include Stroop color naming and Stroop interference naming, and each subtask is restricted to 1 minute. The minimum score is 0 and the maximum score is 126. The higher the score the better a participant does. |
| Changes in Behavior and Level of Disability - Neuropsychiatric Inventory (NPI) | Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment) | Neuropsychiatric Inventory (NPI) - The NPI (Cummings et al. 1994) will be used to evaluate the severity of behavioral symptoms. The severity scale has scores ranging from 1 to 3 points (1=mild; 2=moderate; and 3=severe) and the scale for assessing caregiver distress has scores ranging from 0 to 5 points (0=no distress; 1=minimal distress; 2=mild distress; 3=moderate distress; 4=severe distress; and 5=extreme distress). |
| Changes in Epileptiform Events | Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment) | Epileptiform activity will be measured using a 1-hr resting magnetoencephalogram/electroencephalogram (M/EEG). M/EEG can detect abnormal epileptiform findings called spikes. The M/EEG will be read by an epileptologist with specialized training to assess whether there are any spikes. If spikes are observed during the M/EEG they will be counted to determine their frequency (e.g., 5 spikes per 1 hour recording). The frequency of spikes will then be compared to baseline values from before beginning the study treatment, using statistical tests to determine if the frequency changed with treatment. |
| Changes in Behavior and Level of Disability - ADCS-CGIC | Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment) | ADCS-Clinical Global Impression of Change (ADCS-CGIC) - The ADCS-CGIC is a seven-point scale that gives a global rating of change from baseline (Schneider et al. 1997). The baseline and follow up assessments are based on interviews with the subject and the informant. The ADCS-CGIC is a clinician-rated measure of: global severity at baseline scored from 1 (normal, not at all ill) to 7 (among the most extremely ill patients); and global change at follow-up scored from 1 (marked improvement) to 7 (marked worsening), where 4 indicates no change. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Stroop Interference in AD With Epileptiform Activity | Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment) | Stroop Test - The Stroop Test (Stroop 1935) will be used to assess executive functions including selective attention, cognitive flexibility and processing speed. Subtasks include Stroop color naming and Stroop interference naming, and each subtask is restricted to 1 minute. The minimum score is 0 and the maximum score is 126. The higher the score the better a participant does. The mean below represents the average change in score between the timepoints for all participants. |
| MEG Functional Connectivity Measures | Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment) | Whole-brain alpha-band functional connectivity will be derived from MEG-imaging (MEG-I) using the 60-second artifact-free recording epoch that is selected for the MEG spectral analysis. MEG-I uses MEG sensor data with millisecond precision and applies source reconstruction algorithms to overlay cortical oscillatory activity onto structural brain images. Source-space MEG-I reconstructions and functional connectivity metrics will be computed with the NUTMEG software suite (http://nutmeg.berkeley.edu). The investigators will compute imaginary coherence, which is a reliable metric for functional connectivity with MEG reconstruction. Functional connectivity will measure the strength of coherence between a given region and the rest of the brain. The investigators will perform an unbiased search for MEG-I functional connectivity deficits that correlate with specific cognitive, behavioral, and functional deficits. Hinkley et al. 2011 provides details of the methodology. |
| ADAS-cog in AD With Epileptiform Activity | Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment) | Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-cog) - The ADAS-cog rating instrument (Rosen et al. 1984) will be used to evaluate the global cognitive functioning. The ADAS-cog is a 70-point scale that includes an assessment of verbal memory, language, orientation, reasoning, and praxis.The score is derived from adding point values from each of its subsections. The higher your score on the ADAS-cog, the better you do. |
| Changes in Cognitive Function as Measured by a Virtual Route Learning Test | Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment) | A 20-minute computer-based virtual navigation test will be used to assess how well a subject can navigate a virtual community to reach a goal destination. The subjects will then be measured on their ability to accurately navigate the virtual community after a period of a few hours. The subject's performance after the study treatment will be compared with results from a baseline assessment done before the study treatment, using statistical tests to assess whether there was any significant change. |
| Standardized Assessments of Clinical Fluctuations -The Clinician Assessment of Fluctuation | Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment) | Two standardized methods will be used to quantitate fluctuations of dementia symptoms: The Clinician Assessment of Fluctuation and the One Day Fluctuation Assessment Scale (Walker et al. 2000). : The Clinician Assessment of Fluctuation (score range,0-12 points, with higher scores indicating more fluctuations),26 the One Day Fluctuation Assessment Scale (score range,0-21 points, with higher scores indicatingmore fluctuations). |
| Blood Serum Prolactin Level | Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment) | Blood samples intended for Quest Diagnostics LEV and prolactin serum levels (one 6 mL tube) will be processed in the following manner, as outlined in the Quest Diagnostics lab manual. The whole blood will be allowed to clot for 60 minutes and centrifuged at 2200 - 2500 revolutions per minute (RPM) for at least 15 minutes. The resulting serum will be split into 2 cryovials which will be stored at -20°C and immediately shipped for external assessment of LEV and prolactin levels. Prolactin will be assessed via immunoassay. The concentration of LEV in serum will be measured using validated liquid chromatography/tandem mass spectrometry (LC/MS-MS) methods. |
| NIH EXAMINER in AD With Epileptiform Activity | Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment) | Changes in executive function will be measured using the NIH EXAMINER, a 1-hour computer-based battery of various executive function tasks. The subject's performance after the study treatment will be compared with results from a baseline assessment done before the study treatment, using statistical tests to assess whether there was any significant change. The Examiner assessment consists of the following scales: NIH EXAMINER - antisaccade , NIH EXAMINER - set shifting , NIH EXAMINER - flanker task, NIH EXAMINER - dot counting, NIH EXAMINER - spatial 1-back, NIH EXAMINER - category fluency, and NIH EXAMINER - letter fluency. Scores for this task have an indefinite range. Higher scores however do indicate better performance. Scores for this scale were generated using item response theory (Kramer et al. J Int Neuropsychol Soc. 2014;20(1):11-19. doi:10.1017/S1355617713001094). |
| Standardized Assessments of Clinical Fluctuations - One Day Fluctuation Assessment Scale | Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment) | The One Day Fluctuation Assessment Scale will be used to quantitate fluctuations of dementia symptoms (Walker et al. 2000). The One Day Fluctuation Assessment Scale has a score range of 0-21 points,with higher scores indicatingmore fluctuations. |
| MEG Power Spectrum Measures | Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment) | The power spectral density for different frequency bands will be measured via resting-state magnetoencephalography (MEG). A 60-second artifact-free recording segment from the first 10 minutes of recording (prior to sleep onset) will be manually selected for analysis. In participants who are able to complete additional tests, the investigators will measure dynamics of neural responses during cognitive tasks such as speech preparation and execution. |
Countries
United States
Participant flow
Recruitment details
Recruitment began on October 16,2014. Participants were recruited at the University of California, San Francisco, and the University of Minnesota, Twin Cities.
Pre-assignment details
Participants were excluded if they were older than 80, had no diagnosis of probable AD, had a Mini-Mental State Examination score lower than 18 points or a Clinical Dementia Rating (CDR) score higher than 2 points. Patients receiving antiseizure drugs for any reason were excluded.
Participants by arm
| Arm | Count |
|---|---|
| Levetiracetam-Placebo This group receives levetiracetam for 4 weeks twice daily, then has a break where no treatment is given for 4 weeks, and then receives placebo for 4 weeks.
levetiracetam | 17 |
| Placebo-Levetiracetam This group receives placebo for 4 weeks twice daily, then has a break where no treatment is given for 4 weeks, and then receives levetiracetam for 4 weeks.
levetiracetam | 17 |
| Total | 34 |
Baseline characteristics
| Characteristic | Levetiracetam-Placebo | Placebo-Levetiracetam | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 17 Participants | 17 Participants | 34 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 17 Participants | 16 Participants | 33 Participants |
| Region of Enrollment United States | 17 participants | 17 participants | 34 participants |
| Sex: Female, Male Female | 12 Participants | 9 Participants | 21 Participants |
| Sex: Female, Male Male | 5 Participants | 8 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 34 | 0 / 34 |
| other Total, other adverse events | 7 / 34 | 5 / 34 |
| serious Total, serious adverse events | 0 / 34 | 0 / 34 |
Outcome results
Primary
Changes in Executive Function as Measured by the NIH EXAMINER Computer Battery
Changes in executive function were measured using the NIH EXAMINER, a 1-hour computer-based battery of various executive function tasks. The subject's performance after the study treatment will be compared with results from a baseline assessment done before the study treatment, using statistical tests to assess whether there was any significant change. The Examiner assessment consists of the following scales: antisaccade , set shifting , flanker task, dot counting, spatial 1-back, category fluency, and letter fluency. Scores for this task have an indefinite range. Higher scores however do indicate better performance. Scores for this scale were generated using item response theory. For this study, scores with SEs greater than 0.55 were classified as unreliable and excluded from analysis. Composite scores from 2 participants were excluded on this basis.The EXAMINER ranges for the participants in the study were -2.59 to 1.33.
Time frame: Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Levetiracetam | Changes in Executive Function as Measured by the NIH EXAMINER Computer Battery | -0.06 score on a scale |
| Placebo | Changes in Executive Function as Measured by the NIH EXAMINER Computer Battery | -0.14 score on a scale |
p-value: 0.5595% CI: [-0.18, 0.32]ANOVA
Secondary
Changes in ADAS-cog
Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-cog) - The ADAS-cog rating instrument (Rosen et al. 1984) will be used to evaluate the global cognitive functioning. The ADAS-cog is a 70-point scale that includes an assessment of verbal memory, language, orientation, reasoning, and praxis.The score is derived from adding point values from each of its subsections. The higher your score on the ADAS-cog, the better you do.
Time frame: Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment)
Population: 24 participants in this study did the ADAS-cog at both baseline and treatment.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Levetiracetam | Changes in ADAS-cog | -0.2 score on a scale |
| Placebo | Changes in ADAS-cog | 0.8 score on a scale |
p-value: 0.4395% CI: [-3.4, 1.5]ANOVA
Secondary
Changes in Behavior and Level of Disability - ADCS-ADL
Alzheimer's Disease Cooperative Study Activities of Daily Living Scale (ADCS-ADL) - The ADCS-ADL rating instrument (Galasko et al. 1997) will be used to evaluate functional capacity. The ADCS-ADL is a caregiver rated questionnaire. Scores on the 24-item ADCS-ADL range from 0 to 78. A higher score indicates less severity while a lower score indicates greater severity.
Time frame: Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Levetiracetam | Changes in Behavior and Level of Disability - ADCS-ADL | 0.4 score on a scale |
| Placebo | Changes in Behavior and Level of Disability - ADCS-ADL | 0.3 score on a scale |
p-value: 0.995% CI: [-1.1, 1.3]ANOVA
Secondary
Changes in Behavior and Level of Disability - ADCS-CGIC
ADCS-Clinical Global Impression of Change (ADCS-CGIC) - The ADCS-CGIC is a seven-point scale that gives a global rating of change from baseline (Schneider et al. 1997). The baseline and follow up assessments are based on interviews with the subject and the informant. The ADCS-CGIC is a clinician-rated measure of: global severity at baseline scored from 1 (normal, not at all ill) to 7 (among the most extremely ill patients); and global change at follow-up scored from 1 (marked improvement) to 7 (marked worsening), where 4 indicates no change.
Time frame: Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Levetiracetam | Changes in Behavior and Level of Disability - ADCS-CGIC | 4.0 score on a scale |
| Placebo | Changes in Behavior and Level of Disability - ADCS-CGIC | 4.0 score on a scale |
p-value: 0.895% CI: [-0.3, 0.3]ANOVA
Secondary
Changes in Behavior and Level of Disability - Neuropsychiatric Inventory (NPI)
Neuropsychiatric Inventory (NPI) - The NPI (Cummings et al. 1994) will be used to evaluate the severity of behavioral symptoms. The severity scale has scores ranging from 1 to 3 points (1=mild; 2=moderate; and 3=severe) and the scale for assessing caregiver distress has scores ranging from 0 to 5 points (0=no distress; 1=minimal distress; 2=mild distress; 3=moderate distress; 4=severe distress; and 5=extreme distress).
Time frame: Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Levetiracetam | Changes in Behavior and Level of Disability - Neuropsychiatric Inventory (NPI) | -0.8 score on a scale |
| Placebo | Changes in Behavior and Level of Disability - Neuropsychiatric Inventory (NPI) | 0.2 score on a scale |
p-value: 0.4695% CI: [-3.6, 1.7]ANOVA
Secondary
Changes in Epileptiform Events
Epileptiform activity will be measured using a 1-hr resting magnetoencephalogram/electroencephalogram (M/EEG). M/EEG can detect abnormal epileptiform findings called spikes. The M/EEG will be read by an epileptologist with specialized training to assess whether there are any spikes. If spikes are observed during the M/EEG they will be counted to determine their frequency (e.g., 5 spikes per 1 hour recording). The frequency of spikes will then be compared to baseline values from before beginning the study treatment, using statistical tests to determine if the frequency changed with treatment.
Time frame: Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Levetiracetam | Changes in Epileptiform Events | -0.1 Epileptiform events |
| Placebo | Changes in Epileptiform Events | -0.2 Epileptiform events |
p-value: 0.495% CI: [-0.9, 1.1]ANOVA
Secondary
Changes in Stroop Interference Naming
Stroop Test - The Stroop Test (Stroop 1935) will be used to assess executive functions including selective attention, cognitive flexibility and processing speed. Subtasks include Stroop color naming and Stroop interference naming, and each subtask is restricted to 1 minute. The minimum score is 0 and the maximum score is 126. The higher the score the better a participant does.
Time frame: Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Levetiracetam | Changes in Stroop Interference Naming | 1.5 score on a scale |
| Placebo | Changes in Stroop Interference Naming | -1.4 score on a scale |
p-value: 0.1495% CI: [-1, 6.8]ANOVA
Secondary
Clinical Dementia Rating Sum of Boxes (CDR-SOB)
Clinical Dementia Rating Sum of Boxes (CDR-SOB) - The CDR will be used as a global measure of dementia severity (Morris 1993). The CDR consists of questions addressed to the caregiver/informant. The lowest score one can receive is a 0 and the highest is a 3. Score is measured by getting the mean of the individual scores in each category. Lower scores equate to less dementia severity.
Time frame: Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Levetiracetam | Clinical Dementia Rating Sum of Boxes (CDR-SOB) | 0.1 score on a scale |
| Placebo | Clinical Dementia Rating Sum of Boxes (CDR-SOB) | 0.1 score on a scale |
p-value: 0.6395% CI: [-0.2, 0.4]ANOVA
Other Pre-specified
ADAS-cog in AD With Epileptiform Activity
Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-cog) - The ADAS-cog rating instrument (Rosen et al. 1984) will be used to evaluate the global cognitive functioning. The ADAS-cog is a 70-point scale that includes an assessment of verbal memory, language, orientation, reasoning, and praxis.The score is derived from adding point values from each of its subsections. The higher your score on the ADAS-cog, the better you do.
Time frame: Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment)
Population: Specifically, this analysis is only looking at individuals who displayed epileptiform activity.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Levetiracetam | ADAS-cog in AD With Epileptiform Activity | -1.0 score on a scale | Standard Deviation 4.1 |
| Placebo | ADAS-cog in AD With Epileptiform Activity | 1.5 score on a scale | Standard Deviation 4.5 |
p-value: 0.395% CI: [-7.8, 2.7]ANOVA
Other Pre-specified
Blood Serum Prolactin Level
Blood samples intended for Quest Diagnostics LEV and prolactin serum levels (one 6 mL tube) will be processed in the following manner, as outlined in the Quest Diagnostics lab manual. The whole blood will be allowed to clot for 60 minutes and centrifuged at 2200 - 2500 revolutions per minute (RPM) for at least 15 minutes. The resulting serum will be split into 2 cryovials which will be stored at -20°C and immediately shipped for external assessment of LEV and prolactin levels. Prolactin will be assessed via immunoassay. The concentration of LEV in serum will be measured using validated liquid chromatography/tandem mass spectrometry (LC/MS-MS) methods.
Time frame: Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Levetiracetam | Blood Serum Prolactin Level | 0.1 ng/mL | Standard Deviation 1.9 |
| Placebo | Blood Serum Prolactin Level | 0.2 ng/mL | Standard Deviation 1.5 |
p-value: 0.6395% CI: [-1.1, 0.7]ANOVA
Other Pre-specified
Changes in Cognitive Function as Measured by a Virtual Route Learning Test
A 20-minute computer-based virtual navigation test will be used to assess how well a subject can navigate a virtual community to reach a goal destination. The subjects will then be measured on their ability to accurately navigate the virtual community after a period of a few hours. The subject's performance after the study treatment will be compared with results from a baseline assessment done before the study treatment, using statistical tests to assess whether there was any significant change.
Time frame: Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Levetiracetam | Changes in Cognitive Function as Measured by a Virtual Route Learning Test | -6.0 correct turns |
| Placebo | Changes in Cognitive Function as Measured by a Virtual Route Learning Test | 17.4 correct turns |
p-value: 0.5295% CI: [-8.5, 16]Cohen f
Other Pre-specified
MEG Functional Connectivity Measures
Whole-brain alpha-band functional connectivity will be derived from MEG-imaging (MEG-I) using the 60-second artifact-free recording epoch that is selected for the MEG spectral analysis. MEG-I uses MEG sensor data with millisecond precision and applies source reconstruction algorithms to overlay cortical oscillatory activity onto structural brain images. Source-space MEG-I reconstructions and functional connectivity metrics will be computed with the NUTMEG software suite (http://nutmeg.berkeley.edu). The investigators will compute imaginary coherence, which is a reliable metric for functional connectivity with MEG reconstruction. Functional connectivity will measure the strength of coherence between a given region and the rest of the brain. The investigators will perform an unbiased search for MEG-I functional connectivity deficits that correlate with specific cognitive, behavioral, and functional deficits. Hinkley et al. 2011 provides details of the methodology.
Time frame: Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment)
Other Pre-specified
MEG Power Spectrum Measures
The power spectral density for different frequency bands will be measured via resting-state magnetoencephalography (MEG). A 60-second artifact-free recording segment from the first 10 minutes of recording (prior to sleep onset) will be manually selected for analysis. In participants who are able to complete additional tests, the investigators will measure dynamics of neural responses during cognitive tasks such as speech preparation and execution.
Time frame: Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment)
Other Pre-specified
NIH EXAMINER in AD With Epileptiform Activity
Changes in executive function will be measured using the NIH EXAMINER, a 1-hour computer-based battery of various executive function tasks. The subject's performance after the study treatment will be compared with results from a baseline assessment done before the study treatment, using statistical tests to assess whether there was any significant change. The Examiner assessment consists of the following scales: NIH EXAMINER - antisaccade , NIH EXAMINER - set shifting , NIH EXAMINER - flanker task, NIH EXAMINER - dot counting, NIH EXAMINER - spatial 1-back, NIH EXAMINER - category fluency, and NIH EXAMINER - letter fluency. Scores for this task have an indefinite range. Higher scores however do indicate better performance. Scores for this scale were generated using item response theory (Kramer et al. J Int Neuropsychol Soc. 2014;20(1):11-19. doi:10.1017/S1355617713001094).
Time frame: Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment)
Population: Specifically, this analysis is only looking at individuals who displayed epileptiform activity.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Levetiracetam | NIH EXAMINER in AD With Epileptiform Activity | -0.01 score on a scale |
| Placebo | NIH EXAMINER in AD With Epileptiform Activity | 0.22 score on a scale |
Other Pre-specified
Standardized Assessments of Clinical Fluctuations - One Day Fluctuation Assessment Scale
The One Day Fluctuation Assessment Scale will be used to quantitate fluctuations of dementia symptoms (Walker et al. 2000). The One Day Fluctuation Assessment Scale has a score range of 0-21 points,with higher scores indicatingmore fluctuations.
Time frame: Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Levetiracetam | Standardized Assessments of Clinical Fluctuations - One Day Fluctuation Assessment Scale | 0.3 score on a scale | Standard Deviation 1.8 |
| Placebo | Standardized Assessments of Clinical Fluctuations - One Day Fluctuation Assessment Scale | -0.4 score on a scale | Standard Deviation 1.6 |
p-value: 0.1595% CI: [-0.3, 1.8]ANOVA
Other Pre-specified
Standardized Assessments of Clinical Fluctuations -The Clinician Assessment of Fluctuation
Two standardized methods will be used to quantitate fluctuations of dementia symptoms: The Clinician Assessment of Fluctuation and the One Day Fluctuation Assessment Scale (Walker et al. 2000). : The Clinician Assessment of Fluctuation (score range,0-12 points, with higher scores indicating more fluctuations),26 the One Day Fluctuation Assessment Scale (score range,0-21 points, with higher scores indicatingmore fluctuations).
Time frame: Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Levetiracetam | Standardized Assessments of Clinical Fluctuations -The Clinician Assessment of Fluctuation | 0.9 score on a scale | Standard Deviation 2.6 |
| Placebo | Standardized Assessments of Clinical Fluctuations -The Clinician Assessment of Fluctuation | 0.1 score on a scale | Standard Deviation 3.4 |
p-value: 0.495% CI: [-1, 2.4]ANOVA
Other Pre-specified
Stroop Interference in AD With Epileptiform Activity
Stroop Test - The Stroop Test (Stroop 1935) will be used to assess executive functions including selective attention, cognitive flexibility and processing speed. Subtasks include Stroop color naming and Stroop interference naming, and each subtask is restricted to 1 minute. The minimum score is 0 and the maximum score is 126. The higher the score the better a participant does. The mean below represents the average change in score between the timepoints for all participants.
Time frame: Difference between weeks 0-4 (Baseline) and weeks 8-12 (Treatment)
Population: Specifically, this analysis is only looking at individuals who displayed epoileptiform activity.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Levetiracetam | Stroop Interference in AD With Epileptiform Activity | 4.7 score on a scale | Standard Deviation 7.2 |
| Placebo | Stroop Interference in AD With Epileptiform Activity | -2.6 score on a scale | Standard Deviation 5 |
p-value: 0.04695% CI: [0.2, 14.7]ANOVA