Alzheimer Dementia, Alzheimer Disease, Dementia of Alzheimer Type, Mild Cognitive Impairment
Conditions
Keywords
Mild Alzheimer's Disease, Early Alzheimer's Disease
Brief summary
The aim of this study is to explore the relationship between cortical hyperexcitability, abnormalities of brain network function, and cognitive dysfunction in human patients with AD and whether administration of the antiepileptic medication levetiracetam (LEV) normalizes these measures and improves cognition.
Detailed description
This is a randomized, placebo-controlled crossover study. Participants with early Alzheimer's Disease (AD) will be tested in a double-blind crossover design with placebo, low-dose levetiracetam (LEV) 125 mg twice daily or high-dose LEV 500mg twice daily. These results will be contrasted with results from a demographically similar control group who will undergo baseline testing only, without any intervention, to establish a comparison norm for the AD group. Each subject will undergo four screening and baseline visits consisting of a baseline neurological, medical, and cognitive evaluation. If amyloid status is unknown in AD patients, the participant will have an amyloid PET scan. Additional baseline measures include: a high density electroencephalogram (EEG); a 24 hour ambulatory EEG; functional magnetic resonance imaging (fMRI); neuropsychological testing; and transcranial magnetic stimulation with electromyogram (EMG) and EEG measures to assess cortical excitability. AD participants will be randomized to one of six possible groups that consists of a varying order of 3 treatment periods (LEV 125 mg, LEV 500 mg and placebo). The group assignments will be counterbalanced across subjects. Each treatment period will last for 4 weeks with a 4 week washout between treatments. All participants will be assessed prior to initiation of a treatment period (with the initial assessment occurring as part of the baseline assessment) and at the end of each treatment period. The following measures will be repeated as done at baseline at these time points: fMRI; neuropsychological testing; and TMS-EMG-EEG. AD participants will be enrolled for approximately 5 months.
Interventions
DRUGLevetiracetam
Levetiracetam is an antiepileptic medication that has been shown to reduced network cortical hyperexcitability
DRUGPlacebo oral capsule
The placebo is a capsule that is identical in appearance to the levetiracetam
Sponsors
Beth Israel Deaconess Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Subjects will be provided with identical-appearing tablets containing either placebo, levetiracetam 125 mg, or levetiracetam 500 mg.
Intervention model description
Participants will be tested in a double-blind crossover design with twice daily, low-dose levetiracetam (125 mg twice daily) or high-dose levetiracetam (500mg twice daily) or placebo. Each dose and placebo will be administered for a four week period.The order of interventions will be counterbalanced across subjects, with randomization occurring in blocks of 6. There will be a 4 week washout period between each treatment period.
Eligibility
Sex/Gender
ALL
Age
50 Years to 90 Years
Healthy volunteers
Yes
Inclusion criteria
Inclusion Criteria for the Subjects with early Alzheimer's Disease (AD) * Age 50-90 years old. * On a stable dose of medications for memory loss including cholinesterase inhibitors (for example: donepezil, rivastigmine or memantine) as defined by 4 consecutive weeks of treatment at an unchanging dose * Meeting the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria for probable AD. * Mini Mental State Examination (MMSE) ≥ 20. * Positive amyloid status (as defined by cerebral spinal fluid biomarkers or amyloid positron emission tomography (PET) study. * Clinician Dementia Rating (CDR) of 0.5-1.0. Inclusion Criteria for Healthy Control Subjects * Age 50-90 years old. * Normal neurologic exam * Mini Mental State Examination (MMSE) \> 28 * Clinician Dementia Rating (CDR) of 0
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Neuropsychological Test Battery (NTB) | From enrollment until the end of the treatment periods at 5 months | Our primary cognitive outcome measure will be the mean z-score change relative to baseline on the NTB |
| Transcranial magnetic stimulation (TMS) resting motor threshold | From enrollment until the end of the treatment periods at 5 months | Our primary TMS electrophysiological outcome measure of cerebral cortical excitability will be the change in the TMS resting input-output curve inflection point |
| Transcranial magnetic stimulation (TMS)-evoked electroencephalogram (EEG) hypersynchrony | From enrollment until the end of the treatment periods at 5 months | Our primary electrophysiological measure of cerebral network excitability will be TMS-evoked EEG hypersynchrony with stimulation of parietal cortex |
| Resting-state electroencephalogram (EEG) beta band power | From enrollment until the end of the treatment periods at 5 months | Our primary electrophysiological measure of local network function will be resting-state EEG power in the beta band |
| Resting-state electroencephalogram (EEG) beta band connectivity | From enrollment until the end of the treatment periods at 5 months | Our primary electrophysiological measure of brain network interactions will be resting-state EEG functional connectivity in the beta band |
| Default-mode network resting-state functional magnetic resonance imaging (fMRI) functional connectivity | From enrollment until the end of the treatment periods at 5 months | Our primary imaging measure of integrity of macroscopic brain networks will be mean resting-state fMRI functional connectivity within the default-mode network |
| Change in motor evoked potential (MEP) amplitude | From enrollment until the end of the treatment periods at 5 months | Our primary transcranial magnetic stimulation (TMS) measure of plasticity in cortical excitability will be the change in MEP amplitude 10 minutes after intermittent theta-burst stimulation |
| Change in beta power after theta-burst stimulation | From enrollment until the end of the treatment periods at 5 months | Our primary transcranial magnetic stimulation (TMS) measure of plasticity in cortical oscillations will be change in resting-state electroencephalogram (EEG) beta power after theta-burst stimulation |
Countries
United States
Outcome results
None listed