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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
58
Levetiracetam is an antiepileptic medication that has been shown to reduced network cortical hyperexcitability
The placebo is a capsule that is identical in appearance to the levetiracetam
Beth Israel Deaconess Medical Center
Boston, Massachusetts, United States
Neuropsychological Test Battery (NTB)
Our primary cognitive outcome measure will be the mean z-score change relative to baseline on the NTB
Time frame: From enrollment until the end of the treatment periods at 5 months
Transcranial magnetic stimulation (TMS) resting motor threshold
Our primary TMS electrophysiological outcome measure of cerebral cortical excitability will be the change in the TMS resting input-output curve inflection point
Time frame: From enrollment until the end of the treatment periods at 5 months
Transcranial magnetic stimulation (TMS)-evoked electroencephalogram (EEG) hypersynchrony
Our primary electrophysiological measure of cerebral network excitability will be TMS-evoked EEG hypersynchrony with stimulation of parietal cortex
Time frame: From enrollment until the end of the treatment periods at 5 months
Resting-state electroencephalogram (EEG) beta band power
Our primary electrophysiological measure of local network function will be resting-state EEG power in the beta band
Time frame: From enrollment until the end of the treatment periods at 5 months
Resting-state electroencephalogram (EEG) beta band connectivity
Our primary electrophysiological measure of brain network interactions will be resting-state EEG functional connectivity in the beta band
Time frame: From enrollment until the end of the treatment periods at 5 months
Default-mode network resting-state functional magnetic resonance imaging (fMRI) functional connectivity
Our primary imaging measure of integrity of macroscopic brain networks will be mean resting-state fMRI functional connectivity within the default-mode network
Time frame: From enrollment until the end of the treatment periods at 5 months
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Change in motor evoked potential (MEP) amplitude
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
Time frame: From enrollment until the end of the treatment periods at 5 months
Change in beta power after theta-burst stimulation
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
Time frame: From enrollment until the end of the treatment periods at 5 months