Glutamatergic Dysfunction in Cognitive Aging: Riluzole in Mild Alzheimer's Disease
Overview
- Phase
- Phase 2
- Intervention
- Riluzole
- Conditions
- Alzheimer's Disease
- Sponsor
- Icahn School of Medicine at Mount Sinai
- Enrollment
- 50
- Locations
- 2
- Primary Endpoint
- Imaging Biomarkers N-acetylaspartate (NAA) in Posterior Cingulate (PC) Measured Through 1H MRS
- Status
- Completed
- Last Updated
- 4 years ago
Overview
Brief Summary
Cognitive aging is a major source of disability in an increasingly aging population. The paucity of effective treatments for cognitive aging disorders, and most importantly in Alzheimer's disease instigates a need for further research into novel therapeutic possibilities. Alzheimer's disease is the most common neurodegenerative disorder and its prevalence steeply increases. Glutamate-mediated excitotoxicity in neuropsychiatric disorders and in particular in Alzheimer's disease has been shown to cause significant cerebral damage. Early effective therapeutic intervention in Alzheimer's disease is critical in order to prevent or at least slow down neuropathological progression that will lead to widespread irreversible neuronal loss and significant cognitive dysfunction. Riluzole, a glutamate modulator agent, will be tested in mild Alzheimer's disease patients. Cognitive functional changes along with two established in vivo biomarkers, namely, Magnetic Resonance Spectroscopy (MRS) and Fluorodeoxyglucose (18F) positron emission tomography (FDG-PET) will be evaluated.
Detailed Description
A double-blinded, randomized, placebo-controlled study will be performed. Forty-two individuals with a diagnosis of mild Alzheimer's disease between 50-95 years old will complete the study. All forty-two individuals will have been on an acetylcholinesterase inhibitor, which is FDA approved for the treatment of Alzheimer's disease, for at least 2 months prior to initiating the study, unless the medication was not previously tolerated. Twenty to twenty-two mild Alzheimer's disease patients will receive riluzole and another 20-22 will receive a placebo. All patients will have a neurological evaluation and neuropsychological tests performed to confirm that they meet criteria for probable Alzheimer's disease set out by the National Institute on Aging - Alzheimer's disease Association that recently revisited the NINCDS-ADRDA criteria along with FDG-PET biomarker consistent with Alzheimer's disease.
Investigators
Ana Pereira
Principal Investigator; Assistant Professor of Neurology and Neuroscience
Icahn School of Medicine at Mount Sinai
Eligibility Criteria
Inclusion Criteria
- •Male or female; 50 - 95 years old with mild Alzheimer's disease determined after neurological and neuropsychological evaluation following the National Institute on Aging - Alzheimer's disease Association criteria that recently revisited the NINCDS-ADRDA criteria. For mild Alzheimer's disease, Clinical Dementia Ratings Scale (CDR) should be 0.5 or 1 and Mini Mental State Examination (MMSS) between 19 and
- •Must be on donepezil (Aricept®) or rivastigmine (Exelon®) or galantamine (Razadyne®) at a consistent dose for at least 2 months. Patients will be considered for inclusion if they were previously unable to tolerate acetylcholinesterase inhibitors and as a result, are no longer on the medication for at least 2 months.
- •Must be fluent in English
- •The subject will appoint or have previously appointed a health care proxy specifically designated for research consent and that this be documented.
Exclusion Criteria
- •Severe Alzheimer's disease and other dementias as determined by neuropsychological testing and neurological evaluation.
- •Previous riluzole treatment.
- •MRI contraindication (severe claustrophobia, metal implants, shunts, pacemaker, joint implants, metal valves).
- •Currently taking medications that either have evidence of glutamatergic activity or has previous MRS evidence of effects on brain glutamate levels at the discretion of the PI such as memantine, lamotrigine, lithium, opiates, bupropion, psychostimulants such as amphetamines and methylphenidate, tricyclic antidepressants, benzodiazepines and any other drug that the investigators judge might interfere with the study. (subjects on those medications may still be included in the study however only the values of NAA from MRS will be utilized and not the glutamate measurements).
- •Currently a user of the following illicit drugs: cocaine, methylenedioxymethamphetamine (MDMA) ("ecstasy"), heroin and other opioids or has a history of drug or alcohol abuse within the past 5 years.
- •Serum creatinine \>1.5 times the upper limit of normal.
- •Abnormal liver function test (greater than 2 times the upper limit of normal for alanine aminotransferase (ALT) or aspartate aminotransferase (AST); or bilirubin \>1.5 times the upper limit of normal.
- •History of brain disease including Parkinson's Disease, severe brain trauma, seizures, history of stroke, clinically significant lacunar infarct in a region important for cognition or multiple lacunes or a cortical infarct or focal lesions of clinical significance, multiple sclerosis, mental retardation, normal pressure hydrocephalus, central nervous system (CNS) tumor, Huntington's disease, subdural hematoma or other serious neurological disorder.
- •Uncontrolled diabetes mellitus (Hba1c higher than 7) or chronically uncontrolled hypertension.
- •Subject must not be taking Namenda® (memantine) for 6-weeks prior to study entrance.
Arms & Interventions
age matched cohort 50-95 years old
20-22 subjects between the ages of 50-95 will receive riluzole
Intervention: Riluzole
24 subjects between 50-95 years old
20-22 subjects between 50-95 will receive placebo
Intervention: Placebo
Outcomes
Primary Outcomes
Imaging Biomarkers N-acetylaspartate (NAA) in Posterior Cingulate (PC) Measured Through 1H MRS
Time Frame: Changes from baseline to 6 months
N-acetylaspartate (NAA) is a neuronal viability marker measured through magnetic resonance spectroscopy (1H MRS).In vivo brain levels of NAA, glutamate, tCr and other major metabolites were obtained using 1H MRS and a 2x2x2-cm3 Posterior Cingulate Cortex (PC) voxel of interest in approximately 6.5 minutes using the constant-time point-resolved spectroscopy (CT-PRESS) technique with TE 30 ms, 129 constant-time increments (t1) of 0.8ms, and TR 1500 ms and a receive-only 8-channel phased-array head coil.The levels of NAA and other metabolites were expressed semi-quantitatively as ratios of peak areas relative to that of the unsuppressed water signal (W) from the same voxels. For consistency with earlier MRS literature, levels of the same metabolites were also expressed as peak ratios relative to tCr area in the same voxel.
Imaging Biomarkers FDG-PET SUVR in Regions of Interest
Time Frame: Change from baseline to 6 months
Change from baseline to 6 months in cerebral glucose metabolism measured with FDG PET in posterior cingulate cortex, hippocampus, precuneus, and medial temporal, lateral temporal, inferior parietal, and frontal lobes, referred to collectively as our pre-specified regions of interest. Fluorodeoxyglucose (FDG)-positron emission tomography (PET) is an imaging procedure that measures glucose metabolism in the brain.It is a well-established Alzheimer's disease biomarker and predictor of disease progression. For each FDG PET scan, 5 mCi of fluorodeoxyglucose was administered followed by a 40 minute uptake period during which the participant was in a resting state. Images were acquired on a Siemens Biograph 64mCT scanner as a series of 4 frames of 5 minutes each. Using SPM12 (Wellcome Trust), motion correction was performed and frames averaged into a static image. Each 6 month scan was coregistered to the baseline FDG scan, which was co-registered to the participant's T1-weighted MRI scan.
Secondary Outcomes
- Glutamate Levels Measured Through 1H MRS(Change from baseline to 6 months)
- Alzheimer's Disease Assessment Scale (ADAS) - Cognitive Subscale (ADAScog)(baseline to 6 months)
- Neuropsychiatry Inventory - NPI(baseline to 6 months)
- ADCS Activities of Daily Living(baseline to 6 months)