Alzheimer Disease
Conditions
Brief summary
The aim of the proposed study is to determine if the NMDA receptor antagonist memantine has a neuroprotective effect on magnetic resonance spectroscopic imaging (MRS) measures of brain NAA and magnetic resonance imaging (MRI) volumetric measures of hippocampal volume. In secondary analyses, we will determine if measures of clinical stabilization produced by memantine in the treatment of Alzheimer's disease (AD) parallels stabilization of MRS measures of brain NAA and MRI volumetric measures of hippocampal volume.
Detailed description
Alzheimer's disease (AD) is the most common form of dementia. Currently, there are more than 4 million individuals with dementia in the United States with at least 400,000 deaths annually. AD is a progressive, neurodegenerative disorder, characterized neuropathologically by widespread neuronal loss, presence of neurofibrillary tangles, and deposits of beta amyloid in cerebral blood vessels and neuritic plaques. Since the medial-temporal lobes, hippocampus, and association cortex are significantly impacted it is not surprising that the primary symptom of AD is a decline in cognitive functioning that leads to marked impairment in daily functioning. In particular, memory impairments, visuospatial decline, language difficulties, and loss of executive function are central cognitive symptoms of this illness. Behavioral disturbances such as agitation and hallucinations often accompany disease progression. The illness lasts approximately 7 to 10 years, with patients requiring total care in the latter stages. Thus, AD places a tremendous emotional and economic burden on both patients and their caregivers. Beyond a cure, therapeutic approaches which would alleviate the symptoms or delay progression could be of substantial psychological and economic benefit. Recent placebo controlled clinical trials have shown memantine to be efficacious in the treatment of patients with moderate to severe AD. The aim of the proposed study is to determine if the NMDA receptor antagonist memantine has a neuroprotective effect on magnetic resonance spectroscopic imaging (MRS) measures of brain NAA and magnetic resonance imaging (MRI) volumetric measures of hippocampal volume. In secondary analyses, we will determine if measures of clinical stabilization produced by memantine in the treatment of Alzheimer's disease (AD) parallels stabilization of MRS measures of brain NAA and MRI volumetric measures of hippocampal volume.
Interventions
DRUGMemantine
10mg Memantine
DRUGPlacebo pill
10mg placebo pill
Sponsors
Palo Alto Veterans Institute for Research
Forest Laboratories
Stanford University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
50 Years to 95 Years
Healthy volunteers
No
Inclusion criteria
1. Dementia criteria by DSM-IV. 2\. 50-95 years of age inclusive. 3\. MMSE at screen and baseline 7-28 inclusive. 4\. Conversant in English. 5\. Caregiver/study partner willing to participate, supervise the patient and be available for administration of study medication. 6\. Able to ingest oral medication.
Exclusion criteria
1. History of clinically significant stroke without substantial recovery. 2\. Neurological or medical conditions causing significant disability independent of dementia. 3\. Parkinson's disease. 4\. History in past two years of focal brain lesion, head injury with loss of consciousness or DSM-IV criteria for any major psychiatric disorder including psychosis, major depression, bipolar disorder, alcohol or substance abuse. 5\. Dementia due to Korsakoff's syndrome or infectious diseases such as Creutzfeldt-Jakob disease, herpes, encephalitis, or human immunodeficiency virus. 6\. Sensory impairment that would prevent subject from participating in or cooperating with the protocol. 7\. Significant clinical disorder or laboratory finding that renders the subject unsuitable for receiving an investigational drug including: clinically significant or unstable hematologic, hepatic, cardiovascular, pulmonary, gastrointestinal, endocrine, metabolic, renal, or other systemic disease or laboratory abnormality. 8\. Clinical contraindication to the use of memantine (e.g., hypersensitivity). 9\. History of seizure within past 5 years prior to screening. 10\. Platelet count \< 100,000/mm3. 11\. History of claustrophobia 12\. Presence of metallic implants such as pacemakers, surgical aneurysm clips, or known metal fragments embedded in the body
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| NAA/Cr Ratio | Baseline; Year 1 | To determine if memantine has a neuroprotective effect on magnetic resonance spectroscopic imaging (MRS) measures of hippocampal n-acetyl aspartate (NAA) and magnetic resonance imaging volumetric measures (MRI) of hippocampal volume. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change on the ADAS-Cog Score After 1 Year | Baseline; Year 1 | Progression of cognitive functioning as measured by performance on the Alzheimer's Disease (AD) Assessment Scale-cognitive subscale (ADAS-Cog). ADAS-cog is the most popular cognitive testing instrument used in clinical trials of nootropics, and measures disturbances of of memory, language, praxis, attention and other cognitive abilities which are often referred to as the core symptoms of AD. Responses are summed for an overall score which can range from 0-70. The greater the dysfunction, the higher the score. A typical score for a person without dementia is 5. |
Countries
United States
Participant flow
Recruitment details
17 subjects were randomized. All subjects had completed all participation by October, 2008. All were recruited at VA Palo Alto Health Care System.
Participants by arm
| Arm | Count |
|---|---|
| Memantine 10mg Memantine
Memantine | 7 |
| Control 10mg Placebo pill | 6 |
| Total | 13 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 |
| Overall Study | Protocol Violation | 1 | 1 |
Baseline characteristics
| Characteristic | Memantine | Control | Total |
|---|---|---|---|
| Age, Continuous | 76.5 years | 75.4 years | 75.9 years |
| Region of Enrollment United States | 7 participants | 6 participants | 13 participants |
| Sex/Gender, Customized Female | 1 participants | 4 participants | 5 participants |
| Sex/Gender, Customized Male | 6 participants | 2 participants | 8 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 4 / 9 | 0 / 8 |
| serious Total, serious adverse events | 1 / 9 | 2 / 8 |
Outcome results
Primary
NAA/Cr Ratio
To determine if memantine has a neuroprotective effect on magnetic resonance spectroscopic imaging (MRS) measures of hippocampal n-acetyl aspartate (NAA) and magnetic resonance imaging volumetric measures (MRI) of hippocampal volume.
Time frame: Baseline; Year 1
Population: Participants who could tolerate study medication and who completed the study were included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Memantine | NAA/Cr Ratio | Baseline | 1.47 Ratio | Standard Deviation 0.11 |
| Memantine | NAA/Cr Ratio | Year 1 | 1.62 Ratio | Standard Deviation 0.14 |
| Control | NAA/Cr Ratio | Baseline | 1.38 Ratio | Standard Deviation 0.1 |
| Control | NAA/Cr Ratio | Year 1 | 1.41 Ratio | Standard Deviation 0.1 |
Secondary
Mean Change on the ADAS-Cog Score After 1 Year
Progression of cognitive functioning as measured by performance on the Alzheimer's Disease (AD) Assessment Scale-cognitive subscale (ADAS-Cog). ADAS-cog is the most popular cognitive testing instrument used in clinical trials of nootropics, and measures disturbances of of memory, language, praxis, attention and other cognitive abilities which are often referred to as the core symptoms of AD. Responses are summed for an overall score which can range from 0-70. The greater the dysfunction, the higher the score. A typical score for a person without dementia is 5.
Time frame: Baseline; Year 1
Population: Participants who could tolerate study medication and who completed the study were included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Memantine | Mean Change on the ADAS-Cog Score After 1 Year | Baseline | 44.67 units on a scale | Standard Deviation 10.3 |
| Memantine | Mean Change on the ADAS-Cog Score After 1 Year | 1 Year | 45.75 units on a scale | Standard Deviation 7.99 |
| Control | Mean Change on the ADAS-Cog Score After 1 Year | Baseline | 49.17 units on a scale | Standard Deviation 8.37 |
| Control | Mean Change on the ADAS-Cog Score After 1 Year | 1 Year | 50.39 units on a scale | Standard Deviation 8.88 |