Corticolimbic Degeneration and Treatment of Dementia

Study Overview
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Brief Summary
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The overall purpose of this research is to determine if there is a relationship between your symptoms of Dementia of the Alzheimers type and changes in the size and shape of certain brain structures during combined Donepezil (Aricept®) and Memantine (Namenda®) treatment.

Detailed Description
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In this study we will be using Memantine (Namenda®) in an investigational fashion with individuals with very mild to mild dementia. Donepezil (Aricept®) is approved by the Food and Drug Administration for the treatment of Alzheimers disease. Memantine (Namenda®) is currently approved by the Food and Drug Administration for moderate and severe dementia only. This study may be instrumental in the development of a new therapy for others with similar conditions, and to determine whether Memantine (Namenda®) will be helpful to individuals with very mild to mild dementia. Specific Aim 1. To determine what neuroanatomical measures are most strongly correlated with the progression of clinical and cognitive deficits in patients with dementia of the Alzheimer type (DAT). To accomplish this aim, we will use high-resolution magnetic resonance (MR) imaging and the tools of computational anatomy to assess changes in the structure of selected subcortical (e.g., hippocampus) and cortical (e.g., parahippocampal gyrus and cingulate gyrus) structure along with clinical and cognitive measures of dementia severity in subjects with very mild-to-mild DAT. Specific Aim 2 - To determine whether cholinesterase inhibitors and memantine can slow disease progression in DAT subjects. To accomplish this aim, we will use MR imaging and the tools of computational anatomy to compare the rate of change in the neuroanatomical measures listed above in 1) untreated DAT subjects, 2) DAT subjects treated with donepezil alone, and 3) DAT subjects treated with the combination of donepezil and memantine.

Official Title
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Corticolimbic Degeneration and Treatment of Dementia

Conditions
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Dementia

Intervention / Treatment
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* Drug: Memantine (Namenda®)
* Drug: Donepezil (Aricept®)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1) meets National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association(NINCDS-ADRDA) Alzheimer's criteria for dementia of the Alzheimer's type (DAT), 2) Clinical Dementia Rating (CDR) score of 0.5 or 1, 3) 50-80 years of age, 4) able to give informed consent or has a primary caregiver or legal guardian, who can give informed consent. Exclusion Criteria: 1) other psychiatric (e.g., depression) or neurological (e.g., CVA) disorders that would confound the assessment of dementia symptoms, 2) history of loss of consciousness, and 3) unstable or severe medical illness (e.g., hepatotoxicity) that would make donepezil or memantine treatment or participation in other aspects of the study unsafe.

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 95 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Very Mild to Mild DAT Untreated<br>Group 1) subjects with very mild (CDR 0.5) to mild (CDR 1) DAT that are untreated with either cholinesterase inhibitors or memantine | |
| Active Comparator: Very Mild-Mild DAT Treated W/ Donepezil<br>Group 2) subjects with very mild (CDR 0.5) to mild (CDR 1) DAT that are treated with Donepezil (Aricept®). | Drug: Donepezil (Aricept®)<br>* 5mg/day for six weeks and if no serious side-effects increased to 10mg/dy.<br>* Other names: Aricept;|
| Active Comparator: Very Mild-Mild DAT Treated W/Combination<br>Group 3) subjects with very mild (CDR 0.5) to mild (CDR 1) DAT that are treated with the combination of Donepezil (Aricept®) and Memantine (Namenda®) | Drug: Memantine (Namenda®)<br>* Drug treatment will begin with 5 mg/day of donepezil for six weeks. After six weeks of such treatment, the subjects symptoms will be re-evaluated and any side-effects of treatment assessed and recorded. If no serious side-effects of donepezil are encountered, the dose of donepezil will be increased to 10 mg/day. For subjects prescribed the combination of donepezil and memantine, memantine (20 mg/day) will be added to the drug treatment regimen after the dose of donepezil has been established (i.e., at six weeks). Again, memantine will be initially started at 10 mg/day and increased to its full dose only if no serious side-effects are encountered.<br>* Other names: Namenda;Drug: Donepezil (Aricept®)<br>* 5mg/day for six weeks and if no serious side-effects increased to 10mg/dy.<br>* Other names: Aricept;|
| No Intervention: Nondemented Comparison Subjects<br>Group 4) nondemented comparison subjects. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Change of Hippocampal Volume Slope |  | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison of Combined DAT Patients' Mean (SD) Hippocampal Volume Slope (mm^3/Year) Rate of Change | The ADAS-Cog evaluates cognition and differentiates normal from impaired cognitive functioning. The total score is the summed number of errors in each task. The greater the impairment, the greater the score. We combined the dementia of the Alzheimer's type patients receiving all treatments together and grouped them into 3 subgroups according to the rates of change(roc) of their ADAS-Cog scores. To determine trends in hippocampal volume atrophy over time we compared the patients showing most negative ADAS-Cog rate of change (improving), patients with most positive ADAS-cog roc (worsening), patients with intermediate, near-zero ADAS-Cog roc (stable) . | two years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dementia of the Alzheimer type