Dementia
Conditions
Keywords
Dementia of the Alzheimer type
Brief summary
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
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.
Interventions
DRUGMemantine (Namenda®)
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.
5mg/day for six weeks and if no serious side-effects increased to 10mg/dy.
Sponsors
Northwestern University
Washington University School of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
50 Years to 95 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Rate of Change of Hippocampal Volume Slope | 2 years |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Comparison of Combined DAT Patients' Mean (SD) Hippocampal Volume Slope (mm^3/Year) Rate of Change | two years | 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) . |
Participant flow
Pre-assignment details
39 subjects enrolled in Group3.14 maps have passed inspection for quality and are included in final analysis. Subject data from a previously published study of donepezil(Wang et al.,2010) with 18 very mild dementia of the Alzheimer's type patients treated with donepezil,14 untreated with mild DAT, and 56 cognitively normal individuals are included.
Participants by arm
| Arm | Count |
|---|---|
| 1 Very Mild to Mild DAT Untreated Group 1) subjects with very mild (CDR 0.5) to mild (CDR 1) DAT that are untreated with either cholinesterase inhibitors or memantine | 14 |
| 2 Very Mild to Mild DAT Treated With Donepezil Group 2) subjects with very mild (CDR 0.5) to mild (CDR 1) DAT that are treated with donepezil.
Donepezil (Aricept®): 5mg/day for six weeks and if no serious side-effects increased to 10mg/dy. | 18 |
| 3 Very Mild to Mild DAT Treated With the Combination Group 3) subjects with very mild (CDR 0.5) to mild (CDR 1) DAT that are treated with the combination of donepezil and memantine.
Memantine (Namenda®): 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.
Memantine (Namenda®): Initial dose of 10mg/day and increased to full dose of 20mg/day if no serious side-effects | 14 |
| 4 Nondemented Comparison Subjects. Group 4) nondemented comparison subjects. | 56 |
| Total | 102 |
Baseline characteristics
| Characteristic | 1 Very Mild to Mild DAT Untreated | 2 Very Mild to Mild DAT Treated With Donepezil | 3 Very Mild to Mild DAT Treated With the Combination | 4 Nondemented Comparison Subjects. | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 13 Participants | 17 Participants | 14 Participants | 56 Participants | 100 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants |
| Region of Enrollment United States | 14 Participants | 18 Participants | 14 Participants | 56 Participants | 102 Participants |
| Sex: Female, Male Female | 6 Participants | 8 Participants | 6 Participants | 35 Participants | 55 Participants |
| Sex: Female, Male Male | 8 Participants | 10 Participants | 8 Participants | 21 Participants | 47 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 14 | 0 / 18 | 0 / 14 | 0 / 56 |
| serious Total, serious adverse events | 0 / 14 | 0 / 18 | 0 / 14 | 0 / 56 |
Outcome results
Primary
Rate of Change of Hippocampal Volume Slope
Time frame: 2 years
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 1 Very Mild to Mild DAT Untreated | Rate of Change of Hippocampal Volume Slope | left hippocampal volume slope | -70.2418748 mm^3/year | Standard Deviation 31.4801034 |
| 1 Very Mild to Mild DAT Untreated | Rate of Change of Hippocampal Volume Slope | right hippocampal volume slope | -99.9437062 mm^3/year | Standard Deviation 65.1619838 |
| 2 Very Mild to Mild DAT Treated With Donepezil | Rate of Change of Hippocampal Volume Slope | right hippocampal volume slope | -94.3258652 mm^3/year | Standard Deviation 44.7959659 |
| 2 Very Mild to Mild DAT Treated With Donepezil | Rate of Change of Hippocampal Volume Slope | left hippocampal volume slope | -88.4738591 mm^3/year | Standard Deviation 52.2621175 |
| 3 Very Mild to Mild DAT Treated With the Combination | Rate of Change of Hippocampal Volume Slope | left hippocampal volume slope | -94.0768115 mm^3/year | Standard Deviation 48.349487 |
| 3 Very Mild to Mild DAT Treated With the Combination | Rate of Change of Hippocampal Volume Slope | right hippocampal volume slope | -125.0687876 mm^3/year | Standard Deviation 72.5509442 |
| 4 Nondemented Comparison Subjects. | Rate of Change of Hippocampal Volume Slope | left hippocampal volume slope | -46.9484805 mm^3/year | Standard Deviation 83.582553 |
| 4 Nondemented Comparison Subjects. | Rate of Change of Hippocampal Volume Slope | right hippocampal volume slope | -80.0840066 mm^3/year | Standard Deviation 130.3453711 |
p-value: 0.095ANOVA
Secondary
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) .
Time frame: two years
Population: We combined the DAT patients who received any treatment (donepezil or combined) \& used the annual roc in ADAS-Cog to equally separate them into 3 subgroups; improving (1/3 negative ADAS-Cog roc), stable (1/3 near-zero ADAS-Cog change) \& worsening (1/3 positive ADAS-Cog change).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 1 Very Mild to Mild DAT Untreated | Comparison of Combined DAT Patients' Mean (SD) Hippocampal Volume Slope (mm^3/Year) Rate of Change | left hippocampal volume slope | -70 (mm^3/year) | Standard Deviation 56 |
| 1 Very Mild to Mild DAT Untreated | Comparison of Combined DAT Patients' Mean (SD) Hippocampal Volume Slope (mm^3/Year) Rate of Change | right hippocampal volume slope | -77 (mm^3/year) | Standard Deviation 51 |
| 2 Very Mild to Mild DAT Treated With Donepezil | Comparison of Combined DAT Patients' Mean (SD) Hippocampal Volume Slope (mm^3/Year) Rate of Change | left hippocampal volume slope | -106 (mm^3/year) | Standard Deviation 55 |
| 2 Very Mild to Mild DAT Treated With Donepezil | Comparison of Combined DAT Patients' Mean (SD) Hippocampal Volume Slope (mm^3/Year) Rate of Change | right hippocampal volume slope | -141 (mm^3/year) | Standard Deviation 78 |
| 3 Very Mild to Mild DAT Treated With the Combination | Comparison of Combined DAT Patients' Mean (SD) Hippocampal Volume Slope (mm^3/Year) Rate of Change | left hippocampal volume slope | -100 (mm^3/year) | Standard Deviation 37 |
| 3 Very Mild to Mild DAT Treated With the Combination | Comparison of Combined DAT Patients' Mean (SD) Hippocampal Volume Slope (mm^3/Year) Rate of Change | right hippocampal volume slope | -105 (mm^3/year) | Standard Deviation 34 |
Comparison: There would be a treatment effect on the changes of hippocampal measures over time.~Repeated measures ANOVA on hippocampal volume slopes with hemisphere as a within-subject repeated factor, and treatment group as the main effect.p-value: 0.066ANOVA
Comparison: There would be a treatment effect on the changes of hippocampal measures over time.~Repeated measures ANOVA on hippocampal volume slopes with hemisphere as a within-subject repeated factor, and treatment group as the main effect.p-value: 0.009ANOVA
Comparison: There would be a treatment effect on the changes of hippocampal measures over time.~Repeated measures ANOVA on hippocampal volume slopes with hemisphere as a within-subject repeated factor, and treatment group as the main effect.p-value: 0.3ANOVA
Comparison: RM-ANOVA on hippocampal volume slopep-value: 0.0288Repeated Measures ANOVA