Corticolimbic Degeneration and Treatment of Dementia

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.

Study Overview

• Status: Completed
• Conditions: Dementia
• Intervention / Treatment: Drug: Donepezil (Aricept®); Drug: Memantine (Namenda®)

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.

• Study Type: Interventional
• Enrollment (Actual): 39
• Phase: Phase 4

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years to 95 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: 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
Active Comparator: Very Mild-Mild DAT Treated W/ Donepezil; Group 2) subjects with very mild (CDR 0.5) to mild (CDR 1) DAT that are treated with Donepezil (Aricept®).	Drug: Donepezil (Aricept®); 5mg/day for six weeks and if no serious side-effects increased to 10mg/dy.; Other Names: Aricept
Active Comparator: Very Mild-Mild DAT Treated W/Combination; 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: Donepezil (Aricept®); 5mg/day for six weeks and if no serious side-effects increased to 10mg/dy.; Other Names: Aricept; Drug: 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.; Other Names: Namenda
No Intervention: Nondemented Comparison Subjects; Group 4) nondemented comparison subjects.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Collaborators: Northwestern University
• Investigators: Principal Investigator: John Morris, MD, Washington University School of Medicine

Study record dates

Study Major Dates

• Study Start: November 1, 2004
• Primary Completion (Actual): October 1, 2009
• Study Completion (Actual): October 1, 2009

Study Registration Dates

• First Submitted: October 7, 2008
• First Submitted That Met QC Criteria: October 7, 2008
• First Posted (Estimate): October 8, 2008

Study Record Updates

• Last Update Posted (Actual): September 11, 2018
• Last Update Submitted That Met QC Criteria: August 9, 2018
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Keywords: Dementia of the Alzheimer type
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Dementia; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Cholinergic Agents; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Dopamine Agents; Nootropic Agents; Antiparkinson Agents; Anti-Dyskinesia Agents; Cholinesterase Inhibitors; Donepezil; Memantine
• Other Study ID Numbers: 5R01MH060883-06 (U.S. NIH Grant/Contract)