CDP-Choline and Working Memory After TBI: A Neuroimaging Study

Study Overview
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Brief Summary
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The purpose of this study is to determine whether an investigational drug, called CDP-Choline, improves memory in people with traumatic brain injury (TBI). To do this, we are asking for people with traumatic brain injury and people without traumatic brain injury to be a part of this study. We will compare results between each group to see if this investigational drug makes a difference with memory. We will also compare brain imaging results and information collected before and after the taking of the study medication to see if there are any differences. We hypothesize that there will be differences in brain activation patterns between individuals with TBI and healthy controls, as well as differences in performance on memory testing at baseline. We further hypothesize that, after treatment with CDP-Choline, the patterns in neuroimaging findings and cognitive testing results for individuals with TBI will more closely resemble results observed for healthy individuals. We hope that what we learn from this study will be helpful in the future treatment of individuals with head injury.

Detailed Description
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Despite the prevalence of working memory deficits following traumatic brain injury (TBI), the scientific data regarding pharmacological treatment of this problem is limited. As deficits in working memory are known to have a significant impact on functional outcomes for individuals with TBI, further research in this area is essential in order for physicians to be able to treat this problem more effectively. The primary goal of the proposed project is to examine the efficacy of a particular pharmacological agent, CDP-Choline, in the treatment of working memory deficits following traumatic brain injury (TBI). The study sample will consist of 48 subjects: A group of 24 individuals who have sustained moderate to severe TBI, and a group of 24 healthy controls. Each group will be divided into a placebo and treatment group. The project will utilize functional Magnetic Resonance Imaging (fMRI) to investigate the cerebral neurophysiological effects of treatment with CDP-Choline. A working memory task (N-Back) will be employed during fMRI sessions. In addition, the effects of treatment with CDP-Choline on neuropsychological testing performance will also be evaluated, and the correlations between behavioral performance and neuroimaging results will be observed. We will achieve these goals by comparing baseline neuropsychological testing results as well as fMRI results, with a second set of testing and neuroimaging results obtained following 1 month of pharmacological treatment with CDP Choline or placebo. Based on our preliminary studies and the available literature, we expect to see the following: Baseline fMRI results are expected to show that individuals with TBI display altered patterns of cerebral activation during a working memory task, as compared to healthy controls. With CDP-Choline treatment, we expect TBI subjects to display fMRI laterality and dispersion patterns that more closely resemble patterns of healthy controls. In addition, we anticipate improvements in behavioral performance on both the specific working memory task (N-Back), and on traditional neuropsychological tests to be associated with CDP-Choline treatment, with greater magnitude of change on testing results for the TBI group as compared to any changes noted for the control or placebo groups. Finally, we anticipate that specific significant correlations will be observed between neuropsychological testing results and neuroimaging findings, and that the strength of these relationships will be greater for the TBI treatment group, as compared to the placebo or healthy control groups. By conducting the proposed study in this manner, we hope to provide scientific data that will allow for improved treatment, and ultimately improved functional outcomes for individuals who have sustained TBI.

Official Title
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CDP-Choline and Working Memory After TBI: A Neuroimaging Study.

Conditions
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Brain Injuries

Intervention / Treatment
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* Drug: CDP-Choline
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: For individuals with TBI and Health Controls: right hand dominant English speaking No history of neurological illness (for example, stroke, seizure or brain tumor. No significant history of psychiatric illness (for example, schizophrenia or bipolar disorder) or current severe emotional distress. No visual difficulties that would not allow for reading and following written instructions. Free of alcohol or substance abuse. Capable of following basic written and oral instructions. Not taking certain medications that may interact with study medication or interfere with neuroimaging. Be able to take medication in tablet form, or crushed and dissolved in a liquid. Meet the additional criteria associated with MRI safety standards, as required by the University of Pittsburgh Department of Radiology. For example, these criteria include exclusion due to surgical placement of metal plates or electronic implants. In addition: Individuals with TBI must: Have a specific diagnosis of a moderate to severe traumatic brain injury, which can be confirmed through review of medical records or assessments. Be at least 1 year, but no more than 3 years since injury. Must have significant working memory problems, as indicated by performance on a screening test. Normal Control subjects must: Perform within the normal range on a test of working memory. Exclusion Criteria: Prisoners. Males with sexual partners who are planning to become pregnant during the treatment period. Females who are currently pregnant or who are planning to become pregnant during the treatment period. Individuals who are currently enrolled in another medication study Individuals who are currently, or have previously been, treated with CDP-Choline (Citicoline) for research or clinical purposes. Currently in a nursing home in the state of Pennsylvania.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CDP-Choline<br>Treatment with CDP-Choline | Drug: CDP-Choline<br>* 1000 mg CDP-Choline 2 x per day for 6 weeks.<br>* Other names: Cytidine 5'-diphosphocholine;|
| Placebo Comparator: Placebo<br>Treatment with Placebo | Drug: Placebo<br>* Treatment with placebo for 6 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cognitive Composite Score for Group of Subjects With TBI and Healthy Controls Matched by Age, Education, and Treatment Group. | .A mean index score created as a composite cognitive performance across domains. Purpose was to serve as a measure of overall cognitive functioning for data analysis. A higher T-score indicates a higher level of cognitive function. Due to matching criteria of age range, gender and education level, as well as the small number of subjects with TBI who complete the study (n = 5), matched groups required a reduction to 2 subjects per group for analysis as planned per protocol. Due to the small number of subjects in this study overall, although analyses were run, results should be considered with caution. | 6 weeks | 
| Cognitive Composite Score for Group of Subjects With TBI and Unmatched Healthy Controls | A mean index score created as a composite cognitive performance across domains. Purpose was to serve as a measure of overall cognitive functioning for data analysis. Higher T-scores indicate higher levels of cognitive functioning. Due to the small number of subjects in this study, this second analysis was completed using the same number of subjects in the TBI and control groups, but without matching so that a slightly larger number of subject's data could be utilized. Although analyses were run, due to the very small number of participants in this study, results should be considered with caution. | 6 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Traumatic Brain Injury, FMRI, Memory, Cognition, Neuropsychology