Research Cores

The Biorepository Core, located at Uniformed Services University of the Health Sciences (USUHS), manages the storage and processing of blood and saliva samples collected through all CENC protocols. Blood samples consist of plasma, serum, and cells, which will be processed to extract DNA and other biomarkers.

The Biorepository Core, located at Uniformed Services University of the Health Sciences (USUHS), manages the storage and processing of blood and saliva samples collected through all CENC protocols. Blood samples consist of plasma, serum, and cells, which will be processed to extract DNA and other biomarkers. These biological fluids will be catalogued, tracked, and stored at -80°C in a dedicated biorepository facility maintained by Center for Neuroscience and Regenerative Medicine (CNRM) at USUHS. The core will administer requests for use of these biological samples from investigators inside or outside the CENC, according to the data and sample sharing policies of the Consortium.

The ability to measure proteins and other bioactive molecules in accessible biological fluids such as blood and saliva is critical for clinical research, particularly for prospective multicenter observational studies. It is critical that the collection of such samples be standardized and closely monitored, and that assays be carried out in a central laboratory under rigorous quality control. Additionally, a large collection of well curated biological samples linked to comprehensive clinical and imaging data is an enormously valuable resource for future discoveries on the chronic effects of neurotrauma, particularly as the participants in the clinical cohorts become older and the natural history of TBI-related neurodegeneration plays out. Such a collection must be maintained under conditions that ensure the integrity of the samples and provenance of the clinical data. Finally, the availability of these samples must be made known to the wider scientific community, and the sharing of these valuable resources must be carefully managed to ensure that the maximum scientific value will be obtained. In order to fulfill these goals, the CENC's Biorepository Core has the following specific aims:

Blood draw equipmentSpecific aim 1. Provide consistent infrastructure, management, and centralized resources for sample banking. The Biorepository Core serves as the sole recipient of patient samples and has a dedicated staff that trains the clinical sites in the collection of samples and catalogs and tracks received samples.

Specific aim 2. Carry out genotyping assays of common genetic variants. The Biorepository Core performs genotyping for several common genetic variants that have been reproducibly associated with chronic effects of neurotrauma. These include: APOE, DRD2, COMT, BDNF, DAT1, MAO-A. Genotyping at other alleles will be carried out as more information becomes available regarding their association with neurodegenerative disorders after TBI.

Laboratory hoodSpecific aim 3. Carry out biochemical assays to fulfill the specific aims of the research projects.

Assays such as salivary cortisol, plasma IGF-1, testosterone, and Thyroid Stimulating Hormone, plasma amyloid beta peptide assays, and any other assays required for research protocols will be carried out. The Biorepository Core will also coordinate the shipment of samples.

Specific aim 4. Manage the sharing of biological samples with other CENC and outside investigators.

The Biorepository Core works to support CENC or other researchers who wish to research novel measurements of exploratory biomarkers in banked samples collected in the specific projects.

Contact: Brian Cox, PhD (Co-PI, USUHS liaison); brian.cox@usuhs.edu | Kimbra Kenney, M.D. (Co-PI, CENC liaison); kimbra.kenney@usuhs.edu

The Biostatistics Core, located at RTI International, provides analytic expertise and statistical programming support for CENC supported studies. This support includes study design and protocol development, ongoing study monitoring, data analysis, reporting, and manuscript development of basic science, pre-clinical, translational, and observational studies as well as randomized clinical trials.

People workingThe Biostatistics Core, located at RTI International, provides analytic expertise and statistical programming support for CENC supported studies. This support includes study design and protocol development, ongoing study monitoring, data analysis, reporting, and manuscript development of basic science, pre-clinical, translational, and observational studies as well as randomized clinical trials.

Biostatistical Specific Aims:

Specific Aim 1. Develop well designed studies that turn a clinical or behavioral investigator's concept into a clinical trial or observational study with appropriate hypotheses, statistical design, measurements, logistical operations, and analysis plans.

Specific Aim 2. Support a high level of academic (publication) productivity that translates research into advances in the treatment of the chronic effects of neurotrauma.

Biostatistics plays a wide range of roles in the planning and conduct of CENC studies, as shown in the table below. Biostatistics has been fully integrated into the planning of all of the CENC studies, and will be continued through study implementation and analysis.

This philosophy will be applied to the development and implementation of any additional studies undertaken by the CENC.

Research Step Role of Biostatistics
Concept: Develop general study concept Biostatistics should be integrated early in the study development process to assure statistical validity of the study.
Hypotheses: State specific hypotheses to be investigated Assure that primary and secondary hypotheses are well stated using measurable concepts that can be reliably quantified.
Measurements: Determine specific outcomes to measure Assure that measurements relate directly to the hypotheses, can be measured with little bias and low variability and that appropriate methods are used to obtain the measurements.
Design: Establish the design of the study Develop statistical design (for example, random assignment or selection) that best supports the hypotheses to be evaluated. Determine sample size allocation that yields adequate power and does not waste resources. Assure that measurements are temporally taken for valid assessment of causation and/or correlation.
Protocol: Prepare a protocol that guides the conduct of the study Assure that all aspects of the study relating to statistical validity are properly addressed, including: study objectives and hypotheses, ethics and protection of human subjects, inclusion and exclusion criteria, design and sample size justification, randomization or selection methods, measurement bias and variance, data management, QC/QA, Data Monitoring and Safety Committee reporting for safety and efficacy, analysis plans, and publication plans.
Analysis Planning: Develop detailed analysis plans Develop detailed analysis specifications which are mapped against all primary and secondary hypotheses. Select methods that appropriately reflect the distributional properties of the data, missing data issues and any interim analyses. Specify specific data files and variables to be created to support the analyses. Specify quality assurance procedures to ensure accuracy of results.
Analysis Implementation: Conduct analyses as planned Implement analysis plan and document any deviations. Assure that data have been properly cleaned and locked. Conduct quality assurance to ensure accuracy of results.
Publications: Disseminate results and findings Participate in manuscript/presentation preparation and review. Author methods sections and ensure that all analyses are properly interpreted and conclusions are statistically valid and support by the study design and data.

Contact: Rick Williams, PhD; rwilliams@rti.org

The Data Management and Study Management Core, located at RTI International, centrally and securely maintains all CENC-collected data, oversees the clinical monitoring of research sites, and provides a Consortium Research Manager who interacts with the Clinical Research Coordinators from the Research Study Sites to expedite and guide clinical protocols through regulatory approval processes and coordinates patient accrual and study activities across sites.

People workingThe Data Management and Study Management Core, located at RTI International, centrally and securely maintains all CENC-collected data, oversees the clinical monitoring of research sites, and provides a Consortium Research Manager who interacts with the Clinical Research Coordinators from the Research Study Sites to expedite and guide clinical protocols through regulatory approval processes and coordinates patient accrual and study activities across sites.

Data Management Specific Aims:

Specific Aim 1. Provide efficient data capture and data transfer procedures that speed the availability of translational results.

Specific Aim 2. Provide central data management that maximizes the availability of the data to the CENC and to the wider research community.

Specific Aim 3. Provide data security that safeguards the confidentiality, integrity and availability of the data.

Study Management Specific Aims:

Specific Aim 1. Establish Consortium communication processes that enhance the efficiency and productivity of the Consortium.

Specific Aim 2. Develop study procedures and materials that provide valid and reliable data across the research sites.

Specific Aim 3. Manage study operations so that studies move forward quickly, enrolling patients as planned, and efficient use is made of Consortium resources.

Specific Aim 4. Manage human subjects' protections that satisfy the requirements of DoD, VA and the participating sites.

Specific Aim 5. Manage regulatory affairs processes that support FDA regulated studies.

Contact: Rick Williams, PhD; rwilliams@rti.org

The Neuroimaging Core, located at Baylor College of Medicine (BCM), is composed of experts from the fields of neuroradiology, neuropsychology, magnetic resonance imaging (MRI) physics, information technology and computer programming, and statistics. The core will facilitate sequence development and pulse programming, training and supervision of technologists and support personnel, acquisition of imaging data, quality assurance (QA), conventional and advanced imaging analysis, transfer, and storage of imaging data, and assistance in the interpretation of neuroimaging data.

Brain scans

The Neuroimaging Core, located at Baylor College of Medicine (BCM), is composed of experts from the fields of neuroradiology, neuropsychology, magnetic resonance imaging (MRI) physics, information technology and computer programming, and statistics. The core will facilitate sequence development and pulse programming, training and supervision of technologists and support personnel, acquisition of imaging data, quality assurance (QA), conventional and advanced imaging analysis, transfer, and storage of imaging data, and assistance in the interpretation of neuroimaging data.

The main goal of the imaging core is to facilitate collection and analysis of structural and functional MRI to detect imaging-related changes following TBI. Objectives of the imaging core are to: 1) assist in the acquisition of brain imaging data, including conventional magnetic resonance imaging (MRI), detailed volumetry and cortical thickness, diffusion tensor imaging (DTI), arterial spin labeling (ASL), and resting state functional connectivity MRI (fcMRI); 2) transfer, convert, analyze, and store the brain imaging data; 3) direct and assist in performing quality assurance of the scanners at all sites involved in imaging data collection; and 4) communicate with the investigators to facilitate integration of the brain imaging data into the projects to address their aims and hypotheses.

Military and VA Benefit

Repetitive TBI is of great significance in view of recent reports of chronic traumatic encephalopathy (CTE) resulting from repetitive sports concussions and (Guskiewicz, Marshall et al. 2005), most recently, from trauma experienced during combat (Goldstein, Fisher et al. 2012). CTE is a progressive neurodegenerative disease that has an insidious clinical presentation, including the development of cognitive and emotional symptoms, and some cases also develop Parkinsonian symptoms (Saulle and Greenwald 2012). The diagnosis of CTE is difficult due to the lack of consensus on diagnostic criteria and insufficient longitudinal data addressing clinicopathologic correlations (Saulle and Greenwald 2012)(Gavett, Stern et al. 2011). The population of OEF/OIF/OND veterans is relatively young, and it may be some time before their increased risk for mild cognitive impairment (Fischer, Jungwirth et al. 2007) and Alzheimer's and dementia can be accurately assessed. However, degeneration can occur in younger TBI populations, including declines associated with CTE (Saulle and Greenwald 2012),(Gavett, Stern et al. 2011), and comorbid conditions such as PTSD and depression likely interact with the TBI-related neuropathology to produce greater cognitive and functional decline. Gaps in current knowledge include sparse research on chronic effects of repeated exposures to blast-related TBI and combined effects of blast and non- blast mechanisms, especially studies using longitudinal designs. Recent literature on outcomes of OEF/OIF/OND veterans sustaining TBI consists primarily of cross-sectional studies lacking brain imaging.

The CENC longitudinal projects are designed to differentiate persistence of sequelae from progression of deficits, as well as the identification and characterization of individuals with a possible neurodegenerative condition secondary to remote TBI. Declines in cognition and functional status could be due to a variety of factors, including adjustment issues, psychiatric conditions, and neuropathology secondary to the injury. Our research design and the use of multiple assessment modalities are intended to allow the examination of these separate factors and to relate them to outcome. Although the length of the follow-up period is limited due to the funding mechanism, the proposed studies have been designed to perform detailed, multi-modality examination of subjects. See an interactive neuroanatomy trainer.

Brain scans

Contact: Elisabeth Wilde, PhD; ewilde@bcm.edu

The Neuropathology Core, located at VA Boston, in collaboration with the Uniformed Services University of the Health Sciences (USUHS), has established a brain bank for Veterans who have experienced blast and/or concussive traumatic brain injury (TBI). The Core manages the collection of brain specimens from participants; fully characterizes the tissue neuropathologically and stores tissues for use by qualified investigators from within or outside the CENC; administers requests for use of these tissues according to sample sharing policies of the Consortium; and tracks the results of these collaborative studies. As the program progresses, the Core will expand to involve brains from medical examiners using the same standardized neuropathological methods of brain donation, harvesting, dissection, processing, storage, and analysis.

Gaps in mTBI Research

TBI due to exposure to explosive blasts (mostly related to IEDs) is responsible for over 70% of the combat casualties associated with Operation Iraqi Freedom (OIF), Operation Enduring Freedom (OEF), and Operation New Dawn (OND) [3,4]. While most of these TBIs are classified as mild, they can have disabling long-term consequences. Mild TBI (mTBI) is widely recognized as the signature injury of modern warfare, and yet little is known about its acute effects on the brain or its long-term consequences, particularly in individuals who have suffered multiple mTBIs. With the current practice of repeated redeployment, the opportunities for Service Members to experience multiple TBIs increase dramatically.

While much work has been done to study TBI in animal model systems, the specific details of the neuropathological changes and the impact of trauma from exposure to IED blast waves on the human brain remains unknown. Moreover, the repair responses of the brain to these injuries and their long-term consequences are similarly unclear.

The primary reason for this major gap in knowledge has been the lack of available brain specimens for morphologic and molecular study derived from deceased active or returned combatants who suffered mTBI. Access to brain specimens that will be collected and made available to researchers through the Core is needed to develop and advance methods for the diagnosis, treatment, and prevention of mTBI and its long-term effects

Neuropathology Core, Boston VA

The Neuropathology Core, VA Boston, will recruit as many VA brain donors as possible, casting a wide net aimed at acute and chronic neurotrauma, single and multiple TBI, mild to severe TBI, and TBI from many possible sources including blast injury, concussion, motor vehicle accidents, sports-related injuries, and falls; however, we will emphasize military-related blast and concussive injury in OEF/OIF/OND Veterans in our recruitment.

The Core will build on the experience and procedures of the Boston University Alzheimer's Disease Center (BUADC) Brain Bank and the CTE Center Brain Bank (VA-BU-SLI CTE Brain Bank), which collectively house over 1200 brain specimens, including over 350 brain and spinal cord specimens from civilians and Veterans with TBI. Additionally, the Core will build on the brain banking experience developed at VA Boston for the VA ALS brain bank, the VA Gulf War brain bank and most recently, the VA PTSD brain bank. The harvesting, neuropathological characterization, storage and distribution of brain and other central nervous system (CNS) tissue will be precisely standardized using state-of-the-art techniques. A uniform dataset of neuropathological findings will be determined on each case and entered into a privacy-protected database. The collection of brain, spinal cord, and eye tissue from a broad range of traumatic injuries and the uniform dataset will facilitate statistical analysis through wide-ranging TBI parameters for correlation with military history, medical records, and clinical signs and symptoms.

Specific Aims

1. Obtain brain specimens on all cases referred to the brain bank among those enrolled in CENC studies who die and for whom consent for brain donation is provided.

2. Accession the brain specimen derived from any Veteran who had been deployed in OIF, OEF, or OND, who dies and the next-of-kin requests brain donation for research studies of TBI.

3. Dissect and preserve the brain and CNS tissues using standard protocol to maximize their use for TBI research.

4. Perform detailed neuropathological evaluations of all accessioned brain specimens and issue a complete diagnostic neuropathology report.

5. Document the extent and distribution of relevant pathology present within each brain specimen.

6. Make tissue specimens available to qualified researchers engaged in TBI-related research.

7. Maintain permanently all pertinent specimen-related data and neuropathological results in a manner accessible to all investigators within the Consortium, as well as more broadly to other qualified researchers.

Contact: Ann McKee, MD, Investigator, Neuropathology Core Leader; amckee@bu.edu