Alzheimer’s Disease Research CenterThe Wake Forest ADCC will coalesce exceptional resources around research related to AD and the Center’s theme of the contribution of metabolic pathways to AD pathogenesis. Below, we summarize specific Wake Forest resources on which the Wake ADCC will build and which are essential to its mission.

J. Paul Sticht Center on Aging and Section on Gerontology and Geriatric MedicineThe Wake ADCC will be a close partner of the Sticht Center on Aging. The Sticht Center on Aging was

founded in 1987 by William Hazzard, MD to coordinate clinical, educational and research activities in gerontology/geriatrics at WFBMC. The J. Paul Sticht Center on Aging and Rehabilitation building was constructed with a $40 million investment in 1997. In September 2006, the Aging Center program was designated as an official “University wide” Center by Dean William Applegate (a geriatrician), with Dr. Stephen Kritchevsky as its first director. This designation entails the provision of institutional dollars to support the development and coordination of research programs of relevance to aging at WFSM. Dr. Barbara Nicklas is Deputy Director of the Aging Center, and Drs. Jeff Williamson (Interim Chair, Internal Medicine) and Suzanne Craft are the Center’s Associate Directors. The Center’s membership includes 95 scientists from 15 departments across the university. The total amount of extramural funding to Aging Center members in FY15 was $24.2 million, $11.8 million of which is from the National Institute on Aging.

The Sticht Center has a close relationship with the Section on Gerontology and Geriatrics (Dr. Kaycee Sink, Interim Section Head), and ranks among the top geriatric programs in the nation. The Section has 23 full-time faculty members. Clinical activities include an outpatient geriatric consult clinic, an outpatient memory assessment clinic, a home care program, an Acute Care for the Elderly inpatient unit, the Brookridge assisted living and nursing homes, and a clinical geriatrics fellowship program. Also, the Section has been active in both the marketing of geriatrics and the promotion of aging related research as part of an active and formalized strategy to increase the number of physicians entering geriatric training. Since 2008, WFSM has been designated as a John A. Hartford Center of Excellence (HCoE, Dr. Williamson, PI). The goal of this program is to expand the recruitment of medical students and residents and fellows into careers in academic geriatrics and gerontology by introducing them not only to geriatric clinical care, but also to clinical research through the systematic inclusion of information about research opportunities for student and resident trainees in every clinical lecture given by faculty in the Section. The Center is a major draw for recruiting new faculty who are outstanding clinicians with high interest and promise for academic geriatrics and supports the career development of these academic geriatricians who have demonstrated leadership potential as clinician scientists or clinician educators. Currently the HCoE at WFU supports 5 scholars. In addition to the HCoE, Wake Forest was also awarded a Donald W. Reynolds Foundation (DWRF) Geriatrics Education Program in 2009. The DWRF program is focused on the translation of evidence based knowledge in geriatrics and gerontology to the bedside teaching to the spectrum of trainees throughout the entire institution. Thus, our Geriatrics Section has the clinical resources, patient population, and a core faculty of geriatricians to provide resources and strong support for the conduct of clinical research. The Center and Section are housed in a four- story, 150,000 sq. ft. building uniting geriatric outpatient services, geriatric psychiatry, geriatric rehabilitation, the Acute Care for the Elderly unit, administrative and faculty offices, several conference rooms, the Roena Kulynych Center for Memory and Cognition Research (see below), the Geriatric Research Center, and a Geriatric Clinical Research Unit (CRU) satellite site that opened in 2002 (the first General Clinical Research Center devoted to geriatrics in the nation, see below). The Center contains 128 beds for geropsychiatry, geriatric medicine, and rehabilitation medicine.

Support for Wake ADCC: The Sticht Center for Aging and Section of Gerontology will be a close partner of the ADCC, and in particular the ADCC will be able to leverage recruitment registries and community relationships established by Sticht Center investigators.

Roena B. Kulynych Center for Memory and Cognition ResearchThe Roena B. Kulynych Center for Memory and Cognition Research (Co-Directors: Dr. Suzanne Craft and

Dr. Jeff D. Williamson) began in 2002 as part of a $3.7 million endowment from the Kulynych Family Foundation. Through this gift, the Section of Gerontology has expanded its research focus on the relationship between cognitive decline, chronic disease and disability in older adults. The mission of the Kulynych Center is to support interdisciplinary, translational research that advances our understanding of the effects of common

medical conditions on brain aging and on the development of Alzheimer’s disease and related disorders. Center investigators will use this knowledge to develop novel approaches to prevention, treatment, and medical/mental health care delivery to maximize the likelihood that older adults who live into their 90’s and beyond will remain healthy, intellectually vigorous contributors to society. The Center will also promote the education of scientists, clinicians, patients, caregivers, and the community in areas of relevance to Alzheimer’s disease. The Kulynych Center endowment generates $125,000 per year, which will be available to support the activities of the ADCC, including funding of pilot work, recruitment of new faculty, and augmenting administrative support to the ADCC.

Claude D. Pepper Older Americans Independence Center (OAIC)The Claude D. Pepper OAIC (Director, Dr. Stephen Kritchevsky) is one of 15 such centers supported

nationally by the National Institute on Aging. In its most recent competing renewal, it achieved the best score in the nation. The Pepper OAIC seeks to assess risk factors of physical disability in older adults, develop and test effective prevention therapies, and train new investigators in research on aging and disability, while developing their leadership qualities. Studies traverse the translational spectrum, including molecular biology, in vitro and animal studies, clinical research, behavioral and social sciences, and epidemiology. The general goal of the OAIC program is to increase scientific knowledge that leads to better ways to maintain or restore independence to older persons. The research objectives are to (1) assess, using translational research, multiple factors such as biological, genetic, co-morbid, psychosocial, and behavioral that contribute to sarcopenia, physical function decline, and progression to disability; and (2) develop and reliably test in clinical and pre-clinical studies pharmacological and behavioral interventions to prevent or delay age-related declines in physical function and progression to disability. The OAIC includes eight integrated cores, which support investigators, junior faculty members, infrastructure, and services in a multidisciplinary environment: the Leadership and Administrative Core, the Research Career Development Core, the Pilot / Exploratory Studies Core, the Clinical and Translational Research Core, the Biostatistics and Data Management Core, the Genomics and Biomarkers Core, and the Body Composition Core, and the Recruitment Core.

The Recruitment Core is especially important to the success of the Wake ADCC. Some of its highly effective recruitment and retention strategies include: The VITAL (Volunteers in Touch with an Active Lifestyle) database, an IRB-approved database of more

than 8,900 older adults interested in volunteering for research. A semiannual newsletter goes to all volunteers in this database.

A quarterly recruitment luncheon attended by all recruiters and coordinators from all OAIC studies and any other WFSM coordinators conducting research in older adults. The group reviews active protocols and hosts speakers with expertise in the science of recruitment and participant adherence, covering topics such as minority recruitment and motivational interviewing. Coordinators regularly refer ineligible participants to another study in which they may qualify.

Three drivers and four vans to provide transportation for study participants unable to drive or find a ride. Regular outreach through health fairs, church-related functions, and community events to target minorities. A 24-hour recruitment phone line, 1-877-BE-VITAL, and recruitment core staff trained in telephone

screening and referral for all OAIC-supported trials.A dedicated OAIC staff member has specific expertise in designing and placing study-specific ads and mailings targeted to older adults with diverse backgrounds.

Support for Wake ADCC: The OAIC collaborates with the Wake ADCC in multidisciplinary research aimed at the identifying modifiable risk factors and barriers contributing to disabilities in activities of daily living among older adults with mild cognitive impairment (MCI) and early stages of AD. The Recruitment Core described above is an especially important asset to the Wake ADCC. The close relationship between the OAIC and the ADCC is underscored by the fact that OAIC PI Steven Kritchevsky is Chair of the ADCC Internal Advisory Board Member.

Geriatric Clinical Research Center (CRU) and General CRUClinical Research Units: Two CRUs are available to the ADCC, a general and a geriatric CRU. The CTSI

Clinical Research Unit provides clinical investigators with the fundamental resources and controlled environment necessary to conduct research with human subjects. The Unit exists to help investigators translate basic scientific knowledge into new or improved methods of patient care. It is the CRU’s policy to

prioritize resources for pilot studies and early-career investigators. CRU resources include clinical staff support including a PA-C, nursing, and technician support. The CRU provides a team of dietary and laboratory personnel trained in research techniques to support dietary related studies and processing of samples. The main unit of the CRU facility of 6,623 sq. ft. of outpatient research space with nine examining rooms, a metabolic kitchen with the necessary equipment to prepare special meals for studies with feeding components, and a CLIA-certified processing core, with state-of-the-art equipment and freezer capacity for tracking samples through FreezerWorks® . In 2005, the institution initiated the first Geriatric CRU satellite in the nation. This space, a 2,500 sq. ft. unit, is adjacent to the Geriatric Research Center for mutual convenience with five outpatient exam rooms, a consult room, nurses’ station, waiting area, patient dining room, and access to all main unit resources.

The Section on Geriatrics and Gerontology supports an additional Geriatric Research Center and is the site of the Wake Forest OAIC’s Clinical Research Core. The Geriatric CRU is a 4,000 sq. ft. area with facilities for state-of-the-art clinical research, including cognitive testing, lumbar puncture, metabolic and vascular function and physical performance including gait analysis, exercise training, exercise stress testing, echocardiography, strength and functional status testing, and office space for research staff. The Internal Medicine section on Geriatrics and Gerontology supports the Geriatric Research Center. The GRC also includes a reception/waiting area and seven private offices. Six wheelchair-accessible examination rooms are located on the ground floor in the outpatient clinic area. These examination rooms are available and currently used for both clinical research and patient care. In addition, a standard examination room is located on the first floor within the GRC area.

The GRC Cardiopulmonary Laboratory, a 420 sq. ft. facility located in the GRC, is equipped with a Trackmaster treadmill, 12 lead ECGs, a Medgraphics expired gas analysis system, lockable storage, and automated and manual blood pressure gauges. Facilities for blood collection, processing and storage include a refrigerated centrifuge and a -80°C freezer. Additionally, the lab is equipped with a fully stocked crash cart, and practice codes are conducted with GRC staff every other month. A physician is on call during each stress test for safety. There are eight treadmills located in the GRC for use in exercise training studies.

Support for Wake ADCC: The CRUs will support Wake ADCC by providing critical facilities, nursing staff, and clinical research expertise for its study visits and exams.

Imaging Informatics Resources

Josh Tan, MS, Medical Imaging Engineer/Analyst Programmer, oversees all phases of database design, development, and management. He is also responsible for administration of TeraRecon servers and workstations, and training investigators, faculty, and study coordinators in best methods of data collection and image analysis. He collaborates with investigators to determine image analysis requirements to achieve study/grant objectives. Equipment and software resources include the following.

TeraRecon Systems

TeraRecon AquariusNET servers

Distributed 2-D/3-D/4-D real-time rendering and visualization on any windows PC via local network Total of 15TB of storage space for Medical Imaging in RAID5+1 configuration directly connected to

servers Concurrently 3-D render ~36,000 images in real-time Render images from any modality in 3-D from a stack of 2-D DICOM images Virtual Endoscopy MPR, MIP, 3-D, 4-D Image fusion JPEG, AVI, and DICOM output

TeraRecon Aquarius workstations

Advanced 2-D/3-D/4-D real-time rendering and visualization imaging workstation 500GB of direct attached storage space for storage of medical images

Each workstation can concurrently render 3,400 images in real-time Render images from any modality in 3-D from a stack of 2-D DICOM images Volumetric, area, and distance measurement capabilities Advanced segmentation and analysis modules Virtual Endoscopy MPR, MIP, 3-D, 4-D Image fusion JPEG and AVI output

OsiriX

2-D/3-D/4-D advanced imaging software for Macintosh Volumetric, area, and distance measurement capabilities Advanced segmentation and analysis modules Open source software QuickTime Virtual Reality movies

o Interactive movies for medical imaging o Embeddable movies into PowerPoint presentations o Embeddable movies into web pages

Mimics

Advanced 2-D/3-D modeling software for PC Volumetric, area, and distance measurement capabilities Advanced segmentation and analysis modules Generates 3-D AutoCAD files for printing on 3-D printer

Amira

Advanced 2-D/3-D modeling software for PC Volumetric, area, and distance measurement capabilities Advanced segmentation and analysis modules Generates 3-D autocad files for printing on 3-D printer

ImageJ

Advanced imaging software Open source software Based on Java for various platforms of operating systems Advanced segmentation and analysis capabilities

LCModel

Automatic quantification of in vivo proton MR spectra Fully developed over 15 years with spectra analyzed from a wide variety of scanners and field strengths

at more than 400 sites

GE Advantage Workstations

Advanced 2-D/3-D/4-D real-time rendering and visualization imaging workstation Render images from any modality in 3-D from a stack of 2-D DICOM images Volumetric, area, and distance measurement capabilities Advanced segmentation and analysis modules

MPR, MIP, 3-D, 4-D

MIPAV

Advanced imaging software Advanced segmentation and analysis capabilities

DICOM server

Digital Imaging and Communications in Medicine Network storage of medical images from all modalities in DICOM format Imaging workstation and imaging modalities can send images in DICOM format for storage and

retrieval from the DICOM server Image database for organization of medical images DCM4CHEE (www.dcm4che.org) PHP (www.php.net) MYSQL (www.mysql.com) Apache (www.apache.org)

Apple Workstations and Servers

Blu-ray DVD backup Exabyte 320GB tape archive Audio/Video editing and encoding workstations Training videos and images generated on these workstations Website development Database development 3-D/4-D medical animation and illustration Final Cut video editing software and hardware ~30TB hard drive storage systems

Autodesk Maya 9

Animation software for 3-D rendering Animate 3-D objects generated from CT and MR scans Rendering capabilities to 1080p

Medical Imaging Resource Center (MIRC) Software & Hardware

Medical Imaging Resource Center WFBMC helped to develop Beta site Open source Software for secure image transmission using the Internet Coordinating and reading centers use MIRC to automate the sending and receiving of DICOM images

from various hospitals and cities around the world Functionality to automatically de-identify medical images

More than 363,000 diagnostic procedures are performed each year by personnel of the Department of Radiology of WFUHS. The Department of Radiology occupies 92,697 square feet of clinical space. Newly remodeled space formerly occupied by the Emergency Department now houses sophisticated reading rooms and a lecture hall.

A fully staffed outpatient imaging facility is available. This facility contains:

Five (5) 1.5 Tesla MRI Scanners for clinical and research use One (1) whole body high resolution, 3 Tesla (3T) MR scanner for clinical and research use a CT-PET scanner three multislice CT scanners one x-ray bone densitometry unitThe Nuclear Medicine section has eight gamma cameras, including whole body and dual and triple-headed

SPECT units; an integrated medical computer system; and an in-house radiopharmacy. The PET Center, which includes a cyclotron and scanner, is utilized for both clinical and research applications. The MRI Center operates five state of-the-art high-field magnetic resonance imaging units, one of which is cardiac optimized, three of which have parallel imaging, and one which operates at 3T. Most subspecialties have multifilm automatic view boxes as well as standard viewing equipment. Several areas have videotape units and computerized data storage units. Digitization and filmless storage of ultrasound studies is accomplished with KINETiCS, a digital ultrasound management system. Patient radiographic data can be accessed by two methods. One method allows for accessing the transcribed radiology report through LastWord, the electronic medical records database. WFUHS utilizes a comprehensive, filmless picture archiving and communication system (PACS). The high-speed ATM-based system connects five photostimulable phosphorus plate devices serving musculoskeletal, intensive care, and emergency department areas. The reusable plate technology makes it possible to capture standard x-ray images for conversion to digital format. In addition, the GE network, maintaining seven CT scanners and three MR imagers, and nuclear medicine's Pegasus system, is connected to PACS. The automated radiology information system (RIS) provides the demographic input for the PACS.

WFUHS’s radiology imaging systems are linked electronically behind a secure firewall, with all imaging information stored on servers and accessible in real time anywhere within WFUHS. Radiologic readings are placed in LastWord, and fulfilled using radiology’s infrastructure.

As noted above, departmental operations are managed by an automated radiology information system (RIS) with functions that include scheduling, patient and film folder tracking, transcription, electronic report approval, and teaching codes. The RIS is connected to the hospital information system (HIS), which offers order entry and reporting capabilities.

A department-wide office automation system (GAS) supports users with central access to functions such as electronic mail, word processing, databases, spreadsheets, and connectivity into other computing systems.Complete integration of the RIS, HIS, GAS, and PACS provides an efficient environment for collecting, processing, and managing data.

Magnetoencephalography (MEG)The MEG facility consists of an 1,800 sq. ft.suite with a 275-channel whole-head neuromagnetometer

housed within a 208 sq. ft. Vacuumschmelze magnetically-shielded room, 10 dedicated high performance workstations, a five terabyte RAID array for data storage, and a 20-node computer cluster for data processing. The CTF MEG 2005 model instrument is equipped with 275 first-order axial-gradiometers and has the capability for simultaneous acquisition of 64-channel EEG. The system has a full array of nine reference magnetometers and 20 reference gradiometers positioned optimally along the dewar to provide the capacity for synthetic third-gradient balancing; an active noise cancellation technique that removes the external non-biological noise sensed by the MEG reference channels. The system is also configured for continuous head localization, which is an advanced technique that allows MEG data to be corrected for any inadvertent head movements that may have occurred during the acquisition period. The MEG lab maintains an array of magnetically-silent stimulus delivery equipment including remote auditory transducers for pneumatic sound delivery, video projection onto an opaque screen, electrical and pneumatic somatosensory stimulation, and fiber-optic pads for recording subject responses during task performance. Stimuli are controlled via a 3 GHz PC with current-state 24-bit audio and dual-output video cards and presentation software including E-Prime (Psychology Software Tools, Inc) and Presentation (Neurobehavioral Systems). The suite includes a subject prep room for affixing EEG electrodes and for administering consent forms and questionnaires. Both clinical and research studies are performed using the MEG at Wake Forest University Health Sciences.

ANSIR Laboratory Facilities (Directors, Drs. Whitlow, Jung)

The ANSIR Lab at Wake Forest University encompasses approximately 1,000 square feet of space in the Department of Radiology specifically for conducting image processing-related research. The space contains a large conference room for laboratory meetings, data presentations, and journal club meetings, as well as a computer lab containing Linux and Solaris machines for general use and data analysis.

Offices. All neuroradiology fellows, post-docs, and graduate students associated with the ANSIR laboratory have personal cubicle space. All faculty have at least 100 square feet of office space. Secretarial support is available through the Department of Radiology.

Computer (ANSIR Lab). The ANSIR laboratory maintains a rack-configured cluster dedicated to distributed image processing consisting of 13 Linux computers providing 71 compute nodes scheduled through the SUN Grid Engine. Computing power includes five 3 GHz dual core units with 4GB RAM, five 3.3GHz dual core units with 16GB RAM, one 2.8 GHz dual 6-core unit with 32GB RAM, one 3.5GHz dual 6-core unit with 96GB RAM, and one 3.5GHz dual 6-core unit with 192GB RAM that also contains four C2070 Nvidia Tesla GPUs. Nine terabytes of network-attached storage are available and connected over a gigabit Ethernet backbone. All computers are configured to run Matlab via a floating license and are used for functional image processing and analysis. These computers can communicate directly with the Department of Radiology DICOM digital archive, as well as with the clinical and research MRI and CT scanners. All computers are password protected and secured behind the University firewall, and data storage is maintained and backed up by WFUSM Information Services group. The ANSIR laboratory also maintains a data processing resource for all investigators that perform brain imaging studies. Image processing software (WFU_Pipeline [http://www.nitrc.org/projects/wfu_pipeline/]), developed by Dr. Maldjian, facilitates the processing of large amounts of neuroimaging data and provides an interface to SPM/FSL/XNAT.

ANSIR Lab Structural, Perfusion, DTI and MEG Processing Pipelines The ANSIR lab at Wake Forest has been at the forefront of functional

imaging processing methods, implementing a fully automated processing pipeline in 2001 including features such as distributed grid processing, automated error recovery, and data provenance. This has enabled us to become the leading institution in the world in clinical ASL, with seamless translation of image acquisition, automated post-processing, and

insertion into the Picture Archiving and Display System (PACS), with over 15000 clinical ASL MRI studies performed over the last 3 years. This number is unapproached by any MR center anywhere. We have published extensively on our perfusion experience and have delivered numerous invited plenary presentations on our ASL experience (ASNR, ASFNR, ISMRM, RSNA). Our implementation has shown excellent reproducibility in normals (Figure 1), and sensitivity to a variety of disease states. We have added fully automated diffusion tensor processing and tractography to our pipeline, routinely producing exquisite atlas-based tract extractions (Figure 2). We have also implemented a high-throughput fully automated MEG analysis pipeline for high density source-space analysis of resting state MEG data, incorporating a variety of head models, forward models, beamformers, and connectivity metrics.

Figure 1. ASL CBF map in a young normal subject.

Figure 2. Automated Diffusion Tractography. Fully automated atlas-based extraction of corticospinal and pontine fiber tracts.

Figure 3. Group resting state seed-based DMN

Seed based connectivity pipeline. We have implemented fully automated seed-based processing of resting state fMRI data for clinical and research studies. It operates from the point of data acquisition and uses labels defined in our wfu_pickatlas software or pre-defined user ROIs. Figure 4 demonstrates a group default mode network (DMN) constructed from a study of 10 subjects using a posterior cingulate seed region of interest (p< 0.05 corrected).

Graph Theoretical pipeline. We have also implemented a fully automated pipeline for voxel-wise as well as wfu_pickatlas label-based node definition graph theory analysis of resting state data. Figure 4 is an automatically generated log-log plot of the complementary cumulative voxel-wise degree

distribution (1 – F(k)) with the best fit following an exponentially truncated power law as determined using Akaike’s Information Criterion. Figure 5 demonstrates group degree maps for controls (A) and PTSD subjects (B) with significantly greater connectivity in the posterior cingulate DMN for controls [t(600)= 5.65, p<2.5 x10-8]. Figure 6 is a connectivity diagram for the same posterior cingulate ROI used in the seed-based analyses demonstrating a striking decrease in connections to the posterior cingulate (green) for a Post Traumatic Stess Disorder (PTSD) group (bottom row) as compared to controls (top row), most notably to anterior frontal and bilateral

parietal default mode regions.

XNAT and Data ArchivalThe ANSIR laboratory also supports and administers XNAT databases for investigators that perform brain

imaging studies, including the Diabetes Heart Study (DHS-Mind) of over 600 participants, and the African American DHS-Mind study of ~600 participants. The XNAT databases are project specific, and allow storage, retrieval, and complex queries of imaging and metadata. The images, databases and other critical system data are maintained by Information Services at WFUHS.

MEG analysis pipeline. The ANSIR lab has developed a high-throughput fully automated MEG analysis pipeline for high density source-space analysis of resting state MEG data (Figure 7). The pipeline is written in Matlab and can use three open source packages (spm, fieldtrip, nutmeg) and one proprietary package (CTF VSM MedTech Ltd). It allows mixing of components from different software packages including head/forward models, beamformers and multiple connectivity metrics. It also incorporates automated artifact rejection, allows optional regression-based signal leakage correction, and outputs 4D source space MEG time series normalized to MNI space using structural MRI transformations. The pipeline is designed to generate source space MEG time series that can be used for additional network connectivity analyses including seed-based, independent component analysis, and graph-theoretic

Figure 4. Complementary cumulative voxel-wise degree distribution, fitted using power law (green), exponential (dotted blue), and truncated power law (red). Truncated Power Law provides best fit based on Akaike’s Information Criterion.

Figure 5. Group degree maps for control (A) and PTSD (B) demonstrating significantly greater connectivity in posterior cingulate/precuneus for control subjects (p < 2.5 x10-8).

Figure 6. Group connectivity diagrams for posterior cingulate seed (green) for controls (top) and PTSD (bottom). Sagittal (left) and axial (right) views, with edges displayed in red and connected nodes in blue. PTSD group demonstrates a marked decrease in connectivity between seed region and anterior frontal and bilateral parietal DMN regions.

Figure 7. MEG pipeline schematic.

approaches. Figure 8 demonstrates a beta-band MEG graph theoretic network across 22 subjects following spatial leakage correction with hubs in the default mode network (DMN).Automated NHP structural analysis pipeline. The ANSIR lab has developed a

fully automated structural image analysis pipeline for non-human primates (NHP). We have used this procedure successfully on a variety of NHP populations including vervets, cynomolgus and rhesus macaques. The pipeline generates exquisite NHP structural segmentations and mappings to the most detailed NHP atlas available. In comparison, the only other vervet atlases currently available have a maximum of 10 structures, and there are no available cynomolgus atlases. Additionally, currently available “automated” NHP skull-stripping and segmentation tools typically perform very poorly without manual interventions. Our implementation is fully automated, extremely robust across NHP species and brain positioning, and uses the most sophisticated morphometric analysis tools available, adapted for use with NHP (Figures 9-11). The NHP atlases have been fully integrated into our pickatlas software to allow direct region-based hypothesis testing through SPM.

NHP [ 11 C]-PIB PET image processing . The ANSIR lab has developed an automated [11C] PIB NHP processing methodology. PIB is synthesized in the Wake Forest PET radiochemistry lab using previously published methods. All procedures are conducted in compliance with State and Federal laws, standards of the US Department of Health and Human Services, and guidelines established by the Wake Forest University Institutional Animal Care and Use Committee as well as the National Institute of Health Guide for the Care and Use of Laboratory Animals (NIH Publications No. 80-23). Dynamic PET imaging is performed using a GE CT/PET VCT scanner.

Laboratory for Complex Brain Networks Dr. Paul Laurienti directs the Laboratory for Complex

Brain Networks (LCBN) along with co-founding laboratory members, Jonathan Burdette, MD, and Satoru Hayasaka, PhD. There is approximately 3,500 newly renovated sq. ft. of laboratory space available. This space includes private offices for faculty and staff, a large conference room with video conferencing for team meetings, a small conference room, and space for graduate students and post-doctoral fellows. The laboratory maintains hardware and software necessary to perform complex network analyses. Most of the software utilized has been generated by members of the LCBN over the past five years. Processing codes generally are written in Matlab, PERL, and C++. The laboratory has full-time staff to maintain data processing software. This group works collaboratively across the institution to study relationships between physical function, exercise, and network connectivity in the brain.

Extant Epidemiologic Studies and Clinical Trial (ESCT) Databases Relevant to Aging. This resource, developed by the Wake Forest Claude D. Pepper Older Americans Independence Center (OAIC), provides access to a unique, valuable, and

Figure 9. ANSIR lab Vervet atlas overlaid on vervet template brain (over 700 labels).

Figure 10. ANSIR Lab vervet population template (40 subj.) Left to right: Vervet template with skull, skull-stripped template, grey matter, white matter, CSF segmentations, NeuroMap label atlas.

Figure 8. MEG graph theoretic leakage-corrected network (top 20% of connections across 22 subjects) demonstrates hubs in DMN (posterior cingulate, biparietal).

growing collection of data from 40 multicenter studies (28 intervention trials and 12 observational cohorts) involving 192,496 participants (including biological specimens). These include many studies with data on cognitive function and cognitive impairment. However, even those that do not directly assess cognition include data and measurement protocols for may risk factors for cognitive decline and AD; these could well be useful to the design of ADCC studies. Work is underway to enfold additional studies involving cognitive function (see Appendix B for examples) into this resource as their data become available, creating a single portal for access to these data for ADCC investigators. This resource is possible partly because Wake Forest is the coordinating center and a field site for many large epidemiological studies and clinical trials relevant to aging. This resource facilitates exploratory analyses to test novel hypotheses, generate preliminary data, and produce high-impact publications at low cost, particularly important for junior investigators lacking preliminary data. The addition of WakeOne and the Translational Data Warehouse (noted above) further enhance these resources.

Intervention Trials in the (ECST) DatabasesCOMPLETED TRIALS

Action to Control Cardiovascular Risk In Diabetes - MIND (ACCORD-MIND) was a 40-month intervention of 2,977 older adults with type 2 diabetes whose Hba1c levels were over 7.5% at baseline. Participants were randomized to standard or intensive glycemic treatment, and either treatment for high blood pressure or high cholesterol. The aim is to determine whether intensive treatment of diabetes can reduce the decline of cognitive function and alter brain structure (via MRI).

Arthritis, Diet and Activity Promotion Trial (ADAPT) was an NIA-funded randomized controlled trial on the effects of exercise and diet intervention among 316 older obese persons with knee osteoarthritis. Main outcomes, assessed at 6 and 18 months, are physical disability, pain, radiographic disease severity, physical performance and muscle strength. (This is different from the Alzheimer’s Disease Anti-Inflammatory Prevention Trial, also known as ADAPT).

DIAMOND is a completed trial of the novel glucose cross-link breaker alagebrium in a similar population and with similar outcomes.

Diet, Exercise and Metabolism in Older Women (DEMO) was a randomized exercise intervention, the goal of which was to determine the cellular mechanisms by which aerobic exercise intensity affects the loss of abdominal (both subcutaneous and visceral) adipose tissue under conditions of equal energy deficit in postmenopausal women with abdominal obesity.

Fitness, Arthritis in Seniors Trial (FAST) was an NIA-funded randomized controlled trial on the effects of aerobic and resistance exercise among 439 older persons with knee osteoarthritis. Main outcomes, assessed at 3, 9 and 18 months, are physical disability, physical performance, pain, radiographic disease severity, and muscle strength.

Gingko Biloba Evaluation Memory Study (GEM) was a randomized controlled trial among 3,500 older persons on the effect of Gingko Biloba on cognitive decline. Assessments conducted over 5 years included cognitive function, onset of dementia, cardiovascular disease and physical disability/ performance.

Hy-Lo Hy-Lo I, II, and III were completed randomized, blinded, cross-over trials of angiotensin receptor antagonists compared with placebo, hydrochlorothiazide, and verapamil, respectively, for improvement in exercise capacity and quality of life in 100 patients with diastolic dysfunction.

Lifestyle Interventions and Independence for Elders Pilot (LIFE-pilot) is a completed randomized controlled trial of a physical activity intervention in 424 participants aged 70-89 at high risk for mobility disability. Follow-up was for up to 18 months. Cognitive function was assessed in a subgroup of participants.

Optimizing Body Composition for Function in Older Adults (OPTIMA) compared the main effects of 2 interventions (factorial design) on body composition, physical function, and fat distribution in 88 older (age 65-79 yrs) men and women with low physical function and an indication for weight loss. All participants consumed a hypocaloric diet for 4 months with or without resistance training (RT), and received either Pioglitazone/Actos™ (30 mg/day) or a placebo.

Pharmacological interventions in older patients with diastolic heart failure and preserved ejection fraction (Pharmacological Intervention in the Elderly, or PIE): PIE-I and PIE-II were randomized controlled trials of an ACE inhibitor and spironolactone, respectively. Both are completed and have a combined total of approximately 160 older patients with heart failure with preserved ejection fraction

with detailed physiological outcomes of cardiac and vascular structure and function, physical performance, and quality of life at baseline and follow-up.

Prospective Aerobic Reconditioning Intervention Study (PARIS) is an NIA-funded randomized controlled trial of exercise training and physiologic function in 119 older patients with heart failure due to left ventricular diastolic dysfunction. Standardized outcome assessments over 12 months of follow-up include physical performance, quality of life, cardiac and vascular function, and neuroendocrine function.

Reconditioning Exercise and COPD Trial (REACT I and REACT II) were randomized controlled trials of exercise interventions in 260 older participants with chronic obstructive pulmonary disease supported by NIA. Main follow-up outcomes are physical disability, physical performance, and pulmonary function.

Systolic Hypertension in the Elderly Project (SHEP) was a randomized controlled trial on the clinical effects of antihypertensive medication among 4,736 older persons with systolic hypertension. Routine assessments of cardiovascular risk factors, morbidity, mortality, cognition and physical disability were conducted.

ONGOING INTERVENTION TRIALS Cardiovascular Health and Maintenance Program (CHAMP) is a randomized controlled trial to examine

the efficacy of a long-term lifestyle activity intervention in 140 older adults with cardiovascular disease. Persons in a 3-month traditional exercise program are compared to those in an 18-month lifestyle activity intervention on cardiovascular risk factors, physical performance, disability and quality of life.

Cooperative Lifestyle Intervention Program (CLIP) is a 3-arm 18-month randomized, controlled trial of the effectiveness of physical activity, with and without weight loss, in the treatment of mobility disability in 288 older (60-79 years), overweight/obese men and women with evidence of CVD or metabolic syndrome. The primary outcome is mobility disability, as assessed by the distance walked during a 400 m walk. Secondary outcomes include: CV disease risk factors, physical activity and dietary intake, body composition, and on health-related quality of life. In an innovative model, the interventions are delivered in conjunction with county agricultural Cooperative Extension Centers.

Cooperative Lifestyle Intervention Program II (CLIP-II), which builds on the results of the CLIP study, is a 3-arm randomized trial to evaluate the effect of dietary weight loss with either resistance training or aerobic training, compared to weight loss alone, on physical function in 275 obese, older adults with cardiovascular disease or metabolic syndrome. The interventions are being implemented through community partnerships with 4 local YMCAs.

HF-ACTION is an ongoing NHLBI-funded trial in 2,400 patients with systolic heart failure with 5-year follow-up primary outcome of mortality and key secondary outcomes of physical function and quality of life.

Improving Muscle for Functional Independence Trial (I’M FIT) is a 2-arm, 5-month randomized trial in 130 older (65-79 yrs), obese (BMI=3035 kg/m2), sedentary men and women with low baseline physical function. Participants are randomized to a resistance training intervention alone (RT) or to an RT with caloric restriction (RT+CR; 600kcal/day deficit). The goal is to determine whether addition of caloric restriction to a standardized resistance training program enhances improvements in skeletal muscle and overall physical function in older, obese men and women.

Intensive Dietary Restriction and Exercise in Arthritis (IDEA) is a randomized trial in 450 older (>60 yrs), overweight/obese men and women with knee OA randomized to either 18 months of a diet only, exercise only, or diet + exercise intervention. The primary aim is to compare the effects of the interventions on inflammatory biomarkers and knee joint loads, self-reported physical function, pain, and mobility, and disease progression measured by changes in quantitative MRI.

Investigating Fitness Interventions in the Elderly (INFINITE) is a 3-arm, 5-month long trial in 180 older (65-79 yrs), obese (BMI=30-35 kg/m2), sedentary men and women. The study is designed to determine the effects of adding moderate (250 kcal/d deficit) and intensive (600 kcal/d deficit) caloric restriction to a standardized aerobic exercise training intervention on maximal aerobic capacity, functional endurance, CVD risk factors and inter-muscular, visceral and pericardial fat volumes.

I-PRESERVE is a randomized international clinical trial of angiotensin receptor antagonism in 4,500 older patients with diastolic heart failure.

Lifestyle Interventions and Independence for Elders (LIFE) is an 8-site, 1635 person long-term (3 yr) exercise study in older adults in follow-up to the LIFE-P study. The study will determine whether there are long-term effects of physical activity on major mobility disability, and secondary outcomes, including cognitive function, serious fall injuries, disability in basic activities of daily living, cardiovascular events, hospitalization, nursing home admission, and quality-of-life measures such as depression, sleep quality, stress and life satisfaction.

Look AHEAD Movement and Memory Study (Look AHEAD M&M) is evaluating the role of weight loss on physical and cognitive function. Look AHEAD (Action for Health in Diabetes) is a multicenter (16 sites), trial to examine the effects of a 4-year lifestyle intervention designed to achieve and maintain weight loss in overweight/obese adults (45-74 years old) with type 2 diabetes. This ancillary study is adding measures of physical and cognitive function to the year 8 follow-up visit–during the trial’s weight maintenance phase–in 1,084 participants at 4 field sites.

Strength Training for Osteoarthritis Trial (START) is a 3-arm randomized trial to test the effect an 18-month high-intensity strength training or low-intensity strength training, compared to attention control, on pain and function in 375 older adults with knee osteoarthritis.

Study of the Effect of Caloric Restriction and Exercise Training in Patients With Heart Failure and a Normal Ejection Fraction Study of the Effects of Caloric Restriction and Exercise Training (SECRET) is an ongoing 20-week long randomized, controlled, single-blinded intervention, utilizing a 2x2 design trial to examine the effects of weight loss via hypocaloric diet, aerobic exercise training, combined hypocaloric diet and exercise training, and attention control in 200 obese patients with heart failure and normal ejection fraction.

Systolic Blood Pressure Intervention Trial (SPRINT) will determine if reducing systolic blood pressure more than is currently recommended (to levels that are normal for young persons, i.e.120/80 mmHg) can reduce the risk of cardiovascular disease (CVD) events. Participants (n=7500) are age 50 and older with SBP greater than 130 and at least one other risk factor for cardiovascular disease, study duration is up to 5 years. A cohort of 2,100 additional participants aged >75 years (SPRINT-SENIORS). These participants will receive standardized assessments of physical function at baseline and follow-up.

Systolic Blood Pressure Intervention Trial Memory and cognition In Decreased Hypertension (SPRINT-MIND) will test whether the lower SBP goal influences the rate of incident dementia and mild cognitive impairment, global and domain-specific cognitive function, and total and regional brain volumes and ischemic lesion volumes. It will interface with SPRINT-SENIORS and later, with SPRINT-HEART to examine interactions between cognition, physical function, and cardiovascular function in older persons during intensive blood pressure reduction.

Systolic Blood Pressure Intervention Trial-HEART (SPRINT-HEART) is an NIH-funded ancillary study that will examine the effect of intensive BP reduction on LVH and its related abnormalities and their relationships to CV events in 340 participants enrolled in the SPRINT trial. Subjects will undergo a detailed cardiac magnetic resonance exam and echocardiography-Doppler at baseline and 18-month follow-up with measurements of: LV mass, volumes, strain, myocardial fibrosis, left atrial volume, and aortic stiffness. This study will also add physical function measurements to all patients under age 75 in order to examine changes in the relationships between cardiac and physical function as a result of the intervention.

OBSERVATIONAL COHORT STUDIES Established Populations for Epidemiologic Studies of the Elderly (EPESE) is 10-year longitudinal

observational study with six annual assessments of more than 10,000 older persons in four US regions. Assessments include among others physical disability, physical performance, mortality, morbidity, hospitalization and various biomarkers.

Health, Aging and Body Composition Study (Health ABC) is a 10-year longitudinal observational study with annual assessments among 3,075 well-functioning older black and white men and women. This study conducts annual assessments of body composition (DXA, CT), biomarkers and physical performance and semiannual assessments of disability, to examine changes in these variables over time and their interrelationships.

Women’s Health Initiative Observational Study (WHI-OS) observational study is examining the relationship between lifestyle, risk factors and specific disease outcomes in 93,676 women (aged 50-79 years). Recruitment for the observational study was completed in 1998 and women were followed for 8-12 yrs. A WHI Extension Study has enrolled consenting women from each of the original WHI study components for an additional 10 years of follow-up (until 2015). Annual updates on health outcomes are currently collected by mail from the 115,400 participants enrolled in the Extension Study. The WHI aging interest group is managed by the Southeast Regional Center located at Wake Forest.

Cardiovascular Health Study / CHS All-Stars (CHS) is a longitudinal observational study of 5,888 older men and women on risk factors of cardiovascular disease. Detailed assessments (over 11 years) of subclinical and clinical indicators of cardiovascular health and physical disability and performance are available.

HyperGen is a large (N=1201), population-based observational study of the genetics of hypertension and its consequences. It also contains details measures of adiposity and body composition.

Multi-Ethnic Study of Atherosclerosis (MESA) is an ongoing 6-year longitudinal observational study of 6,500 older adults on risk factors of subclinical cardiovascular disease. Detailed assessments include ECG, CT, MRI and ultrasound measures of subclinical cardiovascular disease.

Observational Arthritis Study in Seniors (OASIS) was a 30-month observational study on progression of physical disability in 480 older adults with knee osteoarthritis. Three assessments collect detailed information on disease severity and physical disability and performance.

Atherosclerosis Risk In Communities study (ARIC) is a population-based cohort study to investigate the etiology of atherosclerosis in a biracial population. The study population comprises 15,792 persons aged 45-65 years.

Action to Control Cardiovascular Risk In Diabetes (ACCORD) is an ongoing 9-year intervention of over 10,000 older adults with type II diabetes and Hba1c levels over 7.5% at baseline. Participants are randomized to standard or intensive glycemic treatment, and treatment for either high blood pressure or cholesterol.

Diabetes Heart Study and African American-DHS (DHS; AA-DHS) is a single-center genetic and epidemiological study of 1,443 European Americans and African Americans from 564 families with multiple cases of type II diabetes (mean age 61 years) in western North Carolina. Main outcomes include subclinical cardiovascular disease, CVD risk factors. Heritability and GWAS data are available. Ancillary studies are examining cognition, brain structure, bone, body composition, and social factors.

HEALTHY is a key resource developed for referent standards and as normal, age and gender matched controls for cross-sectional comparison studies. This includes multiple key outcomes: physical and cognitive function assessments; quality-of-life surveys; CT, MRI, and DEXA scans for comprehensive body and regional composition; MRI and ultrasound exams for comprehensive cardiac and vascular function; skeletal muscle tissue biopsy; a number of biomarkers; and stored serum, plasma, and genetic material in 60 sedentary adults (62% female, mean age 69 years) who were not hypertensive or diabetic and did not take any prescription medication.

Vascular Stiffness and Pulmonary Congestion (PREDICT) enrolled 608 older adults at risk for flash pulmonary edema (hypertension, diabetes, CHD) but with left ventricular ejection fractions >40% to determine if stress-induced change in left ventricular performance or aortic stiffness predict congestive heart failure. Participants undergo an MRI stress test; rest and stress measures of left and right ventricular volumes and wall motion myocardial perfusion, and aortic stiffness; and quantification of prior infarction. After baseline assessment, participants are followed up by questionnaire 3 times per year over 4 years.

OAIC Integrated Aging Studies Databank and Repository (IASDR). The OAIC Integrated Aging Studies Databank and Repository (IASDR) is an innovative, robust, OAIC theme-specific data resource that serves as a successful model that the ADCC will follow. This resource was possible because of a strategic OAIC leadership mandate in 2000 that OAIC-related studies should incorporate, whenever possible, comprehensive, standardized measures of physical function, body composition, and quality of life. This resource includes data, specimens, and images from over 29 studies and more than 3,100 unique participants. Physical function assessments, including the Standardized Physical Performance Battery (SPPB), and questionnaires are administered by the OIAC Clinical Research Core to ensure efficiency, validity, and uniformity of data collection. The OIAC Integrative Biology Core manages acquisition, processing, and storage of blood, DNA, skeletal muscle, and adipose tissues. The OAIC Bioimaging Core manages acquisition, processing, and archival of DEXA, CT, MRI, and ultrasound imaging data. The OAIC Biostatistics Core captures all data and inventories specimens and images in the IASDR. A web-based query and data request system managed is embedded into the WFU OAIC Coordinating Center website, making the IASDR available to all investigators in the OAIC national network (see Figures 13 and 14). This robust, growing database currently includes a broad array of relevant data relevant from 29 studies with over 3,000 participants, including age-matched controls from the HEALTHY study.

OIAC Biospecimen Repository. The Wake Forest OAIC has developed an IRB-approved Biological Specimen Repository and Distribution Center (PI: Nicklas) as a centralized system for the proper collection, transfer, and storage of biological tissue to be used for conducting future ancillary studies by investigators in aging-related research. The Repository currently holds >99,000 cryovials of serum or plasma collected from >3,100 research participants enrolled in 24 different studies. The Repository also has >1,260 DNA samples collected from research participants. All samples are collected from study participants enrolled in research protocols at Wake Forest. Written informed consent was obtained from each participant providing permission to have their samples stored for future, undesignated research. All samples are stored in cryovials in 80C freezers connected to an emergency power supply and a CO2 backup system. IRB approval is required to receive samples and priority is given to new investigators. A screenshot of the biospecimen repository inventory access webpage is shown in Figure 14.