John Mazziotta - US grants

Plans for the fifth year of funding involve four general research areas: 1 The development and improvement of standardized methods for the tracer kinetic study of brain function, 2. Standardization of anatomical approaches to functional image analysis. 3. The evaluation of normal subjects in resting states and during specific sensory, motor and cognitive tasks and 4. The continued evaluation and collaboration with other investigators in the study of patients with Huntington's Disease, Aphasia, Epilepsy, Affective Disorders and Dementia. In the area of methodological development, I will continue the human and animal experimentation needed to validate the bolus approach to oxygen utilization studies. In the realm of anatomical standardization, I will complete a series of NIMH sponsored workshops for the standardization and identification of regions from functional images obtained with PET and SPECT. In our own laboratory these approaches will be implemented and a laboratory wide data base will be established for the integrated exchange of data between experimental protocols in both animals and humans. Studies in normal subjects with PET will include the use of oxygen-15 labeled compounds and FDG for our new tomograph. These studies will provide new values for kinetic rate constants of the deoxyglucose model and initial high resolution values for the human brain for cerebral glucose metabolism, blood flow, blood volume, oxygen utilization and oxygen extraction fraction. Continued studies of the motor system will expand our original approach in normal subjects to evaluate tasks in patients with motor system diseases including Huntington's Disease, Wilson's Disease, Tardive Dyskinesia and Parkinson's Disease. Other patient studies will include the continuation of our work in Huntington's Disease with emphasis on correlating our studies in at risk patients with genetic linkage studies performed for the identification of the Huntington's Disease gene. Expansion of our work in patients with affective disorders will include provocative stimuli from both behavioral tasks and pharmacological manipulations with antidepressant drugs and stimulants.

The primary goal of this program is the continuing development of a probabilistic reference system for the human brain as an important neuroinformatics tool for use by the neuroscience community. In our original application we proposed to build the tools and determine the feasibility of this approach in the domain of structural neuroanatomy. Both goals have been achieved. In this renewal application, we propose to add functional (fMRI and PET) and microscopic structural (cyto- and chemoarchitectural) information about the brain to this system through the development of unique informatics tools and strategies. An important neuroscience outcome of this plan will be the opportunity to examine, for the first time, the stability, relationships and distribution of micro- and macroscopic structure to function in the human brain. This issue, although a major area of interest, has remained a vexing problem because of the difficulty in obtaining data sets of sufficient magnitude, diversity, number and organization to answer such questions. These goals will be achieved through an integrated program made up of six separate institutions (UCLA, Montreal Neurologic Institute, University of Texas at San Antonio, Stanford University, Albert Einstein College of Medicine and H. Heine University in Dusseldorf). Six specific aims are proposed: 1) Develop the neuroinformatics tools, algorithms and protocols to integrate functional information about the human brain, from fMRI and PET, through the identification of functional landmarks. 2) Establish and validate a Functional Reference Battery (FRB) of behavioral tasks that reliably produces functional landmarks across subjects and modalities 3) Extend the range, magnitude and attributes of structural data from both in vivo and post mortem sources; the latter to include cyto-and chemoarchitectural information for selected brain regions. 4) Develop the statistical and warping pools to analyze these data sets in a unified and formal multivariate environment. 5) Create a database structure, organized in four dimensions and tested in three, designed for query-by-content of large, multi-attribute data sets. 6) Beta test, at new sites beyond our consortium, those developed through the program, including independent evaluation of their commercial value. The use of a consortium structure where the distribution of labor can be separated into parallel, complementary tasks, executed by established leaders in the field, has been efficient, in both cost and time, as compared to isolated efforts at each site. It has also created a "real world" environment among participants such that differences in equipment, software and protocols actually reflect a microcosm of the larger neuroscience and neuroinformatics communities.

positron emission tomography; magnetic resonance imaging; image processing; brain mapping; biomedical facility; brain imaging /visualization /scanning; touch; visual stimulus; glucose metabolism; blood flow measurement; human tissue; Macaca mulatta; postmortem; human subject;

Neuroimaging has increasing importance in the diagnosis and differential diagnosis of dementia. Imaging is required to meet research diagnostic criteria for probable Alzheimer's disease, vascular dementia, frontotemporal dementias, and other dementing disorders. The activities of the Imaging Core are integrated with the NIH-funded Human Brain Imaging Project. UCLA has a well developed imaging program and neuroimaging is one of the central strengths of the UCLA Alzheimer's Disease Center (ADC). Thus far, 634 structural and functional images have been obtained and analyzed. Contributions have been made to understanding the relationship of genetic status to imaging in AD as well as to imaging alterations in frontotemporal dementias and vascular dementia. In the renewal period we will enhance the availability of imaging results through further development of the imaging node on the ADC net linking UCLA ADC sites; increase standardization of images across different ADC sites; correlate imaging, clinical and pathological changes of patients studied in the ADC; develop new techniques for brain imaging of dementia patients; and continue to develop an environment that facilities imaging research and training. The Imaging Core will collaborate with the Education/Information Transfer Core to train ADC personnel to reliably interpret changes in structural and functional images. UCLA ADC sites have access to an unprecedented breadth of neuroimaging resources. Computerized tomography (CT) and magnetic resonance imaging (MRI) are available at all sites; magnetic resonance spectroscopy (MRS) is operational at Harbor-UCLA and UCLA Medical Center; positron emission tomography (PET) is available at UCLA Medical Center and West LA Veterans Affairs Medical Center (VAMC); single photon emission computed tomography (SPECT) can be procured from all sites; QEEG can be obtained at all sites except Drew/King; and functional MRI is operational at UCLA Medical Center and is being developed at Harbor-UCLA. A cryomacrotome at UCLA allows slicing of human heads, digitization of each slice, and subsequent computerized reconstruction of the images. These images can be studied to address questions relevant to the relationship of imaging to pathology. The Imaging Core has made an important contributions and is poised to make additional advances in the renewal period.

health science research support; building /facility design /renovation; biomedical facility;

functional magnetic resonance imaging; positron emission tomography; magnetic resonance imaging; information systems; data collection; image processing; brain imaging /visualization /scanning; brain mapping; biomedical facility; digital imaging; electroencephalography; blood flow measurement; young adult human (21-34); human middle age (35-64); human old age (65+); human tissue; human subject; postmortem;

bioimaging /biomedical imaging; brain imaging /visualization /scanning; computer graphics /printing; computer program /software; computer system design /evaluation

[unreadable] DESCRIPTION (provided by applicant): The primary goal of this program is the continuing development of a probabilistic reference system for the human brain as an important neuroinformatics tool for use by the neuroscience community. In the course of this project we proposed and have succeeded in building and expanding the tools available to establish this system for structural and functional neuroanatomy on both macroscopic (in vivo) and microscopic (post mortem) levels. We have already incorporated the results of over 7,000 subjects into this system along with the most extensive collection of human cyto- and chemoarchitecture thus far obtained for the human brain. In this renewal application, we propose to add studies of human cerebral white matter tracts (DTI-MRI and differential myelin staining), cerebral vasculature (MRA, MRV), chemoanatomy (ketanserin-autoradiography and altanserin-PET) and, for the first time, studies of connectivity in the human brain using fMRI-transcranial magnetic stimulation-PET. We also propose to expand our neuroinformatics tools for data sharing including the "Conforming Site System," which allows laboratories worldwide to contribute data to our evolving atlas, and through the implementation of the ICBM data sharing policy space, to foster data exchange while still providing for scientific credit assignment and subject confidentiality. These goals will be achieved through an integrated program made up of four primary institutions (UCLA, Montreal Neurologic Institute, University of Texas at San Antonio, and the Institute of Medicine, Juelich/H. Heine University, Dusseldorf, Germany). In addition, data acquisition sites in Asia and Europe will continue to be part of this international program. By linking our efforts with those developing a pediatric MRI atlas (MNI site), information about the human brain will be available throughout the entire human life span (Birth - 90 years). We will continue to use our beta test sites to independently test tools and data sets developed through the consortium with regard to their scientific and practical value. The use of a consortium structure, where the distribution of labor can be separated into parallel, complementary tasks, executed by established leaders in the field, has been efficient, in both cost and time, as compared to isolated efforts of each site. It has also created a "real world" environment among participants such that differences in equipment, software and protocols actually reflect the microcosm of the larger neuroscience and neuroinformatics communities. [unreadable] [unreadable] OVERALL PROJECT: [unreadable] [unreadable]