Kamalini G. Ranasinghe - US grants

? DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the most frequent neurodegenerative disorder and the most common cause of dementia in the elderly. Unfortunately, there are still no effective treatments to prevent, halt, or reverse AD. As new clinical trials focus on the initial stages of disease, early diagnosis is now more important than ever. Human neuroimaging has greatly improved our knowledge of this disease by demonstrating selectively vulnerable large-scale networks whose connectivity declines in AD. Transgenic mouse models of AD have identified specific brain regions whose aberrant excitatory activity causes neuronal network dysfunction. However, the exact relationship between neural network abnormalities in animal models with that in the human condition remains unknown. To better understand the altered neural dynamics underlying clinical symptoms in AD will require novel techniques and methodologies. Speech and language abnormalities are evident in AD patients from the very early stages of the disease. We propose to use a novel magnetoencephalographic imaging (MEGI) approach to determine the speech- motor-network deficits of AD-spectrum patients. MEGI provides direct recordings of brain activity with precise millisecond resolution. The goal of this study is to understand the spatial patterns and temporal dynamics of speech encoding and speech execution in AD patients. Using customized software we will measure brain activity patterns across high and low frequency bands. We expect to find unique signatures of speech-motor- network dysconnectivity in AD. Such knowledge will be related to underlying synaptic dysfunctions of vulnerable neuronal populations as early biomarkers of the disease and will have important implications for translational research. The candidate is a physician-scientist with a strong commitment to a career in neurodegenerative dementia research. The candidate has an MD and a PhD in cognition and neuroscience. The research proposal and career development plan build upon her training in rodent neurophysiology and auditory and speech processing to provide expertise in human brain connectivity and its relationship to cognitive deficits in AD. Dr. Keith Vossel, a physician-scientist who cares for patients with dementia and specializes in transgenic mouse models of neurodegenerative disease, is the candidate's sponsor. The mentoring and research experience described in this proposal will facilitate the candidate's goal of developing a strong independent research career.

PROJECT SUMMARY This is an application for a K08 Mentored Clinical Scientist Research Career Development Award to promote the candidate's development as an independent researcher in clinical neuroscience, with a focus on understanding the neurophysiological abnormalities in Alzheimer's disease (AD), and eventually, in other dementia syndromes. Dr. Ranasinghe's long-term career goal is to develop a deep knowledge base on brain- behavior relationships associated with specific pathophysiological processes in neurodegenerative diseases. The current research project proposes a multimodal, longitudinal brain imaging study, integrating magnetoencephalographic imaging (MEGI) with positron emission tomography (PET), and with progressive trajectories of neurodegenerative processes, in AD patients. AIM-1 examines the distinct patterns of network synchronization deficits in patients with AD using MEGI, and their specific associations to PET-derived molecular markers of amyloid beta and tau. AIM-2 conducts longitudinal MEGI assessments of network deficits combined with cognitive and volumetric measures with annual follow-ups for two years. The results will uncover neurophysiological signatures of aberrant neuronal functions in AD, in humans, and will have important implications for translational research and clinical trials. This K08 will provide Dr. Ranasinghe with the support necessary to accomplish the following goals: (1) Training in application and analysis of multimodal neuroimaging techniques; (2) Clinical training in patient evaluations and longitudinal follow-up; (3) Gaining greater depth of knowledge in mechanisms of AD; (4) Training in advanced biostatistical analyses in clinical research; (5) Training in grant writing, career development, and research ethics. To achieve these goals, Dr. Ranasinghe has assembled a mentoring team including her primary mentor: Dr. Katherine Rankin (a neuropsychologist with expertise in neurodegenerative diseases); and two co-mentors: Drs. Gil Rabinovici (a behavioral neurologist with expertise in molecular imaging), and Srikantan Nagarajan (a neuroscientist with expertise in magnetoencephalography). The collaborators of Dr. Ranasingh'e project include Drs. Maria Luisa Gorno-Tempini (a behavioral neurologist with expertise in neuroimaging), Joel Kramer (a neuropsychologist with expertise in cognitive ageing), Lea Grinberg (a neuropathologist with expertise in neurobiology of AD), and Maria Glymour (a biostatistician). The candidate is a physician-scientist with a strong commitment to a career in neurodegenerative dementia research. The University of California San Francisco Memory and Aging Center is an ideal environment for the proposed training, being a top dementia research institute in the nation with access to world leading experts in clinical and translational research. The research and training experience described in this proposal will enable the candidate's goal of developing a strong independent research career in the field of neurophysiological assessments in neurodegenerative diseases.