Dementia is a multi-factorial process of which Alzheimer's disease (AD) is often the major component pathology. Detecting disease before overt symptoms arise is becoming particularly important as new disease-modifying therapies are likely to be most effective in the earliest stages of disease. Although a variety of biomarkers are sensitive to pre-symptomatic AD, new tools are needed to identify other pathological processes that combine with AD to cause dementia. This project will examine the clinical and neuroimaging correlates of impaired saccadic eye movement control in normal elderly (NE) and people with mild cognitive impairment (MCI). Age-related changes occur in the brain network that controls saccades and covert shifts of attention, and the structure and function of this network are also highly sensitive to the effects of brain disease. Saccades can be easily quantified and represent a proven tool for the tracking of brain function. One of the most robust and widely-studied eye movement assessments is the antisaccade (AS) task. Our laboratory has found that AS performance strongly correlates with neuropsychological measures of executive function, disease severity and brain structure in dementia, and is useful in the diagnosis of a variety of clinical dementia syndromes. In a variety of neurological disorders, AS is exquisitely sensitive to disease before overt symptoms arise, and in our series, 20% of NE were impaired on this task. By analogy to biomarkers of AD that identify NE with potentially pre-symptomatic disease, we hypothesize that impaired AS performance may identify early dysfunction of the frontoparietal saccade/attention brain network, which may in turn contribute to a risk of cognitive decline. To test this hypothesis, we will longitudinally measure AS performance in 100 NE and 100 MCI subjects recruited through the UCSF AD Research Center (ADRC). Participants will receive yearly saccade testing, neuropsychological testing and functional ratings. At baseline, functional MRI will be used to study the AS-related brain network in NE subjects, and structural MRI measurements of gray and white matter integrity will be used to identify which components of this network are related AS task performance in all subjects. In addition, well-established clinical and imaging markers of AD, including PET scans with the amyloid-binding agent Pittsburgh Compound B (PIB), hippocampal volumes and episodic memory scores, will be used to assess the added value of AS measurement over traditional AD markers for the prediction of cognitive decline. Specifically, we aim to: 1) Determine the ability of the AS task to predict neuropsychological and functional decline in NE and MCI, 2) Delineate the anatomical networks associated with AS performance in NE and MCI, and 3) Determine the added value of AS measurement over conventional AD risk factors for prediction of cognitive and functional impairment.

Public Health Relevance

For new therapies that have the potential to protect the brain from damage due to Alzheimer's Disease (AD) to be most effective, individuals with very early disease must be identified and therapy initiated ideally before symptoms arise, so that clinical symptoms may be effectively prevented. This project will investigate the causes and long term consequences of eye movement control problems in normal individuals and individuals with mild memory problems who are at risk for AD. The data generated from this project will provide a new test to physicians that they can use during a patient visit to help decide who is at greatest risk for dementia and potentially who may benefit from such early treatment.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Clinical Neuroscience and Neurodegeneration Study Section (CNN)
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Hsiao, John
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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