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.
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.
|Tarawneh, Rawan; D'Angelo, Gina; Crimmins, Dan et al. (2016) Diagnostic and Prognostic Utility of the Synaptic Marker Neurogranin in Alzheimer Disease. JAMA Neurol 73:561-71|
|Marlow, Colleen A; Viskontas, Indre V; Matlin, Alisa et al. (2015) Temporal Structure of Human Gaze Dynamics Is Invariant During Free Viewing. PLoS One 10:e0139379|
|Albers, Mark W; Gilmore, Grover C; Kaye, Jeffrey et al. (2015) At the interface of sensory and motor dysfunctions and Alzheimer's disease. Alzheimers Dement 11:70-98|
|Wagshal, Dana; Sankaranarayanan, Sethu; Guss, Valerie et al. (2015) Divergent CSF ? alterations in two common tauopathies: Alzheimer's disease and progressive supranuclear palsy. J Neurol Neurosurg Psychiatry 86:244-50|
|Li, Yun; Chen, Jason A; Sears, Renee L et al. (2014) An epigenetic signature in peripheral blood associated with the haplotype on 17q21.31, a risk factor for neurodegenerative tauopathy. PLoS Genet 10:e1004211|
|Pa, Judy; Dutt, Shubir; Mirsky, Jacob B et al. (2014) The functional oculomotor network and saccadic cognitive control in healthy elders. Neuroimage 95:61-8|
|Scherling, Carole S; Hall, Tracey; Berisha, Flora et al. (2014) Cerebrospinal fluid neurofilament concentration reflects disease severity in frontotemporal degeneration. Ann Neurol 75:116-26|
|Lee, Suzee E; Khazenzon, Anna M; Trujillo, Andrew J et al. (2014) Altered network connectivity in frontotemporal dementia with C9orf72 hexanucleotide repeat expansion. Brain 137:3047-60|
|Tartaglia, Maria Carmela; Hu, Bei; Mehta, Kala et al. (2014) Demographic and neuropsychiatric factors associated with off-label medication use in frontotemporal dementia and Alzheimer's disease. Alzheimer Dis Assoc Disord 28:182-9|
|Woolley, Josh D; Khan, Baber K; Natesan, Alamelu et al. (2014) Satiety-related hormonal dysregulation in behavioral variant frontotemporal dementia. Neurology 82:512-20|
Showing the most recent 10 out of 42 publications