The objective of this proposal is to support the candidate's development of skills necessary to perform patient-oriented research in the systems neuroscience of behavior and motor control. The training component includes the mentored development of skills in human ocular motor physiology, systems neuroscience, advanced methods of structural MRI analysis and correlative neuropathology, and includes coursework and mentored training in ocular motor physiology, neuroimaging, biostatistics, systems neuroscience, correlative neuropathology and the responsible conduct of research. The proposed research plan will support the candidate's development of these skills by giving him the opportunity to investigate the physiology, anatomy and clinical/pathological correlates of ocular motor dysfunction in frontotemporal lobar degeneration (FTLD) patients. This disease causes severe deficits in decision-making, which in turn lead to behavioral, cognitive and motor impairments. FTLD is associated with atrophy of the frontal lobe eye movement control areas, is genetically and pathologically related to disorders which cause ocular motor dysfunction, and based on preliminary data presented here, is also associated with eye movement abnormalities. This study will longitudinally measure basic eye movements and ocular motor decision-making tasks, in 80 FTLD patients, 40 demented controls with Alzheimer's disease, and 40 normal controls. MRI scans, clinical neurological and neuropsychological data from evaluations at the UCSF Memory and Aging Center will be analyzed in conjunction with the ocular motor data to address the following hypotheses: 1) FTLD patients will have measurable voluntary eye movement abnormalities that are distinct from AD patients. 2) Ocular motor abnormalities will have specific neuropsychological correlates in FTLD. 3) When present, certain ocular motor abnormalities observed in motor system disorders related to FTLD (e.g. PSP, CBD), will predict the subsequent emergence of motor impairment in FTLD. 4) Differences in performance on ocular motor tasks among different subtypes of FTLD will be explained by differences in the anatomical pattern of brain damage, and ocular motor performance will correlate with atrophy of frontal lobe eye movement areas.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Mentored Patient-Oriented Research Career Development Award (K23)
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NST-2 Subcommittee (NST)
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Sieber, Beth-Anne
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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Mirsky, Jacob B; Heuer, Hilary W; Jafari, Aria et al. (2011) Anti-saccade performance predicts executive function and brain structure in normal elders. Cogn Behav Neurol 24:50-8
Boxer, Adam L; Mackenzie, Ian R; Boeve, Bradley F et al. (2011) Clinical, neuroimaging and neuropathological features of a new chromosome 9p-linked FTD-ALS family. J Neurol Neurosurg Psychiatry 82:196-203
Kerchner, Geoffrey A; Tartaglia, Maria Carmela; Boxer, Adam (2011) Abhorring the vacuum: use of Alzheimer’s disease medications in frontotemporal dementia. Expert Rev Neurother 11:709-17
Kerchner, Geoffrey A; Boxer, Adam L (2010) Bapineuzumab. Expert Opin Biol Ther 10:1121-30
Bei Hu; Ross, Leslie; Neuhaus, John et al. (2010) Off-label medication use in frontotemporal dementia. Am J Alzheimers Dis Other Demen 25:128-33
Pa, Judy; Boxer, Adam; Chao, Linda L et al. (2009) Clinical-neuroimaging characteristics of dysexecutive mild cognitive impairment. Ann Neurol 65:414-23
Boxer, Adam L; Lipton, Anne M; Womack, Kyle et al. (2009) An open-label study of memantine treatment in 3 subtypes of frontotemporal lobar degeneration. Alzheimer Dis Assoc Disord 23:211-7
Webb, Amy; Miller, Bruce; Bonasera, Stephen et al. (2008) Role of the tau gene region chromosome inversion in progressive supranuclear palsy, corticobasal degeneration, and related disorders. Arch Neurol 65:1473-8
Garbutt, Siobhan; Matlin, Alisa; Hellmuth, Joanna et al. (2008) Oculomotor function in frontotemporal lobar degeneration, related disorders and Alzheimer's disease. Brain 131:1268-81
Boxer, A L; Rabinovici, G D; Kepe, V et al. (2007) Amyloid imaging in distinguishing atypical prion disease from Alzheimer disease. Neurology 69:283-90

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