This is a K23 award application for Dr. Zachary A. Miller, a behavioral neurologist at the University of California, San Francisco Memory and Aging Center (MAC) who is establishing himself as a young investigator in patient-oriented clinical research focusing on language processing in neurodegenerative disease. This K23 award will provide Dr. Miller with the necessary support to accomplish the following: (1) gain expertise in neurodegenerative disease and the cognitive neuroscience of language processing; (2) develop proficiency in the use and analysis of structural and functional neuroimaging; (3) gain experience in evaluating neurodevelopmental and genetic factors in neurodegenerative patients; (4) advance his knowledge of biostatistics; (5) gain exposure and training in the neuropathology of language disorders; and (6) develop an independent clinical research career. To achieve these goals, he assembled a multidisciplinary mentoring team with two primary mentors: Dr. Maria Luisa Gorno-Tempini (a neurologist with expertise in language disorders and advanced neuroimaging techniques) and Dr. Bruce Miller (a neurologist with expertise in behavior, neurodegenerative disease, and clinical research); a co-mentor: Dr. Srikantan Nagarajan (a bioengineer with expertise in magnetoencephalography); and three advisors: Dr. Matt State (a psychiatrist with expertise in neurodevelopmental disorders and genetics), Dr. William Seeley (a neurologist with expertise in neuropathology and functional imaging), and Dr. John Neuhaus (a biostatistician with expertise in multivariate analyses). The proposed research investigates the effect of pre-morbid, individual characteristics related to language disabilities and clinical presentation in neurodegenerative diseases. The central hypothesis is that neurodevelopmental factors are associated with increased vulnerability of the language networks to disease, leading to specific language presentations, imaging changes, and disease progression. We will study PPA and FTD gene carriers to examine the consequences of language learning disability and hand preference on clinical, cognitive, and neuroimaging phenotype. We will collect a standardized neurodevelopmental history, detailed cognitive assessment, and imaging data to determine phenotypic differences between PPA patients with and without a history of language-learning disabilities at presentation (Aim 1). We will establish hand preference and language lateralization patterns using magnetoencephalography in PPA and healthy control subjects and correlate them with measures of structural brain symmetry (Aim 2). We will collect longitudinal cognitive and neuroimaging data on PPA and FTD gene carriers and compare patterns of progression in subjects with and without language learning disabilities (Aim 3). This research will increase understanding of pre-morbid factors on clinical heterogeneity in PPA, direct future studies into early diagnostic and treatment strategies, and offer novel neurodevelopmental and imaging measures as new tools for PPA characterization and diagnosis. This K23 training will enable Dr. Miller to apply concepts of selective neurodevelopmental vulnerability to the understanding of other neurodegenerative diseases.]

Public Health Relevance

We have preliminary evidence to suggest that neurodevelopment shapes phenotypic presentation of specific neurodegenerative diseases. The ability to understand the association between neurodevelopment and neuronal vulnerability holds transformative potential for disease prediction and prevention strategies, with relevance to all neurodegenerative disorders.]

National Institute of Health (NIH)
National Institute on Aging (NIA)
Mentored Patient-Oriented Research Career Development Award (K23)
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Neuroscience of Aging Review Committee (NIA-N)
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Opanashuk, Lisa Ann
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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Erkkinen, Michael G; Zúñiga, Raquel Gutiérrez; Pardo, Cristóbal Carnero et al. (2018) Artistic Renaissance in Frontotemporal Dementia. JAMA 319:1304-1306
Iaccarino, Leonardo; Tammewar, Gautam; Ayakta, Nagehan et al. (2018) Local and distant relationships between amyloid, tau and neurodegeneration in Alzheimer's Disease. Neuroimage Clin 17:452-464
Santos-Santos, Miguel A; Rabinovici, Gil D; Iaccarino, Leonardo et al. (2018) Rates of Amyloid Imaging Positivity in Patients With Primary Progressive Aphasia. JAMA Neurol 75:342-352
Sha, Sharon J; Miller, Zachary A; Min, Sang-Won et al. (2017) An 8-week, open-label, dose-finding study of nimodipine for the treatment of progranulin insufficiency from GRN gene mutations. Alzheimers Dement (N Y) 3:507-512
Ranasinghe, Kamalini G; Hinkley, Leighton B; Beagle, Alexander J et al. (2017) Distinct spatiotemporal patterns of neuronal functional connectivity in primary progressive aphasia variants. Brain 140:2737-2751
Steele, Natasha Z R; Carr, Jessie S; Bonham, Luke W et al. (2017) Fine-mapping of the human leukocyte antigen locus as a risk factor for Alzheimer disease: A case-control study. PLoS Med 14:e1002272
Spinelli, Edoardo G; Mandelli, Maria Luisa; Miller, Zachary A et al. (2017) Typical and atypical pathology in primary progressive aphasia variants. Ann Neurol 81:430-443
Bejanin, Alexandre; Schonhaut, Daniel R; La Joie, Renaud et al. (2017) Tau pathology and neurodegeneration contribute to cognitive impairment in Alzheimer's disease. Brain 140:3286-3300
Sirkis, Daniel W; Bonham, Luke W; Aparicio, Renan E et al. (2016) Rare TREM2 variants associated with Alzheimer's disease display reduced cell surface expression. Acta Neuropathol Commun 4:98
Miller, Zachary A; Sturm, Virginia E; Camsari, Gamze Balci et al. (2016) Increased prevalence of autoimmune disease within C9 and FTD/MND cohorts: Completing the picture. Neurol Neuroimmunol Neuroinflamm 3:e301

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