Herman Moreno, MD - US grants

[unreadable] DESCRIPTION (provided by applicant): The availability of genetically modified mice has advanced our understanding of Alzheimer's disease (AD). Nevertheless, conventional tools of cellular neurobiology, which require the sacrifice of an animal to obtain information about neuronal function, preclude the use of longitudinal study designs. Functional Magnetic Resonance Imaging (fMRI) is a technology that can obtain information about the metabolic state of the brain non-invasively and thus allows the use of longitudinal study designs in both rodents and humans. Some fMRI protocols, such as those designed to measure cerebral blood volume (CBV), are especially sensitive to long term metabolic changes in the brain caused by neurodegenerative disease. Mounting evidence suggests that calcium-binding proteins (CaBPs) play a role in Alzheimer's disease (AD). In this proposal, the technologies of fMRI and transgenic engineering will be combined to accomplish the following primary goals: First, to acquire expertise in mouse fMRI as it specifically applies to AD research. Second, to rely on mouse fMRI to investigate the role calcium-binding proteins play in AD pathophysiology. [unreadable] This goal will be achieved by crossing mouse models of AD with transgenic mice in whom calcium-binding proteins have been manipulated, and then by imaging these mice prospectively over time. As a secondary goal, in vitro techniques will be used to confirm and extend the in vivo findings. These experiments will test the specific single cell calcium abnormalities in different cellular compartments of the hippocampal formation. The training aspects of this proposal will lead to a new investigator in the field of AD research with combined expertise in clinical neurology and mouse fMRI. The scientific aspects of this proposal will test a specific mechanism regarding AD pathophysiology, which might inform future therapeutic goals. It is also important to emphasize that advances in mouse fMRI can be easily applied to humans, e.g. evaluation of the response to a given treatment by brain fMRI parameters. [unreadable] [unreadable] [unreadable]

? DESCRIPTION (provided by applicant): The main goal of this proposal is to study the interplay of diabetes, cerebrovascular disease (CVD), and Alzheimer's disease (AD) in response to RFA-AG-15-010 Interdisciplinary Research to Understand the Vascular Contributions to Alzheimer's Disease (R01). Type 2 diabetes and pre-diabetes affect one third of United States adults, and the majority of persons aged 60 years and older, who are most susceptible to AD. Diabetes is a strong risk factor for CVD and for vascular cognitive impairment. Diabetes is also associated with a higher risk of the clinical manifestations of AD including dementia and amnestic mild cognitive impairment, but it is unclear whether AD, CVD, or both, mediate this association, and whether this association is causal. We hypothesize that diabetes causes AD in addition to CVD, and that the coexistence of AD and CVD mediate the association of diabetes with memory impairment, the earliest manifestation of AD. We will test these hypotheses in human and mouse studies. Our primary aim is to examine the association of diabetes with the interplay of AD and CVD in humans and mice. We will conduct a brain imaging study with 2 waves in a cohort of 200 persons with a mean age of 62 years followed at 2-year intervals in order to examine the cross-sectional and longitudinal association of diabetes with AD. We will categorize diabetes as pre-diabetes, diabetes, and normal glucose tolerance (NGT), and examine glycemia continuously using HbA1C. We will ascertain AD with amyloid ? (A?) imaging using Positron Emission Tomography with 18F-Florbetaben. We will characterize CVD with brain magnetic resonance imaging (MRI) as white matter hyperintensities (WMH) and infarcts. We will also explore the coexistence of aggregate and regional CVD, AD, and cerebral amyloid angiopathy (CAA, ascertained as microbleeds on MRI) in relation to diabetes. We will explore if AD mediates the association of diabetes with memory impairment, and whether CVD modifies this association. We will compare among diabetic, AD (J20), AD/diabetic mice, and appropriate controls the distribution and load of AD neuropathology (phosphorylated tau, soluble A? peptides, and plaques) in three ages (2, 5 and 14 months) with and without transient occlusion of the middle cerebral artery (MCA). We will also compare cognitive performance in these groups. Our secondary aim is to examine if diabetes is related with AD-like brain functional correlates in humans and mice. Our exploratory aims are to explore in humans whether AD predicts incident pre-diabetes and diabetes and increasing glycemia among persons with NGT, whether AD mice are more likely to develop hyperglycemia, explore the plasma lipidomic and proteomic profile predictive of clinical, pathologic, and physiologic outcomes, and explore the association of correlates of diabetes, such as adiposity, dyslipidemia, inflammation, hypertension, insulin resistance, with AD.