Many experimental and associative studies indicate decreased insulin activity In specific regions of brain as a potential contributor to Alzheimer's disease (AD) and perhaps related neurodegenerative diseases. Importantly, recent pilot clinical trials have concluded that augmenting central nervous system (CNS) insulin activity improves or protects cognitive function in patients with amnestic Mild Cognitive Impairment (aMCl) or mild AD, perhaps especially patients without an e4 allele of the apolipoprotein E gene {APOE). We hypothesize that specific insulin-induced changes in the human cerebrospinal fluid (CSF) proteome will illuminate a set of biomarkers responsive to alterations In CNS Insulin activity. We will this hypothesis by achieving the following specific aims: (i) discover, confirm, and validate a novel """"""""CNS Insulin-Responsive Multi-Analyte Profile (MAP)"""""""" of specific changes In the CSF proteome with Increased CNS insulin activity using samples from two placebo-controlled randomized trials of intranasal insulin in patients with aMCI/mild AD, including Project 2, (ii) determine the significance of decreased CNS insulin activity In age-related cognitive decline, pre-clinical AD, and related diseases using our CNS Insulin-Responsive MAP, CSF samples and cognitive testing data from our Clinical Core and collaborative UWADRC CSF Bank, and established AD CSF biomarkers from our Neuropathology and Targeted Molecular Testing (NP&TMT) Core, and (iii) quantify brain regional concentration and cellular distribution of selected proteins from our CNS Insulin-Responsive MAP in a large series of autopsies from Controls and patients with AD who did or did not have diabetes mellitus (DM) whose tissue already is in the NP&TMT Core. When successfully completed, our proposed studies will have generated new knowledge about the mechanisms of action of increased CNS insulin activity in patients with aMCI/mild AD receiving insulin therapy, inversely determined the functional significance and specificity of decreased CNS insulin activity In age-related cognitive decline, preclinical AD, and related neurodegenerative diseases, and explored the regional and cellular distribution of selected key protein candidates in a well-characterized autopsy series of AD patients and controls with and without DM.

Public Health Relevance

AD is a looming public health disaster for US citizens, both patients and caregivers, and our health care system. There is no effective treatment for AD. This application is a direct response to the therapeutic imperative for AD, it is highly translational, and it draws on existing NIH-funded resources.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Specialized Center (P50)
Project #
5P50AG005136-30
Application #
8459477
Study Section
Special Emphasis Panel (ZAG1-ZIJ-4)
Project Start
Project End
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
30
Fiscal Year
2013
Total Cost
$176,829
Indirect Cost
$63,478
Name
University of Washington
Department
Type
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Young, Jessica E; Fong, Lauren K; Frankowski, Harald et al. (2018) Stabilizing the Retromer Complex in a Human Stem Cell Model of Alzheimer's Disease Reduces TAU Phosphorylation Independently of Amyloid Precursor Protein. Stem Cell Reports 10:1046-1058
Gallagher, Damien; Kiss, Alex; Lanctot, Krista et al. (2018) Depression and Risk of Alzheimer Dementia: A Longitudinal Analysis to Determine Predictors of Increased Risk among Older Adults with Depression. Am J Geriatr Psychiatry 26:819-827
Lin, Ming; Gong, Pinghua; Yang, Tao et al. (2018) Big Data Analytical Approaches to the NACC Dataset: Aiding Preclinical Trial Enrichment. Alzheimer Dis Assoc Disord 32:18-27
Haaksma, Miriam L; Calderón-Larrañaga, Amaia; Olde Rikkert, Marcel G M et al. (2018) Cognitive and functional progression in Alzheimer disease: A prediction model of latent classes. Int J Geriatr Psychiatry 33:1057-1064
Wang, Lucy Y; Raskind, Murray A; Wilkinson, Charles W et al. (2018) Associations between CSF cortisol and CSF norepinephrine in cognitively normal controls and patients with amnestic MCI and AD dementia. Int J Geriatr Psychiatry 33:763-768
Moreno, Monica A; Or-Geva, Noga; Aftab, Blake T et al. (2018) Molecular signature of Epstein-Barr virus infection in MS brain lesions. Neurol Neuroimmunol Neuroinflamm 5:e466
Blue, E E; Yu, C-E; Thornton, T A et al. (2018) Variants regulating ZBTB4 are associated with age-at-onset of Alzheimer's disease. Genes Brain Behav 17:e12429
Condello, Carlo; Lemmin, Thomas; Stöhr, Jan et al. (2018) Structural heterogeneity and intersubject variability of A? in familial and sporadic Alzheimer's disease. Proc Natl Acad Sci U S A 115:E782-E791
Goins, R Turner; Schure, Mark; Jensen, Paul N et al. (2018) Lower body functioning and correlates among older American Indians: The Cerebrovascular Disease and Its Consequences in American Indians Study. BMC Geriatr 18:6
Ramsey, Christine M; Gnjidic, Danijela; Agogo, George O et al. (2018) Longitudinal patterns of potentially inappropriate medication use following incident dementia diagnosis. Alzheimers Dement (N Y) 4:1-10

Showing the most recent 10 out of 753 publications