The goal of this project is to evaluate novel candidate protein biomarkers for Alzheimer's disease that we have previously identified in CSF using a non-biased proteomics approach (two-dimensional difference in gel electrophoresis [2D-DIGE] coupled with liquid chromatography and tandem mass spectrometry [LCMS/MS]) that compared the CSF proteomes of samples derived from two groups of well-characterized subjects: one with mild dementia of the Alzheimer's type (DAT) and evidence of amyloid deposition in the brain (low CSF Ab42 levels) (N=24);and another without demenia and no evidence of amyloid deposition in the brain (high CSF Ab42 levels) (N=24). To evaluate these candidate biomarkers, in Aim 1 we will develop specific quantitative assays (e.g. ELISA) and validate them assays using CSF from the original 'discovery'cohort of subject samples.
In Aim 2, we will apply these validated assays to a Iarger, independent set of CSF samples obtained from well-characterized volunteer subjects followed longitudinally at the WU ADRC, in order to evaluate each assay's diagnostic and prognostic utility.
In Aim 3, we propose to perform 'top down'proteomics on a small number of these candidate biomarkers that exhibited aberrant patterns of migration on 2D-DIGE suggestive of unusual post-translational modifications characterizing such distinguishing modifications will enable the development of additional biomarker assays in the future, and may yield insights into the pathophysiology of AD.

Public Health Relevance

This study is intended to discover novel CSF AD biomarkers and evaluate their diagnostic and prognostic utility. These biomarkers are expected to: 1) facilitate the diagnosis of AD prior to dementia onset;2) aid in identification of cognitively normal individuals most likely to progress to dementia, 3) aid in identification of very mildly demented patients whose dementia is most likely to worsen, and 4) yield new insights into the pathophysiology of AD. These findings will directly impact future clinical trial enrollment and patient care.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Specialized Center (P50)
Project #
5P50AG005681-30
Application #
8459490
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
$139,463
Indirect Cost
$47,535
Name
Washington University
Department
Type
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Su, Yi; Blazey, Tyler M; Snyder, Abraham Z et al. (2015) Partial volume correction in quantitative amyloid imaging. Neuroimage 107:55-64
Shim, Yong Soo; Yang, Dong-Won; Roe, Catherine M et al. (2015) Pathological correlates of white matter hyperintensities on magnetic resonance imaging. Dement Geriatr Cogn Disord 39:92-104
Wang, Li-San; Naj, Adam C; Graham, Robert R et al. (2015) Rarity of the Alzheimer disease-protective APP A673T variant in the United States. JAMA Neurol 72:209-16
Karch, Celeste M; Goate, Alison M (2015) Alzheimer's disease risk genes and mechanisms of disease pathogenesis. Biol Psychiatry 77:43-51
Ghoshal, Nupur; Perry, Arie; McKeel, Daniel et al. (2015) Variably Protease-sensitive Prionopathy in an Apparent Cognitively Normal 93-Year-Old. Alzheimer Dis Assoc Disord 29:173-6
Hurth, Kyle; Tarawneh, Rawan; Ghoshal, Nupur et al. (2015) Whipple's disease masquerades as dementia with Lewy bodies. Alzheimer Dis Assoc Disord 29:85-9
Aschenbrenner, Andrew J; Balota, David A; Tse, Chi-Shing et al. (2015) Alzheimer disease biomarkers, attentional control, and semantic memory retrieval: Synergistic and mediational effects of biomarkers on a sensitive cognitive measure in non-demented older adults. Neuropsychology 29:368-81
Dobrowolska, Justyna A; Kasten, Tom; Huang, Yafei et al. (2014) Diurnal patterns of soluble amyloid precursor protein metabolites in the human central nervous system. PLoS One 9:e89998
Benitez, Bruno A; Jin, Sheng Chih; Guerreiro, Rita et al. (2014) Missense variant in TREML2 protects against Alzheimer's disease. Neurobiol Aging 35:1510.e19-26
Gusareva, Elena S; Carrasquillo, Minerva M; Bellenguez, CĂ©line et al. (2014) Genome-wide association interaction analysis for Alzheimer's disease. Neurobiol Aging 35:2436-43

Showing the most recent 10 out of 427 publications