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.
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.
|Kirson, Noam Y; Scott Andrews, J; Desai, Urvi et al. (2018) Patient Characteristics and Outcomes Associated with Receiving an Earlier Versus Later Diagnosis of Probable Alzheimer's Disease. J Alzheimers Dis 61:295-307|
|Roe, Catherine M; Ances, Beau M; Head, Denise et al. (2018) Incident cognitive impairment: longitudinal changes in molecular, structural and cognitive biomarkers. Brain 141:3233-3248|
|La Joie, Renaud; Bejanin, Alexandre; Fagan, Anne M et al. (2018) Associations between [18F]AV1451 tau PET and CSF measures of tau pathology in a clinical sample. Neurology 90:e282-e290|
|Day, Gregory S; Musiek, Erik S; Morris, John C (2018) Rapidly Progressive Dementia in the Outpatient Clinic: More Than Prions. Alzheimer Dis Assoc Disord 32:291-297|
|Ihara, Ryoko; Vincent, Benjamin D; Baxter, Michael R et al. (2018) Relative neuron loss in hippocampal sclerosis of aging and Alzheimer's disease. Ann Neurol 84:741-753|
|Swarup, Vivek; Hinz, Flora I; Rexach, Jessica E et al. (2018) Identification of evolutionarily conserved gene networks mediating neurodegenerative dementia. Nat Med :|
|Sato, Chihiro; Barthélemy, Nicolas R; Mawuenyega, Kwasi G et al. (2018) Tau Kinetics in Neurons and the Human Central Nervous System. Neuron 97:1284-1298.e7|
|Sutphen, Courtney L; McCue, Lena; Herries, Elizabeth M et al. (2018) Longitudinal decreases in multiple cerebrospinal fluid biomarkers of neuronal injury in symptomatic late onset Alzheimer's disease. Alzheimers Dement 14:869-879|
|Bussy, Aurélie; Snider, B Joy; Coble, Dean et al. (2018) Effect of apolipoprotein E4 on clinical, neuroimaging, and biomarker measures in noncarrier participants in the Dominantly Inherited Alzheimer Network. Neurobiol Aging 75:42-50|
|Vardarajan, Badri N; Barral, Sandra; Jaworski, James et al. (2018) Whole genome sequencing of Caribbean Hispanic families with late-onset Alzheimer's disease. Ann Clin Transl Neurol 5:406-417|
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