Elevated Osteopontin Levels in Mild Cognitive Impairment and Alzheimer’s Disease

Sun, Yuan; Yin, Xue; Guo, Hong; Han, Rui; He, Rui; Li, Jun

doi:10.1155/2013/615745

Cited by 56 publications

(57 citation statements)

References 44 publications

(41 reference statements)

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“…The same authors also showed CSF and serum osteopontin concentrations were higher in PD patients than controls (33). A more recent study reported increased CSF and plasma concentrations in mild cognitive impairment and AD patients (34). Interestingly, the peptide (AIPVAQDLNAPSDWDSR, unmodified) used in our study displayed lower levels in PD; this could be related to the changes in post-translational modifications (e.g.…”

Section: Discussionsupporting

confidence: 65%

Cerebrospinal Fluid Peptides as Potential Parkinson Disease Biomarkers: A Staged Pipeline for Discovery and Validation*

Shi

Movius

Dator

et al. 2015

Molecular & Cellular Proteomics

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a Finding robust biomarkers for Parkinson disease (PD) is currently hampered by inherent technical limitations associated with imaging or antibody-based protein assays.To circumvent the challenges, we adapted a staged pipeline, starting from our previous proteomic profiling followed by high-throughput targeted mass spectrometry (MS), to identify peptides in human cerebrospinal fluid (CSF) for PD diagnosis and disease severity correlation. In this multicenter study consisting of training and validation sets, a total of 178 subjects were randomly selected from a retrospective cohort, matching age and sex between PD patients, healthy controls, and neurological controls with Alzheimer disease (AD). From ϳ14,000 unique peptides displaying differences between PD and healthy control in proteomic investigations, 126 peptides were selected based on relevance and observability in CSF using bioinformatic analysis and MS screening, and then quantified by highly accurate and sensitive selected reaction monitoring (SRM) in the CSF of 30 PD patients versus 30 healthy controls (training set), followed by diagnostic (receiver operating characteristics) and disease severity correlation analyses. The most promising candidates were further tested in an independent cohort of 40 PD patients, 38 AD patients, and 40 healthy controls (validation set). A panel of five peptides (derived from SPP1, LRP1, CSF1R, EPHA4, and TIMP1) was identified to provide an area under curve (AUC) of 0.873 (sensitivity ‫؍‬ 76.7%, specificity ‫؍‬ 80.0%) for PD versus healthy controls in the training set. The performance was essentially confirmed in the validation set (AUC ‫؍‬ 0.853, sensitivity ‫؍‬ 82.5%, specificity ‫؍‬ 82.5%). Additionally, this panel could also differentiate the PD and AD groups (AUC ‫؍‬ 0.990, sensitivity ‫؍‬ 95.0%, specificity ‫؍‬ 97.4%). Furthermore, a combination of two peptides belonging to proteins TIMP1 and APLP1 significantly correlated with disease severity as determined by the Unified Parkinson's Disease Rating Scale motor scores in both the training (r ‫؍‬ 0.381, p ‫؍‬ 0.038)j and the validation (r ‫؍‬ 0.339, p ‫؍‬ 0.032) sets. The novel panel of CSF peptides, if validated in independent co-

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Section: Discussionsupporting

confidence: 65%

Cerebrospinal Fluid Peptides as Potential Parkinson Disease Biomarkers: A Staged Pipeline for Discovery and Validation*

Shi

Movius

Dator

et al. 2015

Molecular & Cellular Proteomics

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“…Separate from the metabolic pathway, we observed increased levels of M4 proteins osteopontin (SPP1), dickkopf-related protein 3 (DKK3), and CD44. SPP1 has been nominated as an AD CSF biomarker in previous studies [106][107][108][109] . SPP1 is known to be involved in tissue repair 110 , and promotes phagocytosis of amyloid-β and an anti-inflammatory microglial phenotype 111,112 .…”

Section: Discussionmentioning

confidence: 99%

A Consensus Proteomic Analysis of Alzheimer’s Disease Brain and Cerebrospinal Fluid Reveals Early Changes in Energy Metabolism Associated with Microglia and Astrocyte Activation

Johnson

Dammer

Duong

et al. 2019

Preprint

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Our understanding of the biological changes in the brain associated with Alzheimer's disease (AD) pathology and cognitive impairment remains incomplete. To increase our understanding of these changes, we analyzed dorsolateral prefrontal cortex of control, asymptomatic AD, and AD brains from four different centers by label-free quantitative mass spectrometry and weighted protein co-expression analysis to obtain a consensus protein co-expression network of AD brain.This network consisted of 13 protein co-expression modules. Six of these modules correlated with amyloid-β plaque burden, tau neurofibrillary tangle burden, cognitive function, and clinical functional status, and were altered in asymptomatic AD, AD, or in both disease states. These modules reflected synaptic, mitochondrial, sugar metabolism, extracellular matrix, cytoskeletal, and RNA binding/splicing biological functions. The identified protein network modules were preserved in a community-based cohort analyzed by a different quantitative mass spectrometry approach. They were also preserved in temporal lobe and precuneus brain regions. Some of the modules were influenced by aging, and showed changes in other neurodegenerative diseases such as frontotemporal dementia and corticobasal degeneration. The module most strongly associated with AD pathology and cognitive impairment was the sugar metabolism module, which was enriched in AD genetic risk factors and correlated with APOE genetic risk. This module was also highly enriched in microglia and astrocyte protein markers associated with an antiinflammatory state, suggesting that the biological functions it represents serve a protective role in AD. Proteins from this module were increased in cerebrospinal fluid from asymptomatic AD and AD cases, highlighting their potential as biomarkers of the altered brain network. In this study of >2000 brains and nearly 400 cerebrospinal fluid samples by quantitative proteomics, we identify proteins and biological processes in AD brain that may serve as therapeutic targets and fluid biomarkers for the disease. IntroductionAlzheimer's disease (AD) is a leading cause of death worldwide, with increasing prevalence as global life expectancy increases 1 . Although AD is currently defined on the basis of amyloid-β plaque and tau neurofibrillary tangle deposition within the neocortex 2 , the biochemical and cellular changes in the brain that characterize the disease beyond amyloid-β and tau deposition remain incompletely understood. The genetic architecture of late-onset AD has been extensively studied, and the results of these studies implicate multiple biological pathways that contribute to development of the disease, including immune function, endocytic vesicle trafficking, and lipid homeostasis, among others 3-5 . In addition to genetic studies, transcriptomic studies on postmortem AD brain tissue have identified changes in mRNA co-expression that correlate with disease traits and cognitive decline 6,7 . However, given that mRNA levels correlate only modestly to protein le...

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“…Increased CSF osteopontin levels have been reported in patients with AD and MCI compared with healthy controls (Supplementary Table 2). Larger increases in CSF osteopontin may represent disease progression and acutephase disease 79 . However, reports have been contradictory in terms of specificity for AD.…”

Section: Other Candidate Inflammation-related Biomarkersmentioning

confidence: 99%

New fluid biomarkers tracking non-amyloid-β and non-tau pathology in Alzheimer’s disease

2020

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Cerebrospinal fluid (CSF) biomarkers based on the core pathological proteins associated with Alzheimer's disease (AD), i.e., amyloid-β (Aβ) and tau protein, are widely regarded as useful diagnostic biomarkers. However, a lack of biomarkers for monitoring the treatment response and indexing clinical severity has proven to be problematic in drug trials targeting Aβ. Therefore, new biomarkers are needed to track non-Aβ and non-tau pathology. Many proteins involved in the pathophysiological progression of AD have shown promise as new biomarkers. Neurodegeneration-and synapse-related biomarkers in CSF (e.g., neurofilament light polypeptide [NFL], neurogranin, and visinin-like protein 1) and blood (e.g., NFL) aid prediction of AD progress, as well as early diagnosis. Neuroinflammation, lipid dysmetabolism, and impaired protein clearance are considered important components of AD pathophysiology. Inflammation-related proteins in the CSF, such as progranulin, intercellular adhesion molecule 1, and chitinase-3-like protein 1 (YKL-40), are useful for the early detection of AD and can represent clinical severity. Several lipid metabolism-associated biomarkers and protein clearance-linked markers have also been suggested as candidate AD biomarkers. Combinations of subsets of new biomarkers enhance their utility in terms of broadly characterizing AD-associated pathological changes, thereby facilitating precise selection of susceptible patients and comprehensive monitoring of the treatment response. This approach could facilitate the development of effective treatments for AD.

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Elevated Osteopontin Levels in Mild Cognitive Impairment and Alzheimer’s Disease

Cited by 56 publications

References 44 publications

Cerebrospinal Fluid Peptides as Potential Parkinson Disease Biomarkers: A Staged Pipeline for Discovery and Validation*

Cerebrospinal Fluid Peptides as Potential Parkinson Disease Biomarkers: A Staged Pipeline for Discovery and Validation*

A Consensus Proteomic Analysis of Alzheimer’s Disease Brain and Cerebrospinal Fluid Reveals Early Changes in Energy Metabolism Associated with Microglia and Astrocyte Activation

New fluid biomarkers tracking non-amyloid-β and non-tau pathology in Alzheimer’s disease

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