Plasma osteopontin as a biomarker of Alzheimer\u2019s disease and vascular cognitive impairment

Joyce R. Chong,Saima Hilal,Alan P. Kumar,Christopher P. Chen,Ainiah R. Raquib,Mitchell K. P. Lai,Yuek Ling Chai,Gautam Sethi,Boon Yeow Tan,Xin Xu,Narayanaswamy Venketasubramanian

doi:10.1038/s41598-021-83601-6

Abstract

Cerebrovascular disease (CeVD) and neurodegenerative dementia such as Alzheimer’s disease (AD) are frequently associated comorbidities in the elderly, sharing common risk factors and pathophysiological mechanisms including neuroinflammation. Osteopontin (OPN) is an inflammatory marker found upregulated in vascular diseases as well as in AD. However, its involvement in vascular dementia (VaD) and pre-dementia stages, namely cognitive impairment no dementia (CIND), both of which fall under the spectrum of vascular cognitive impairment (VCI), has yet to be examined. Its correlations with inflammatory cytokines in cognitive impairment also await investigation. 80 subjects with no cognitive impairment (NCI), 160 with CIND and 144 with dementia were included in a cross-sectional study on a Singapore-based memory clinic cohort. All subjects underwent comprehensive clinical, neuropsychological and brain neuroimaging assessments, together with clinical diagnoses based on established criteria. Blood samples were collected and OPN as well as inflammatory cytokines interleukin (IL)-6, IL-8 and tumor necrosis factor (TNF) were measured using immunoassays. Multivariate regression analyses showed significant associations between increased OPN and VCI groups, namely CIND with CeVD, AD with CeVD and VaD. Interestingly, higher OPN was also significantly associated with AD even in the absence of CeVD. We further showed that increased OPN significantly associated with neuroimaging markers of CeVD and neurodegeneration, including cortical infarcts, lacunes, white matter hyperintensities and brain atrophy. OPN also correlated with elevated levels of IL-6, IL-8 and TNF. Our findings suggest that OPN may play a role in both VCI and neurodegenerative dementias. Further longitudinal analyses are needed to assess the prognostic utility of OPN in disease prediction and monitoring.

Highlights

Over 50 million people worldwide are affected by dementia, and the number is estimated to almost triple by the year 2050 (World Alzheimer Report 2018)
In the absence of significant cerebrovascular diseases (CeVD), higher OPN levels were significantly associated with Alzheimer’s disease (AD) (OR = 15.3; 95% confidence intervals (CI) 3.2 to 73.6), but not with cognitive impairment no dementia (CIND) without CeVD (OR = 1.5; 95% CI 0.6 to 3.9)
OPN may be a useful biomarker for identifying patients at risk of developing vascular dementia (VaD), as previous studies have demonstrated the likelihood of CIND patients with CeVD converting to VaD56,57

Summary

Introduction

Over 50 million people worldwide are affected by dementia, and the number is estimated to almost triple by the year 2050 (World Alzheimer Report 2018). AD is a progressive neurodegenerative disease characterized by cortical deposition of amyloid plaques and neurofibrillary tangles, whereas VaD is generally associated with small vessel cerebrovascular diseases (CeVD), and falls under the spectrum of vascular cognitive impairment (VCI). Studies have reported the co-localization of activated microglia and astrocytes with amyloid plaques in AD brains[1], together with elevated levels of various pro-inflammatory cytokines in blood and cerebrospinal fluid[2]. Activated glial cells around vascular lesions in postmortem b rains[3,4] as well as increased cytokines and chemokines have been reported in blood and cerebrospinal fluid of VaD p atients[5,6,7,8]. Stroke, cardiovascular disease, hypertension and atherosclerosis are known risk factors of cognitive impairment and AD10–12. Osteopontin (OPN) has been shown to play an important role in the pathophysiology of CeVD and inflammation

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