Potential Utility of Cerebrospinal Fluid Glycoprotein Nonmetastatic Melanoma Protein B as a Neuroinflammatory Diagnostic Biomarker in Mild Cognitive Impairment and Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is a very common neurodegenerative disorder characterized by the gradual loss of neurons and extracellular amyloid-peptide buildup. There is compelling evidence that the disease process depends on neuroinflammatory alterations, such as the activation of astrocytes and microglia cells. A transmembrane glycoprotein known as glycoprotein nonmetastatic melanoma protein B (GPNMB) plays a neuroprotective role during the development of neurodegeneration. To the best of our knowledge, this is the first investigation discussing the potential clinical usefulness of this protein in the AD continuum, especially in the MCI (mild cognitive impairment) stage. A total of 71 patients with AD or MCI as well as controls were enrolled in this study. The concentrations of GPNMB, YKL-40, Aβ1-42 (amyloid beta 1-42), Tau, and pTau and the Aβ1-42/1-40 ratio in the CSF (cerebrospinal fluid) were tested using immunological methods. The concentrations of both GPNMB and YKL-40 in the cerebrospinal fluid were significantly higher in patients with AD and MCI compared to the controls. Moreover, both proteins were biochemically associated with classical biomarkers of AD and were especially associated with the Aβ1-42/1-40 ratio and Tau and pTau levels in the whole study group. Elevated concentrations of GPNMB were observed in the Aβ(+) group of AD patients compared to the Aβ(-) subjects. Additionally, the diagnostic performance (AUC value) of GPNMB was higher than that of amyloid β1-42 in MCI patients compared with controls. Our study indicates that GPNMB might be a promising neuroinflammatory biomarker for the early diagnosis and prognosis of the AD continuum, with potential utility as a therapeutic target.

Keywords: Alzheimer’s disease; GPNMB; YKL-40; neuroinflammation.

Figure 1

Cerebrospinal fluid levels of GPNMB by group. GPNMB—glycoprotein nonmetastatic melanoma protein B; AD—Alzheimer’s disease; MCI—mild cognitive impairment; CTRL—control; CSF—cerebrospinal fluid.

Figure 2

Cerebrospinal fluid levels of YKL-40 in AD, MCI, and CTRL groups. AD—Alzheimer’s disease; MCI—mild cognitive impairment; CTRL—control; CSF—cerebrospinal fluid.

Figure 3

Spearman’s correlations between neurochemical biomarkers and tested proteins in the entire study population. MMSE—mini mental state examination score.

Figure 4

Comparison of area under ROC curves (AUC) for GPNMB, YKL-40, and classical biomarkers in AD between AD and CTRL groups.

Figure 5

Comparison of area under ROC curves (AUC) for GPNMB, YKL-40, and classical biomarkers between MCI and CTRL groups.