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Blood Biomarkers Associated with Cognitive Decline in Early Stage and Drug-Naive Parkinson's Disease Patients.

Santiago JA, Potashkin JA - PLoS ONE (2015)

Bottom Line: Levels of EFTUD2 and PTBP1 were significantly higher in cognitively normal PD patients (PD-CN) compared to cognitively impaired PD patients (PD-MCI).Interestingly, blood glucose levels were significantly higher in PD and PD-MCI patients (≥ 100 mg/dL, pre-diabetes) compared to HC.Further, our results show that drug-naïve PD and PD-MCI patients have glucose levels characteristic of pre-diabetes patients, suggesting that impaired glucose metabolism is an early event in PD.

View Article: PubMed Central - PubMed

Affiliation: The Cellular and Molecular Pharmacology Department, The Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States of America.

ABSTRACT
Early diagnosis of Parkinson's disease (PD) continues to be a major challenge in the field. The lack of a robust biomarker to detect early stage PD patients has considerably slowed the progress toward the development of potential therapeutic agents. We have previously evaluated several RNA biomarkers in whole blood from participants enrolled in two independent clinical studies. In these studies, PD patients were medicated, thus, expression of these biomarkers in de novo patients remains unknown. To this end, we tested ten RNA biomarkers in blood samples from 99 untreated PD patients and 101 HC nested in the cross-sectional Parkinson's Progression Markers Initiative by quantitative real-time PCR. One biomarker out of ten, COPZ1 trended toward significance (nominal p = 0.009) when adjusting for age, sex, and educational level. Further, COPZ1, EFTUD2 and PTBP1 mRNAs correlated with clinical features in PD patients including the Hoehn and Yahr scale, Movement Disorder Society revision of Unified Parkinson's Disease Rating Scale (MDS-UPDRS) and Montreal Cognitive Assessment (MoCA) score. Levels of EFTUD2 and PTBP1 were significantly higher in cognitively normal PD patients (PD-CN) compared to cognitively impaired PD patients (PD-MCI). Interestingly, blood glucose levels were significantly higher in PD and PD-MCI patients (≥ 100 mg/dL, pre-diabetes) compared to HC. Collectively, we report the association of three RNA biomarkers, COPZ1, EFTUD2 and PTBP1 with clinical features including cognitive decline in early drug-naïve PD patients. Further, our results show that drug-naïve PD and PD-MCI patients have glucose levels characteristic of pre-diabetes patients, suggesting that impaired glucose metabolism is an early event in PD. Evaluation of these potential biomarkers in a larger longitudinal study is warranted.

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EFTUD2 and PTBP1 mRNAs as biomarkers for cognitive decline in PD.A. Relative abundance of EFTUD2 in PD patients with normal cognition (circles) compared to PD patients with mild cognitive impairment (triangles). B. Relative abundance of PTBP1 in PD patients with normal cognition (circles) compared to PD patients with mild cognitive impairment (triangles). Error bars represent the 95% confidence interval. A p-value of less than 0.05 was regarded as significant based on a Student t-test (two-tailed). PD-CN is cognitively normal PD patients, PD-MCI is PD patients with mild cognitive impairment.
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pone.0142582.g002: EFTUD2 and PTBP1 mRNAs as biomarkers for cognitive decline in PD.A. Relative abundance of EFTUD2 in PD patients with normal cognition (circles) compared to PD patients with mild cognitive impairment (triangles). B. Relative abundance of PTBP1 in PD patients with normal cognition (circles) compared to PD patients with mild cognitive impairment (triangles). Error bars represent the 95% confidence interval. A p-value of less than 0.05 was regarded as significant based on a Student t-test (two-tailed). PD-CN is cognitively normal PD patients, PD-MCI is PD patients with mild cognitive impairment.

Mentions: Given the significant correlation between EFTUD2 and PTBP1 with MoCA score we evaluated their capability to distinguish PD-CN from PD-MCI patients. Expression of EFTUD2 was significantly up-regulated in PD-CN (mean (SD) [95% CI] p-value, 1.21 (0.66) [1.04–1.38] p = 0.04) compared to PD-MCI (0.93 (0.60) [0.72–1.14]) (Fig 2A). In parallel, expression of PTBP1 was significantly up-regulated in PD-CN (1.30 (0.84) [1.09–1.51] p = 0.02) compared to PD-MCI (0.93 (0.56) [0.73–1.12]) (Fig 2B). Pearson correlation analysis showed that EFTUD2 expression was independent of age, gender and years of education (p> 0.5). Similarly, PTBP1 expression did not correlate with age (p = 0.8), and gender (p = 0.19), but it showed a significant but weak correlation with years of education (r = -0.20, p = 0.05). This analysis was repeated using a general linear regression model adjusting for confounding variables including age, sex, educational level, Hoehn and Yahr, disease duration, and MDS-UPDRS. Both biomarkers, EFTUD2 (ß = 0.27, p = 0.01) and PTBP1 (ß = 0.22, p = 0.04) reached statistical significance. ROC analysis for EFTUD2 and PTBP1 resulted in AUC values of 0.64 and 0.63, respectively.


Blood Biomarkers Associated with Cognitive Decline in Early Stage and Drug-Naive Parkinson's Disease Patients.

Santiago JA, Potashkin JA - PLoS ONE (2015)

EFTUD2 and PTBP1 mRNAs as biomarkers for cognitive decline in PD.A. Relative abundance of EFTUD2 in PD patients with normal cognition (circles) compared to PD patients with mild cognitive impairment (triangles). B. Relative abundance of PTBP1 in PD patients with normal cognition (circles) compared to PD patients with mild cognitive impairment (triangles). Error bars represent the 95% confidence interval. A p-value of less than 0.05 was regarded as significant based on a Student t-test (two-tailed). PD-CN is cognitively normal PD patients, PD-MCI is PD patients with mild cognitive impairment.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4643881&req=5

pone.0142582.g002: EFTUD2 and PTBP1 mRNAs as biomarkers for cognitive decline in PD.A. Relative abundance of EFTUD2 in PD patients with normal cognition (circles) compared to PD patients with mild cognitive impairment (triangles). B. Relative abundance of PTBP1 in PD patients with normal cognition (circles) compared to PD patients with mild cognitive impairment (triangles). Error bars represent the 95% confidence interval. A p-value of less than 0.05 was regarded as significant based on a Student t-test (two-tailed). PD-CN is cognitively normal PD patients, PD-MCI is PD patients with mild cognitive impairment.
Mentions: Given the significant correlation between EFTUD2 and PTBP1 with MoCA score we evaluated their capability to distinguish PD-CN from PD-MCI patients. Expression of EFTUD2 was significantly up-regulated in PD-CN (mean (SD) [95% CI] p-value, 1.21 (0.66) [1.04–1.38] p = 0.04) compared to PD-MCI (0.93 (0.60) [0.72–1.14]) (Fig 2A). In parallel, expression of PTBP1 was significantly up-regulated in PD-CN (1.30 (0.84) [1.09–1.51] p = 0.02) compared to PD-MCI (0.93 (0.56) [0.73–1.12]) (Fig 2B). Pearson correlation analysis showed that EFTUD2 expression was independent of age, gender and years of education (p> 0.5). Similarly, PTBP1 expression did not correlate with age (p = 0.8), and gender (p = 0.19), but it showed a significant but weak correlation with years of education (r = -0.20, p = 0.05). This analysis was repeated using a general linear regression model adjusting for confounding variables including age, sex, educational level, Hoehn and Yahr, disease duration, and MDS-UPDRS. Both biomarkers, EFTUD2 (ß = 0.27, p = 0.01) and PTBP1 (ß = 0.22, p = 0.04) reached statistical significance. ROC analysis for EFTUD2 and PTBP1 resulted in AUC values of 0.64 and 0.63, respectively.

Bottom Line: Levels of EFTUD2 and PTBP1 were significantly higher in cognitively normal PD patients (PD-CN) compared to cognitively impaired PD patients (PD-MCI).Interestingly, blood glucose levels were significantly higher in PD and PD-MCI patients (≥ 100 mg/dL, pre-diabetes) compared to HC.Further, our results show that drug-naïve PD and PD-MCI patients have glucose levels characteristic of pre-diabetes patients, suggesting that impaired glucose metabolism is an early event in PD.

View Article: PubMed Central - PubMed

Affiliation: The Cellular and Molecular Pharmacology Department, The Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States of America.

ABSTRACT
Early diagnosis of Parkinson's disease (PD) continues to be a major challenge in the field. The lack of a robust biomarker to detect early stage PD patients has considerably slowed the progress toward the development of potential therapeutic agents. We have previously evaluated several RNA biomarkers in whole blood from participants enrolled in two independent clinical studies. In these studies, PD patients were medicated, thus, expression of these biomarkers in de novo patients remains unknown. To this end, we tested ten RNA biomarkers in blood samples from 99 untreated PD patients and 101 HC nested in the cross-sectional Parkinson's Progression Markers Initiative by quantitative real-time PCR. One biomarker out of ten, COPZ1 trended toward significance (nominal p = 0.009) when adjusting for age, sex, and educational level. Further, COPZ1, EFTUD2 and PTBP1 mRNAs correlated with clinical features in PD patients including the Hoehn and Yahr scale, Movement Disorder Society revision of Unified Parkinson's Disease Rating Scale (MDS-UPDRS) and Montreal Cognitive Assessment (MoCA) score. Levels of EFTUD2 and PTBP1 were significantly higher in cognitively normal PD patients (PD-CN) compared to cognitively impaired PD patients (PD-MCI). Interestingly, blood glucose levels were significantly higher in PD and PD-MCI patients (≥ 100 mg/dL, pre-diabetes) compared to HC. Collectively, we report the association of three RNA biomarkers, COPZ1, EFTUD2 and PTBP1 with clinical features including cognitive decline in early drug-naïve PD patients. Further, our results show that drug-naïve PD and PD-MCI patients have glucose levels characteristic of pre-diabetes patients, suggesting that impaired glucose metabolism is an early event in PD. Evaluation of these potential biomarkers in a larger longitudinal study is warranted.

Show MeSH
Related in: MedlinePlus