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. 2019 Jul 19:15:2073-2085.
doi: 10.2147/NDT.S205550. eCollection 2019.

Evaluation of α-synuclein and apolipoprotein E as potential biomarkers in cerebrospinal fluid to monitor pharmacotherapeutic efficacy in dopamine dictated disease states of Parkinson's disease and schizophrenia

Ashish Kumar Gupta  1 , Ruchika Pokhriyal  1 , Uddipan Das  1 , Mohd Imran Khan  1 , Domada Ratna Kumar  1 , Rishab Gupta  2 , Rakesh Kumar Chadda  2 , Rashmi Ramachandran  3 , Vinay Goyal  4 , Manjari Tripathi  4 , Gururao Hariprasad  1
Affiliations

Evaluation of α-synuclein and apolipoprotein E as potential biomarkers in cerebrospinal fluid to monitor pharmacotherapeutic efficacy in dopamine dictated disease states of Parkinson's disease and schizophrenia

Ashish Kumar Gupta et al. Neuropsychiatr Dis Treat. .

Erratum in

Abstract

Background and objective: Dopamine plays an important role in the disease pathology of Parkinson's disease and schizophrenia. These two neuropsychiatric disorders represent disease end points of the dopaminergic spectrum where Parkinson's disease represents dopamine deficit and schizophrenia represents dopamine hyperactivity in the mid-brain. Therefore, current treatment strategies aim to restore normal dopamine levels. However, during treatment patients develop adverse effects due to overshooting of physiological levels of dopamine leading to psychosis in Parkinson's disease, and extrapyramidal symptoms in schizophrenia. Absence of any laboratory tests hampers modulation of pharmacotherapy. Apolipoprotein E and α-synuclein have an important role in the neuropathology of these two diseases. The objective of this study was to evaluate cerebrospinal fluid (CSF) concentrations of apolipoprotein E and α-synuclein in patients with these two diseases so that they may serve as biomarkers to monitor therapy in Parkinson's disease and schizophrenia.

Methods: Drug-naïve Parkinson's disease patients and Parkinson's disease patients treated with dopaminergic therapy, neurological controls, schizophrenic patients treated with antidopaminergic therapy, and drug-naïve schizophrenic patients were recruited for the study and CSF was collected. Enzyme-linked immunosorbent assays were carried out to estimate the concentrations of apolipoprotein E and α-synuclein. Pathway analysis was done to establish a possible role of these two proteins in various pathways in these two dopamine dictated diseases.

Results: Apolipoprotein E and α-synuclein CSF concentrations have an inverse correlation along the entire dopaminergic clinical spectrum. Pathway analysis convincingly establishes a plausible hypothesis for their co-regulation in the pathogenesis of Parkinson's disease and schizophrenia. Each protein by itself or as a combination has encouraging sensitivity and specificity values of more than 55%.

Conclusion: The dynamic variation of these two proteins along the spectrum is ideal for them to be pursued as pharmacotherapeutic biomarkers in CSF to monitor pharmacological efficacy in Parkinson's disease and schizophrenia.

Keywords: Parkinson’s disease; apolipoprotein E; biomarkers; cerebrospinal fluid; dopamine; schizophrenia; treatment monitoring; α-synuclein.

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Conflict of interest statement

The authors report no conflicts of interest in regard to this work.

Figures

Figure 1
Figure 1
ELISA for expression of (A) apolipoprotein E and (B) α-synuclein in the cerebrospinal fluid (CSF) of Parkinson’s disease, neurological controls, and schizophrenia patients. Clinical phenotypes comprise of Parkinson’s disease naïve (P), Parkinson’s treated (PRx), neurological controls of patients with urological and gynecological diseases needing surgical intervention (NC), schizophrenia treated (SRx), and schizophrenia naïve patients (S). Mean ± Standard error of mean of the values is shown by horizontal lines. The bars represent the concentrations as the average of duplicate readings of each patient sample. Trend lines of apolipoprotein E (y=−0.25x+3.78; R2=0.91) and α-synuclein (y=−0.14x+2.63; R2=0.94) across the five clinical phenotypes is shown as a blue dotted line in (A) and (B), respectively. Diagrammatic representation of the dopamine concentration in cerebrospinal fluid (CSF) is shown along the x-axis.  Concentrations of dopamine in the CSF across the clinical phenotypes has been estimated in Gao et al and Jensen et al., * indicates statistical significance with p<0.05.
Figure 2
Figure 2
Correlation analysis for apolipoprotein E expression and alpha-synuclein. The correlation coefficient (R2) has a value of 0.5 and a statistical significance (p) of 0.05. Abbreviation: CSF, cerebrospinal fluid.
Figure 3
Figure 3
Receiver Operating Characteristic (ROC) for cut-offs that best differentiate disease from controls. (A) Apolipoprotein E for Parkinson’s disease and neurological control; (B) Apolipoprotein E for schizophrenia and control; (C) α-synuclein for Parkinson’s disease and control; and, (D) α-synuclein for schizophrenia and control.
Figure 4
Figure 4
Pathway analysis shows apolipoprotein E and alpha-synuclein, and their respective interactions. apolipoprotein E and alpha-synuclein are shown in white nodes, interacting nodes in Parkinson’s disease pathway are highlighted in green, interacting nodes in schizophrenia pathway are highlighted in pink, and nodes that common to both the groups are highlighted in yellow. Those nodes in the schizophrenia group that have four or more than four interactions are indicated in larger size boxes and those less than four are indicated by smaller boxes. All the interactions are shown by gray lines.
Figure 5
Figure 5
Diagrammatic representation of neuronal synapse depicting experimental result-based hypotheses that explain molecular events in Parkinson’s disease, neurological controls, and schizophrenia. Abbreviations: HSPG, Heparan Sulphate Proteo-Glycan; TLR2, Toll-Like Receptor 2; LRP, Low density lipid Receptor Protein; L-DOPA, Levo-Dopa; P2A, phosphatase 2A; LB, Lewy body; LD, L-decarboxylase; TH, tyrosine hydroxylase; Ty, tyrosine.
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