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Aging and disease    2019, Vol. 10 Issue (3) : 601-610     DOI: 10.14336/AD.2018.0615
Orginal Article |
Mitochondrial Creatine Kinase is Decreased in the Serum of Idiopathic Parkinson’s Disease Patients
Jinghui Xu1, Xiaodi Fu1, Mengqiu Pan2, Xiao Zhou1, Zhaoyu Chen3, Dongmei Wang1, Xiaomei Zhang1, Qiong Chen1, Yanhui Li1, Xiaoxian Huang1, Guanghui Liu1, Jianjun Lu2, Yan Liu4, Yafang Hu1, Suyue Pan1, Qing Wang3, Qun Wang1,*, Yunqi Xu1,*
1Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China
2Department of Neurology, Guangdong 999 Brain Hospital, Guangzhou, China
3Department of Neurology, the Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
4Department of Medical Imaging, Nanfang Hospital, Southern Medical University, Guangzhou, China
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Abstract  

Mitochondrial creatine kinase (MtCK) is vital in the process of mitochondrial energy metabolism, and mitochondrial dysfunction has been implicated in the pathogenesis of Parkinson’s disease (PD). Therefore, we speculated that MtCK activity could be altered in the serum of PD patients. However, no studies to date have investigated this specific topic, so we sought to investigate the serum MtCK activities among a cohort of PD patients. 50 patients with PD and 30 age-matched controls were recruited for this study. Serum ubiquitous MtCK (uMtCK) and sarcomeric MtCK (sMtCK) activities were assayed using an immunoinhibition method. Correlations between serum uMtCK/sMtCK activities and clinical features/parameters were explored in the PD group. Our study revealed a significant decrease in the uMtCK activity in the PD group when compared with the control group. No significant difference was found in the serum sMtCK activity between the PD and control groups. There was a significant correlation between serum uMtCK activities and the disease progression rate, duration, and age at onset in PD patients. While no significant relationship was found between the serum uMtCK activities and the Hoehn & Yahr stage or main non-motor symptoms scale. There was a significant decrease in the uMtCK activity in the serum of PD patients, which was associated with the rate of disease progression, duration, and age at onset of disease. Therefore, uMtCK activity in serum offers a useful clue for identification of PD biomarkers.

Keywords Parkinson’s disease      mitochondrial creatine kinase      ubiquitous mitochondrial creatine kinase      sarcomeric mitochondrial creatine kinase      mitochondrial dysfunction     
Corresponding Authors: Wang Qun,Xu Yunqi   
About author:

These authors contributed equally to this work.

Issue Date: 29 March 2018
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Jinghui Xu
Xiaodi Fu
Mengqiu Pan
Xiao Zhou
Zhaoyu Chen
Dongmei Wang
Xiaomei Zhang
Qiong Chen
Yanhui Li
Xiaoxian Huang
Guanghui Liu
Jianjun Lu
Yan Liu
Yafang Hu
Suyue Pan
Qing Wang
Qun Wang
Yunqi Xu
Cite this article:   
Jinghui Xu,Xiaodi Fu,Mengqiu Pan, et al. Mitochondrial Creatine Kinase is Decreased in the Serum of Idiopathic Parkinson’s Disease Patients[J]. Aging and disease, 2019, 10(3): 601-610.
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http://www.aginganddisease.org/EN/10.14336/AD.2018.0615     OR     http://www.aginganddisease.org/EN/Y2019/V10/I3/601
PDControl
N5030
Age (years)61.7±8.559.8±7.0
Male21 (42%)14 (46.7%)
Female29 (58%)16 (53.3%)
BMI (Kg/m2)21.1±1.820.7±1.4
H&Y stage2.5±0.8-
Disease duration (years)4.9±3.6-
Age of Onset (years)56.8±7.9-
Rate of disease progression1.0±1.0-
MDS-UPDRS Part III32.0±21.2-
MNMSS2.9±1.30
Tremor dominant (%)9 (18%)-
Akinetic-rigid dominant (%)22 (44%)-
Mixed subtype (%)19 (38%)-
Constipation32 (64%)0%
Hyposmia2 9(58%)0%
Cognitive impariment8 (16%)0%
Depression and/or anxiety38 (76%)0%
Sleep disturbances36 (72%)0%
Table 1  The demographic & clinical data of the groups studied.
GroupNAgeSerum uMtCKSerum sMtCKSerum CKMB
(U/L)(U/L)(U/L)
PDTotal5061.7±8.53.5±1.80.32±0.5010.2±6.7
Male2162.5±8.83.3±2.10.32±0.4910.9±6.3
Female2961.1±8.33.6±1.60.32±0.539.7±7.0
Early PD2759.4±7.03.9±1.90.28±0.4610.4±7.3
Late PD2364.3±9.33.0±1.50.38±0.5610.1±6.0
ControlsTotal3059.8±7.05.9±1.80.34±0.489.6±5.5
Male1461.7±6.56.5±1.80.34±0.4810.2±6.2
Female1658.2±7.25.4±1.70.34±0.509.1±4.9
Early control1657.6±7.35.5±1.60.31±0.429.7±5.5
Late control1462.4±5.86.4±2.00.38±0.579.5±5.6
p-value (age adjusted)
PD vs. controls0.32<0.01**0.730.16
M:F (PD)0.580.540.860.85
M:F (C)0.170.160.990.63
EP:LP0.090.291.001.00
EP:EC0.42<0.01**0.730.91
LP:LC0.50<0.01**0.890.82
PD subtypeTD960.9±4.83.3±1.6
AR2261.7±9.23.5±1.8
Mixed subtype1962.0±9.23.5±2.0
p-value (age adjusted)0.950.27
Drug usedWith Medopa4462.4±8.73.5±1.8
Without Medopa656.5±3.63.4±2.3
p-value (age adjusted)0.110.91
Table 2  The serum uMtCK, sMtCK, CK-MB activity, BMI in different groups.
Figure 1.  sMtCK and uMtCK activities are shown using anti-sMtCK and anti-uMtCK antibodies, respectively

Key: Log transformation was performed on concentration (X axis) of actual dose (-2=lg 0.01, -1=lg 0. 1, 0=lg 1, 1=lg 10, 2=lg 100). A preliminary study confirmed 20 µg/ml was the optimal concentration of the anti-MtCK antibody for serum measurements. uMtCK = ubiquitous Mitochondrial Creatine Kinase, sMtCK = sarcomeric Mitochondrial Creatine Kinase.

Figure 2.  Comparisons of serum activities of uMtCK and sMtCK between the different patient groups

A) The PD group had a significantly lower serum uMtCK activity when compared with controls (p<0.01). B, C) Stratified analysis was performed according to disease severity (H&Y stage), revealing a significant decrease in serum uMtCK activity between the EP and EC groups (p<0.01) as well as the LP and LC groups (p<0.01). D) No significant difference in serum sMtCK activity was observed between the PD and control groups (p=0.73).

Figure 3.  Correlation between serum uMtCK activities and rate of disease progression, disease duration, age of onset, H&Y stage, and MNMSS in PD patients

Serum uMtCK activities significantly increased along with the accelerating rate of disease progression (R2=0.233, t=3.676, p=0.001), as well as with older age of onset (R2=0.150, t=2.775, p=0.008), but significantly decreased along with extended disease duration (R2=0.160, t=-2.882, p=0.006) (A-C). No significant correlation was observed between serum uMtCK activities and either H&Y stage or MNMSS (D, E) or between serum sMtCK activities and BMI (F).

Figure 4.  ROC curve of serum uMtCK activity

The area under the curve (AUC) was 0.83 (P<0.01) (95% CI: 0.74 - 0.92). When the uMtCK activity was less than 4.37 U/L, Youden’s index was maximal with a sensitivity of 74.00% (95% CI: 59.66-85.37%) and a specificity of 90.00% (95% CI: 73.47-97.89%). ROC= receiver operator characteristic.

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