Original Paper Eur Neurol 2015;73:205–211 DOI: 10.1159/000377676
Received: October 10, 2014 Accepted: February 1, 2015 Published online: March 10, 2015
The Effect of Creatine and Coenzyme Q10 Combination Therapy on Mild Cognitive Impairment in Parkinson’s Disease Zhenguang Li Pengfei Wang Zhancai Yu Yannan Cong Hairong Sun Jiangshan Zhang Jinbiao Zhang Chao Sun Yong Zhang Xiaohua Ju Department of Neurology, Weihai Municipal Hospital, Binzhou Medical College, Weihai City, China
Abstract Background: To investigate the effect of creatine and coenzyme Q10 (CoQ10) combination therapy on mild cognitive impairment (MCI) in Parkinson’s disease (PD; PD-MCI) and its influences on plasma phospholipid (PL) levels in PD-MCI. Methods: The demographic data of 75 PD-MCI patients who enrolled in this collaborative PD study were collected. These patients were evaluated using the Unified Parkinson’s Disease Rating Scale (UPDRS) III and the Montreal Cognitive Assessment (MoCA). These 75 PD-MCI patients were randomly treated with creatine monohydrate 5 g b.i.d. and CoQ10 100 mg t.i.d. orally or placebo. MoCA evaluation and PL level measurements were performed after 12 and 18 months of treatment. Results: After 12 and 18 months of treatment, the differences in the MoCA scores of the combination therapy and control groups were statistically significant (p < 0.05 at 12 months and p < 0.01 at 18 months), and the plasma PL levels of the combination therapy group were significantly lower than those of the control group (p < 0.01 at 12 months and p < 0.001 at 18 months). Conclusions: Combination
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therapy with creatine and CoQ10 could delay the decline of cognitive function in PD-MCI patients and could lower their plasma PL levels; therefore, this combination therapy may © 2015 S. Karger AG, Basel have a neuroprotective function.
Introduction
Parkinson’s disease (PD) is a common neurodegenerative disease. However, its etiology is still not clear. Currently, it is generally believed to be a result of the combined action of genetic and environmental factors. Oxidative stress, microglial activation, neuroinflammation, mitochondrial dysfunction, protein aggregation and clearance impairment, and autophagic stress are the key events in the pathophysiological mechanism of PD [1]. Mild cognitive impairment in Parkinson’s disease (PDMCI) is one of the disease’s main non-motor symptoms. The early identification of PD-MCI and timely intervention to treat this disease have important significance for the prognosis and quality of life of PD patients. As major components of biological membranes, phospholipids (PLs) are very important for maintaining the integrity and function of cell membranes. However, reports on Professor Pengfei Wang Department of Neurology, Weihai Municipal Hospital Binzhou Medical College, 70 Heping Rd, Huancui District Weihai City, Shandong Province 264200 (PR China) E-Mail wpf5287598 @ 163.com
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Key Words Parkinson’s disease · Mild cognitive impairment · Phospholipids · Creatine · Coenzyme Q10
Subjects and Methods Study Subjects PD was diagnosed based on the UK Parkinson’s Society Brain Bank Clinical Diagnostic Criteria, and the criteria for PD-MCI diagnosis was based on the Criteria for the Diagnosis of PD-MCI [3] formulated by the Movement Disorder Society (MDS) in the United States. The inclusion criteria were as follows: (1) patients who met the UK Parkinson’s Society Brain Bank Clinical Diagnostic Criteria; (2) patients with a confirmed PD diagnosis and gradually declining in cognitive function as reported by the patients or people close to them or observed by clinical physicians; (3) patients with clear cognitive function impairment confirmed by formal neuropsychological testing or an overall cognitive function scale; and (4) the patients’ cognitive function impairment did not significantly interfere with functional independence other than causing mild difficulty during the execution of complex functional tasks. The exclusion criteria were as follows: (1) patients who met the diagnosis of Parkinson’s disease dementia (PDD) formulated by the MDS special team; (2) patients with other disorders that could cause cognitive function impairment (such as delirium, stroke, severe depression, metabolic disorders, drug side effects, and head trauma); (3) patients with PD-associated comorbidity (such as dyskinesia, severe anxiety, depression, excessive daytime sleepiness, or mental disorders). Based on the aforementioned inclusion and exclusion criteria, a total of 75 PD-MCI outpatients and inpatients in the Department of Neurology of our hospital were enrolled from June 2006 to June 2012. There were 50 males, and the ages were between 50 and 76 with an average of 62.65 ± 7.69, and the disease duration was from 4.3 to 12.9 years, with an average of 7.7 ± 1.8 years. The education levels of elementary school and below, high school, and college and above were 18 patients (24.0%), 37 patients (49.3%), and 20 pa-
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Eur Neurol 2015;73:205–211 DOI: 10.1159/000377676
tients (26.7%), respectively. Computer-generated randomization schedules randomly divided the patients into two groups, and blinding to group allocation was ensured. All of the study subjects or their authorized family members signed informed consent forms, and the study protocol was approved by the Medical Ethics Committee of Weihai Municipal Hospital, Binzhou Medical College. Methods Determination Criteria. The Unified Parkinson’s Disease Rating Scale (UPDRS) III was used to evaluate the severity of the patients’ motor symptoms [4]. The UPDRS III score was assessed on treatment after the first levodopa or a pramipexole dose and then after 12 and 18 months of treatment. The Chinese version of the Montreal Cognitive Assessment (MoCA) was used to evaluate mild cognitive impairment. The test examines visuospatial ability, executive ability, naming, attention, language, abstraction, delay recall, and orientation; the total score for this scale ranges from 0–30 points. If the subject had ≤12 years of education, then one point was added to the test results to calibrate the bias of education levels. The testing time was approximately 10 min. Two assessors who had received uniform training performed all of the assessments. Detection of Plasma PLs. All patients were on fasting when 4 ml of venous blood was collected. High-fat diets and drinking of alcohol were avoided before blood collection. Patients with fever, immunization, trauma, or pregnancy and those who were menstruating were excluded from the study. After collection, the whole blood was placed in a tube with special anti-coagulants (provided by Beijing Taifushi Technology Development Co., Ltd) and was centrifuged for 30 min (8,000 r/min, 10 min) to separate out the platelet-poor plasma. The PL levels were measured using 1 ml of platelet-poor plasma from the upper layer. The PLs were measured using chromatography combined with a modified inorganic phosphorus quantitative method; the results are presented as in the shape of the alphabet U. The determination reagent kit was purchased from Beijing Taifushi Technology Development Co., Ltd., and was used according to the instruction manual. The major steps were phospholipid extraction, concentration, separation, and staining. After placement in a 90 ° C water bath for 5 min, the samples were cooled to room temperature and were balanced for 35 min before measurement. Grouping and Treatment. According to the standard, 75 PDMCI patients were randomly divided into a combination therapy group (38 patients) and a control group (37 patients). The control group received basic medications (L-dopa or pramipexole) with the matching placebo, while the combination therapy group received oral creatine monohydrate 5 g b.i.d. (purity over 99%) and oral CoQ10 (Ubidecarenone®, Eisai Pharmaceutical Co., Ltd.) 100 mg t.i.d. on the basis of L-dopa or pramipexole treatment. After 12 and 18 months of treatment, the MoCA and UPDRS III scores were reevaluated, and PL levels were examined again.
Statistical Methods Statistical analysis was performed using SPSS 13.0 software. Quantitative data are presented as the means ± standard deviations (x ± s). Comparisons among multiple groups were performed using one-way analysis of variance (ANOVA). The 95% confidence intervals (CIs) and odds ratio (OR) values were calculated using Woolf statistical software. p < 0.05 was considered statistically significant.
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plasma PL changes in PD-MCI patients are lacking. Creatine and coenzyme Q10 (CoQ10) are important active components of energy metabolism in mitochondria and antioxidants; they have protective effects against neurodegenerative diseases. Yang et al. [2] applied a combination of creatine and CoQ10 to treat a 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP)-induced PD model in mice. The combined administration of these substances not only could improve the depletion of striatal dopamine and inhibit the loss of tyrosine hydroxylase-containing neurons in the substantia nigra pars compacta but also could significantly reduce lipid peroxidation injury and α-synuclein aggregation in substantia nigra neurons. However, creatine-CoQ10’s effects on the clinical treatment of PD-MCI patients have not been reported. This study aimed to observe the effects of combination therapy with creatine and CoQ10 on cognitive function and changes in plasma PL levels in PD-MCI patients to provide bases for early diagnosis and intervention in PDMCI.
Table 1. Comparison of baseline characteristics between patients in the combination therapy and control groups
Patients, n (%) Age at enrollment Disease duration UPDRS III score Male/female Years of education Using L-dopa, % Mean daily levodopa dosage, mg Using receptor agonist, % Mean daily pramipexole dosage, mg MoCA score
Combination therapy group
Control group
p
38 (50.7) 63.2 (53.3–73.4) 7.8 (4.3–12.9) 17.5±7.8 26/12 10.9±6.65 57 562±18.35 43 1.23±0.23 20.15±3.11
37 (49.3) 61.3 (52.6–71.9) 7.6 (4.6–11.8) 18.8±7.4 24/13 11.2±7.54 54 555±16.89 46 1.30±0.27 19.63±4.12
0.379 0.884 0.599 0.920 0.305 0.855 0.754 0.791 0.673 0.632
Table 2. Comparison of the MoCA scale scores for the treatment and control groups (x ± s)
Group
n
Baseline MoCA
MoCA after 12 months
MoCA after 18 months
Combination therapy group Control group
38 37
20.15±3.11 19.63±4.12
19.52±2.74* 16.33±3.37
18.55±4.11** 13.33±3.58
Compared with the control group * p < 0.05; ** p < 0.01.
Table 3. Comparison of the UPDRS III scores for the treatment and control groups (x ± s)
Group
n
Baseline UPDRS III
UPDRS III after 12 months
UPDRS III after 18 months
Combination therapy group Control group
38 37
17.5±7.8 18.8±7.4
18.9±8.4 19.7±8.8
19.3±8.2 20.6±8.5
The baseline demographic characteristics between the patients in the combination therapy and control groups are compared in table 1.
combination therapy group was significantly higher than that of the control group, and two cases had evolved to dementia in the control group at 18 months (p < 0.01; table 2).
Comparison of MoCA Scale Scores between the Treatment and Control Groups The difference in the baseline MoCA scale scores of the combination therapy and control groups was not statistically significant (p > 0.05). After 12 months of treatment, the MoCA score of the combination therapy group was significantly higher than that of the control group (p < 0.05). After 18 months of treatment, the MoCA score of the
Comparison of UPDRS III Scores between the Treatment and Control Groups The UPDRS III scores of subjects in the different groups are shown in table 3. The difference in the baseline UPDRS III scores of the combination therapy and control groups was not statistically significant (p > 0.05). After 12 and 18 months of treatment, there were no significant differences in the UPDRS III scores of the combination therapy group compared to those of the control group (p > 0.05).
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Results
Table 4. Plasma PL levels (U) of the combination therapy and control groups (x ± s)
Group
n
Baseline PLs
PLs after 12 months
PLs after 18 months
Combination therapy group Control group
38 37
6.64±0.71 6.80±0.65
5.26±0.82* 6.90±0.95
4.68±0.77** 7.02±0.60
Comparison of PL Levels in the Treatment and Control Groups The baseline PL levels of the combination therapy and control groups were not significantly different (p > 0.05). After 12 months of treatment, the PL level of the combination therapy group was significantly lower than that of the control group (p < 0.01). After 18 months of treatment, the PL level of the combination therapy group was significantly lower than that of the control group (p < 0.01; table 4).
Discussion
PD-MCI is a syndrome defined by clinical, cognitive, and functional criteria, and assessments for this syndrome involve several neuropsychological tests. However, the MoCA has exhibited high-detection accuracy, sensitivity, and specificity for detecting MCI, including in patients performing in the normal range on the MiniMental State Examination (MMSE). Thus, the MoCA has been developed as a brief screening instrument for MCI and mild AD [5]. In addition, the MoCA has shown excellent performance in discriminating amnestic MCI (aMCI) from normal cognition among elderly people, with reported receiver operating characteristic (ROC) areas under the curve (AUCs) ranging from 0.82 to 0.95, sensitivity ranging from 78 to 97%, and specificity ranging from 60 to 87% [6]. A recent study reported a similar conclusion that the MoCA may be more sensitive than the MMSE in detecting early baseline and longitudinal cognitive impairments in PD [7]. In the Singapore population, the cutoff scores of 26/27 and 24/25 are used to detect aMCI and mild AD, respectively [8]. Moreover, a study on the Chinese version of the MoCA (C-MoCA) has shown that among the rural elderly people, the MoCA showed modest accuracy and was no better than the MMSE in detecting aMCI, especially in those with low education levels, due to the overwhelming effect of education relative to aMCI diagnosis on variations in C-MoCA 208
Eur Neurol 2015;73:205–211 DOI: 10.1159/000377676
performance [9]. Consistent with the above results, the C-MoCA was applied in our study and was successful in accurately screening the PD-MCI and PD-D patients. PD-associated cognitive impairment, including PDMCI and PDD, is one of the major non-motor symptoms of PD [10]. Currently, it is believed that the destruction of the frontal-striatal circuit and an abnormal posterior cortex are associated with PD-MCI and PDD [11]. PDMCI is not rare in non-demented PD (PD-ND) patients; its incidence reached 27% [3] and PD-MCI patients faced a significant risk of progressing to dementia. Therefore, early identification of and timely intervention in PD-associated cognitive impairments are important for improving the prognosis and quality of life of PD patients and decreasing the burdens on the patients and their caretakers. In this study, our results demonstrated that after the administration of a combination of creatine (10 g daily) and CoQ10 (300 mg daily) in PD-MCI patients for 18 months, the average MoCA scale score of the PD group decreased 1.6 points, while the score of the control group decreased 6.3 points, suggesting that combination therapy with creatine and CoQ10 could delay the decline of cognitive function in PD-MCI patients. Moreover, this combination simultaneously reduced the plasma PL levels; therefore, this combination therapy may have a neuroprotective function. Creatine is a nitrogenous organic acid that occurs naturally in the body. It facilitates energy conversion in the mitochondria, stabilizes ATP synthesis, regulates the ATP-ADP ratio, and prevents the excess suppression of ATPase function. As an indirect antioxidant, creatine plays important roles in the prevention of mitochondrial permeability transition (MPT) [12]. Studies in animal models of spinal cord injury, brain trauma, and stroke have shown that creatine can protect against nerve cell injury induced by trauma and ischemia and can promote the recovery of function [13]. Other studies have also shown that creatine can improve the energy supply of hypoxic brain tissues and can reduce neuronal damage induced by excitotoxins and malonates [14]. Importantly, a Li/Wang/Yu/Cong/Sun/Zhang/Zhang/ Sun/Zhang/Ju
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Compared with the control group * p < 0.01; ** p < 0.001.
between mitochondrial complexes I and III and between complexes II and III [22]. CoQ10 deficiency can result in energy metabolism impairment in the mitochondria, the opening of MPT pores, and apoptotic programming initiation. CoQ10 is also an effective intracellular antioxidant and free radical scavenger that can protect against low-density lipoprotein oxidation. The oral administration of CoQ10 in an MPTP-induced mouse model reduced the loss of dopaminergic neurons in the substantia nigra. In addition, CoQ10 can also protect against malic acid-, excitotoxin-, and rotenone-induced toxicity in dopaminergic neurons and had a significant neuroprotective function related to the activation of uncoupling protein 2, the protection of mitochondrial membrane potential and ATP production, and the stabilization of MP [23]. Recently, a study by Shults et al. [24] demonstrated that patients receiving a dose of CoQ10 (1,200 mg/day) had significantly less deterioration in UPDRS scores than patients taking placebo. Our results have shown that the additive treatment of CoQ10 delays the decline of cognitive function in PD-MCI patients. However, a recent study found that a powerful mitochondrial antioxidant, mitoQ, does not slow PD progression in terms of UPDRS scores over a 12-month period [25]. Moreover, a study of the effects of CoQ10 in PD was terminated prematurely owing to a lack of efficacy [26]. Lately, a study has shown that in a phase III randomized, placebo-controlled, double-blind clinical study, CoQ10 showed no evidence of clinical benefits in PD patients [27]. The precise reasons of the observed differences of these results were not completely clear, which may be related to differences in degrees of disease severity, education and race. PLs are important components of the cell membrane. Membrane PLs in the central nervous system are rich in polyunsaturated fatty acids (PUFAs). PUFA metabolism is mainly controlled by phospholipase A2 (PLA2) and acyltransferase, which form the so-called deacylation-reacylation cycle. Under normal circumstances, the free fatty acids (FFAs) released under the action of PLA2 are rapidly taken up by membrane PLs. PLA2 mainly functions on lipoproteins and the acyl bond to sn-2 of glycerophospholipids to release FFAs and lysophospholipids [28]. Under the condition of mitochondrial dysfunction and oxidative stress, PLA2 will be activated, and membrane PLs will be cleaved and released into the blood. Our study has shown that after combination therapy with creatine and CoQ10 in PD-MCI patients for 12 and 18 months, plasma PL levels decreased significantly, suggesting that combination therapy with creatine and CoQ10 can increase PL synthesis and recycling, decrease PL release into
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randomized, double-blind clinical study investigated and evaluated the efficacy of 10 g creatine daily combined with minocycline in early-stage PD patients. That study showed that PD progression in the creatine treatment group was reduced by approximately 50% after one year of treatment and that the tolerance of the treatment regimen was excellent [15]. Another creatine supplementation trial demonstrated neuroprotective features in cellular and animal models of neurodegenerative diseases, including PD [16]. In accordance with the above results, our results have shown that combination therapy with creatine and CoQ10 could delay the decline of cognitive function in PD-MCI patients. However, the results for the creatine protective effect were inconsistent. A pilot study of early PD patients has demonstrated that no difference was evident in UPDRS scores when comparing creatine treatment to placebo for two years [17]. The Neuroprotection Exploratory Trials of PD (NET-PD), sponsored by the National Institute of Neurological Disorders and Stroke (NINDS), initially found no evidence for futility in the use of creatine therapy [18]. Subsequently, PD patients were randomized to creatine or placebo treatments and were followed for a long duration (i.e., 5–7 years). The study utilized a global statistical test (GST) consisting of five clinical rating scales to assess the disease progression and to potentially provide higher power to test the hypothesis [19]. However, according to the NET-PD website, an interim analysis revealed evidence for futility. Interestingly, recent a study utilizing proton magnetic resonance spectroscopy (H-MRS) revealed that patients with PD had significantly lower levels of the ratio of Nacetyl aspartate to creatine (NAA/Cr) within the anterior cingulate cortex (ACC) compared to age-matched controls, findings that have been correlated with cognitive decline, suggesting that neuronal integrity within the ACC may play a critical role in the pathophysiology underlying the related neuropsychiatric features of executive dysfunction [20]. Moreover, another H-MRS study has shown that PD is associated with widespread alterations of increased creatine and higher creatine values in PD samples may reflect greater neuronal energy expenditure early in the disease process that is compensatory in nature [21]. Hence, the protective effects of creatine in PD and PD-MCI patients have to be explored further. It is well acknowledged that reactive oxygen species (ROS) production and the resulting oxidative stress from mitochondrial dysfunction play roles in PD etiology and progression. CoQ10 promotes oxidative phosphorylation responses and protects the integrity of biological membranes. The main action of CoQ10 is to transmit electrons
the central nervous system, and exert neuroprotective effects. The treatment effects of creatine and CoQ10 were considered to be associated with the following factors [2, 29– 32]: (1) stabilized mitochondrial oxidative phosphorylation function, improved energy metabolism, increased mitochondrial complex I activity, decreased free radical production, and protection against oxidative stress damage; (2) inhibition of the loss of tyrosine hydroxylase-containing neurons in the substantia nigra pars compacta and aggregation of α-synuclein in the substantia nigra neurons; (3) stabilized MPT pores, decreased MPT permeability, apoptosis inhibition, prevention of CoQ10 loss from the respiratory chain, oxidative phosphorylation inhibition, loss of mitochondrial membrane potential, and increased MPT permeability induced by oxidative stress and calcium overload; (4) facilitation of energy conversion in the mitochondria by the interconversion between creatine and creatine phosphate, stabilized ATP synthesis, regulation of the ATP-ADP ratio, and prevention of ATPase functional overinhibition; (5) a decrease in the neuronal damage induced by excitotoxin and environmental toxins; and (6) reduction in membrane PL dam-
age caused by oxidative stress and facilitation of PL resynthesis. The exact mechanisms of these factors still await further studies. In summary, PL metabolism impairment plays an important role in the molecular pathology of cognitive impairment in PD patients. As important active components in mitochondrial energy metabolism and antioxidants, creatine and CoQ10 have adjuvant therapy functions in PD-associated cognitive impairment; they have the potential to become new neuroprotective agents in the treatment of PD-MCI to delay disease progression. It is possible that the combination of creatine and CoQ10 could become a new disease-modifying method for treating PD and PD-MCI. The sample size in this study was small; therefore, the long-term efficacy and the influences of different doses of creatine and CoQ10 on PD and PDMCI still require further in-depth studies.
Conflicts of Interest/Disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication.
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Received: October 10, 2014 Accepted: February 1, 2015 Published online: March 10, 2015
The Effect of Creatine and Coenzyme Q10 Combination Therapy on Mild Cognitive Impairment in Parkinson’s Disease Zhenguang Li Pengfei Wang Zhancai Yu Yannan Cong Hairong Sun Jiangshan Zhang Jinbiao Zhang Chao Sun Yong Zhang Xiaohua Ju Department of Neurology, Weihai Municipal Hospital, Binzhou Medical College, Weihai City, China
Abstract Background: To investigate the effect of creatine and coenzyme Q10 (CoQ10) combination therapy on mild cognitive impairment (MCI) in Parkinson’s disease (PD; PD-MCI) and its influences on plasma phospholipid (PL) levels in PD-MCI. Methods: The demographic data of 75 PD-MCI patients who enrolled in this collaborative PD study were collected. These patients were evaluated using the Unified Parkinson’s Disease Rating Scale (UPDRS) III and the Montreal Cognitive Assessment (MoCA). These 75 PD-MCI patients were randomly treated with creatine monohydrate 5 g b.i.d. and CoQ10 100 mg t.i.d. orally or placebo. MoCA evaluation and PL level measurements were performed after 12 and 18 months of treatment. Results: After 12 and 18 months of treatment, the differences in the MoCA scores of the combination therapy and control groups were statistically significant (p < 0.05 at 12 months and p < 0.01 at 18 months), and the plasma PL levels of the combination therapy group were significantly lower than those of the control group (p < 0.01 at 12 months and p < 0.001 at 18 months). Conclusions: Combination
© 2015 S. Karger AG, Basel 0014–3022/15/0734–0205$39.50/0 E-Mail [email protected] www.karger.com/ene
therapy with creatine and CoQ10 could delay the decline of cognitive function in PD-MCI patients and could lower their plasma PL levels; therefore, this combination therapy may © 2015 S. Karger AG, Basel have a neuroprotective function.
Introduction
Parkinson’s disease (PD) is a common neurodegenerative disease. However, its etiology is still not clear. Currently, it is generally believed to be a result of the combined action of genetic and environmental factors. Oxidative stress, microglial activation, neuroinflammation, mitochondrial dysfunction, protein aggregation and clearance impairment, and autophagic stress are the key events in the pathophysiological mechanism of PD [1]. Mild cognitive impairment in Parkinson’s disease (PDMCI) is one of the disease’s main non-motor symptoms. The early identification of PD-MCI and timely intervention to treat this disease have important significance for the prognosis and quality of life of PD patients. As major components of biological membranes, phospholipids (PLs) are very important for maintaining the integrity and function of cell membranes. However, reports on Professor Pengfei Wang Department of Neurology, Weihai Municipal Hospital Binzhou Medical College, 70 Heping Rd, Huancui District Weihai City, Shandong Province 264200 (PR China) E-Mail wpf5287598 @ 163.com
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Key Words Parkinson’s disease · Mild cognitive impairment · Phospholipids · Creatine · Coenzyme Q10
Subjects and Methods Study Subjects PD was diagnosed based on the UK Parkinson’s Society Brain Bank Clinical Diagnostic Criteria, and the criteria for PD-MCI diagnosis was based on the Criteria for the Diagnosis of PD-MCI [3] formulated by the Movement Disorder Society (MDS) in the United States. The inclusion criteria were as follows: (1) patients who met the UK Parkinson’s Society Brain Bank Clinical Diagnostic Criteria; (2) patients with a confirmed PD diagnosis and gradually declining in cognitive function as reported by the patients or people close to them or observed by clinical physicians; (3) patients with clear cognitive function impairment confirmed by formal neuropsychological testing or an overall cognitive function scale; and (4) the patients’ cognitive function impairment did not significantly interfere with functional independence other than causing mild difficulty during the execution of complex functional tasks. The exclusion criteria were as follows: (1) patients who met the diagnosis of Parkinson’s disease dementia (PDD) formulated by the MDS special team; (2) patients with other disorders that could cause cognitive function impairment (such as delirium, stroke, severe depression, metabolic disorders, drug side effects, and head trauma); (3) patients with PD-associated comorbidity (such as dyskinesia, severe anxiety, depression, excessive daytime sleepiness, or mental disorders). Based on the aforementioned inclusion and exclusion criteria, a total of 75 PD-MCI outpatients and inpatients in the Department of Neurology of our hospital were enrolled from June 2006 to June 2012. There were 50 males, and the ages were between 50 and 76 with an average of 62.65 ± 7.69, and the disease duration was from 4.3 to 12.9 years, with an average of 7.7 ± 1.8 years. The education levels of elementary school and below, high school, and college and above were 18 patients (24.0%), 37 patients (49.3%), and 20 pa-
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tients (26.7%), respectively. Computer-generated randomization schedules randomly divided the patients into two groups, and blinding to group allocation was ensured. All of the study subjects or their authorized family members signed informed consent forms, and the study protocol was approved by the Medical Ethics Committee of Weihai Municipal Hospital, Binzhou Medical College. Methods Determination Criteria. The Unified Parkinson’s Disease Rating Scale (UPDRS) III was used to evaluate the severity of the patients’ motor symptoms [4]. The UPDRS III score was assessed on treatment after the first levodopa or a pramipexole dose and then after 12 and 18 months of treatment. The Chinese version of the Montreal Cognitive Assessment (MoCA) was used to evaluate mild cognitive impairment. The test examines visuospatial ability, executive ability, naming, attention, language, abstraction, delay recall, and orientation; the total score for this scale ranges from 0–30 points. If the subject had ≤12 years of education, then one point was added to the test results to calibrate the bias of education levels. The testing time was approximately 10 min. Two assessors who had received uniform training performed all of the assessments. Detection of Plasma PLs. All patients were on fasting when 4 ml of venous blood was collected. High-fat diets and drinking of alcohol were avoided before blood collection. Patients with fever, immunization, trauma, or pregnancy and those who were menstruating were excluded from the study. After collection, the whole blood was placed in a tube with special anti-coagulants (provided by Beijing Taifushi Technology Development Co., Ltd) and was centrifuged for 30 min (8,000 r/min, 10 min) to separate out the platelet-poor plasma. The PL levels were measured using 1 ml of platelet-poor plasma from the upper layer. The PLs were measured using chromatography combined with a modified inorganic phosphorus quantitative method; the results are presented as in the shape of the alphabet U. The determination reagent kit was purchased from Beijing Taifushi Technology Development Co., Ltd., and was used according to the instruction manual. The major steps were phospholipid extraction, concentration, separation, and staining. After placement in a 90 ° C water bath for 5 min, the samples were cooled to room temperature and were balanced for 35 min before measurement. Grouping and Treatment. According to the standard, 75 PDMCI patients were randomly divided into a combination therapy group (38 patients) and a control group (37 patients). The control group received basic medications (L-dopa or pramipexole) with the matching placebo, while the combination therapy group received oral creatine monohydrate 5 g b.i.d. (purity over 99%) and oral CoQ10 (Ubidecarenone®, Eisai Pharmaceutical Co., Ltd.) 100 mg t.i.d. on the basis of L-dopa or pramipexole treatment. After 12 and 18 months of treatment, the MoCA and UPDRS III scores were reevaluated, and PL levels were examined again.
Statistical Methods Statistical analysis was performed using SPSS 13.0 software. Quantitative data are presented as the means ± standard deviations (x ± s). Comparisons among multiple groups were performed using one-way analysis of variance (ANOVA). The 95% confidence intervals (CIs) and odds ratio (OR) values were calculated using Woolf statistical software. p < 0.05 was considered statistically significant.
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plasma PL changes in PD-MCI patients are lacking. Creatine and coenzyme Q10 (CoQ10) are important active components of energy metabolism in mitochondria and antioxidants; they have protective effects against neurodegenerative diseases. Yang et al. [2] applied a combination of creatine and CoQ10 to treat a 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP)-induced PD model in mice. The combined administration of these substances not only could improve the depletion of striatal dopamine and inhibit the loss of tyrosine hydroxylase-containing neurons in the substantia nigra pars compacta but also could significantly reduce lipid peroxidation injury and α-synuclein aggregation in substantia nigra neurons. However, creatine-CoQ10’s effects on the clinical treatment of PD-MCI patients have not been reported. This study aimed to observe the effects of combination therapy with creatine and CoQ10 on cognitive function and changes in plasma PL levels in PD-MCI patients to provide bases for early diagnosis and intervention in PDMCI.
Table 1. Comparison of baseline characteristics between patients in the combination therapy and control groups
Patients, n (%) Age at enrollment Disease duration UPDRS III score Male/female Years of education Using L-dopa, % Mean daily levodopa dosage, mg Using receptor agonist, % Mean daily pramipexole dosage, mg MoCA score
Combination therapy group
Control group
p
38 (50.7) 63.2 (53.3–73.4) 7.8 (4.3–12.9) 17.5±7.8 26/12 10.9±6.65 57 562±18.35 43 1.23±0.23 20.15±3.11
37 (49.3) 61.3 (52.6–71.9) 7.6 (4.6–11.8) 18.8±7.4 24/13 11.2±7.54 54 555±16.89 46 1.30±0.27 19.63±4.12
0.379 0.884 0.599 0.920 0.305 0.855 0.754 0.791 0.673 0.632
Table 2. Comparison of the MoCA scale scores for the treatment and control groups (x ± s)
Group
n
Baseline MoCA
MoCA after 12 months
MoCA after 18 months
Combination therapy group Control group
38 37
20.15±3.11 19.63±4.12
19.52±2.74* 16.33±3.37
18.55±4.11** 13.33±3.58
Compared with the control group * p < 0.05; ** p < 0.01.
Table 3. Comparison of the UPDRS III scores for the treatment and control groups (x ± s)
Group
n
Baseline UPDRS III
UPDRS III after 12 months
UPDRS III after 18 months
Combination therapy group Control group
38 37
17.5±7.8 18.8±7.4
18.9±8.4 19.7±8.8
19.3±8.2 20.6±8.5
The baseline demographic characteristics between the patients in the combination therapy and control groups are compared in table 1.
combination therapy group was significantly higher than that of the control group, and two cases had evolved to dementia in the control group at 18 months (p < 0.01; table 2).
Comparison of MoCA Scale Scores between the Treatment and Control Groups The difference in the baseline MoCA scale scores of the combination therapy and control groups was not statistically significant (p > 0.05). After 12 months of treatment, the MoCA score of the combination therapy group was significantly higher than that of the control group (p < 0.05). After 18 months of treatment, the MoCA score of the
Comparison of UPDRS III Scores between the Treatment and Control Groups The UPDRS III scores of subjects in the different groups are shown in table 3. The difference in the baseline UPDRS III scores of the combination therapy and control groups was not statistically significant (p > 0.05). After 12 and 18 months of treatment, there were no significant differences in the UPDRS III scores of the combination therapy group compared to those of the control group (p > 0.05).
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Results
Table 4. Plasma PL levels (U) of the combination therapy and control groups (x ± s)
Group
n
Baseline PLs
PLs after 12 months
PLs after 18 months
Combination therapy group Control group
38 37
6.64±0.71 6.80±0.65
5.26±0.82* 6.90±0.95
4.68±0.77** 7.02±0.60
Comparison of PL Levels in the Treatment and Control Groups The baseline PL levels of the combination therapy and control groups were not significantly different (p > 0.05). After 12 months of treatment, the PL level of the combination therapy group was significantly lower than that of the control group (p < 0.01). After 18 months of treatment, the PL level of the combination therapy group was significantly lower than that of the control group (p < 0.01; table 4).
Discussion
PD-MCI is a syndrome defined by clinical, cognitive, and functional criteria, and assessments for this syndrome involve several neuropsychological tests. However, the MoCA has exhibited high-detection accuracy, sensitivity, and specificity for detecting MCI, including in patients performing in the normal range on the MiniMental State Examination (MMSE). Thus, the MoCA has been developed as a brief screening instrument for MCI and mild AD [5]. In addition, the MoCA has shown excellent performance in discriminating amnestic MCI (aMCI) from normal cognition among elderly people, with reported receiver operating characteristic (ROC) areas under the curve (AUCs) ranging from 0.82 to 0.95, sensitivity ranging from 78 to 97%, and specificity ranging from 60 to 87% [6]. A recent study reported a similar conclusion that the MoCA may be more sensitive than the MMSE in detecting early baseline and longitudinal cognitive impairments in PD [7]. In the Singapore population, the cutoff scores of 26/27 and 24/25 are used to detect aMCI and mild AD, respectively [8]. Moreover, a study on the Chinese version of the MoCA (C-MoCA) has shown that among the rural elderly people, the MoCA showed modest accuracy and was no better than the MMSE in detecting aMCI, especially in those with low education levels, due to the overwhelming effect of education relative to aMCI diagnosis on variations in C-MoCA 208
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performance [9]. Consistent with the above results, the C-MoCA was applied in our study and was successful in accurately screening the PD-MCI and PD-D patients. PD-associated cognitive impairment, including PDMCI and PDD, is one of the major non-motor symptoms of PD [10]. Currently, it is believed that the destruction of the frontal-striatal circuit and an abnormal posterior cortex are associated with PD-MCI and PDD [11]. PDMCI is not rare in non-demented PD (PD-ND) patients; its incidence reached 27% [3] and PD-MCI patients faced a significant risk of progressing to dementia. Therefore, early identification of and timely intervention in PD-associated cognitive impairments are important for improving the prognosis and quality of life of PD patients and decreasing the burdens on the patients and their caretakers. In this study, our results demonstrated that after the administration of a combination of creatine (10 g daily) and CoQ10 (300 mg daily) in PD-MCI patients for 18 months, the average MoCA scale score of the PD group decreased 1.6 points, while the score of the control group decreased 6.3 points, suggesting that combination therapy with creatine and CoQ10 could delay the decline of cognitive function in PD-MCI patients. Moreover, this combination simultaneously reduced the plasma PL levels; therefore, this combination therapy may have a neuroprotective function. Creatine is a nitrogenous organic acid that occurs naturally in the body. It facilitates energy conversion in the mitochondria, stabilizes ATP synthesis, regulates the ATP-ADP ratio, and prevents the excess suppression of ATPase function. As an indirect antioxidant, creatine plays important roles in the prevention of mitochondrial permeability transition (MPT) [12]. Studies in animal models of spinal cord injury, brain trauma, and stroke have shown that creatine can protect against nerve cell injury induced by trauma and ischemia and can promote the recovery of function [13]. Other studies have also shown that creatine can improve the energy supply of hypoxic brain tissues and can reduce neuronal damage induced by excitotoxins and malonates [14]. Importantly, a Li/Wang/Yu/Cong/Sun/Zhang/Zhang/ Sun/Zhang/Ju
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Compared with the control group * p < 0.01; ** p < 0.001.
between mitochondrial complexes I and III and between complexes II and III [22]. CoQ10 deficiency can result in energy metabolism impairment in the mitochondria, the opening of MPT pores, and apoptotic programming initiation. CoQ10 is also an effective intracellular antioxidant and free radical scavenger that can protect against low-density lipoprotein oxidation. The oral administration of CoQ10 in an MPTP-induced mouse model reduced the loss of dopaminergic neurons in the substantia nigra. In addition, CoQ10 can also protect against malic acid-, excitotoxin-, and rotenone-induced toxicity in dopaminergic neurons and had a significant neuroprotective function related to the activation of uncoupling protein 2, the protection of mitochondrial membrane potential and ATP production, and the stabilization of MP [23]. Recently, a study by Shults et al. [24] demonstrated that patients receiving a dose of CoQ10 (1,200 mg/day) had significantly less deterioration in UPDRS scores than patients taking placebo. Our results have shown that the additive treatment of CoQ10 delays the decline of cognitive function in PD-MCI patients. However, a recent study found that a powerful mitochondrial antioxidant, mitoQ, does not slow PD progression in terms of UPDRS scores over a 12-month period [25]. Moreover, a study of the effects of CoQ10 in PD was terminated prematurely owing to a lack of efficacy [26]. Lately, a study has shown that in a phase III randomized, placebo-controlled, double-blind clinical study, CoQ10 showed no evidence of clinical benefits in PD patients [27]. The precise reasons of the observed differences of these results were not completely clear, which may be related to differences in degrees of disease severity, education and race. PLs are important components of the cell membrane. Membrane PLs in the central nervous system are rich in polyunsaturated fatty acids (PUFAs). PUFA metabolism is mainly controlled by phospholipase A2 (PLA2) and acyltransferase, which form the so-called deacylation-reacylation cycle. Under normal circumstances, the free fatty acids (FFAs) released under the action of PLA2 are rapidly taken up by membrane PLs. PLA2 mainly functions on lipoproteins and the acyl bond to sn-2 of glycerophospholipids to release FFAs and lysophospholipids [28]. Under the condition of mitochondrial dysfunction and oxidative stress, PLA2 will be activated, and membrane PLs will be cleaved and released into the blood. Our study has shown that after combination therapy with creatine and CoQ10 in PD-MCI patients for 12 and 18 months, plasma PL levels decreased significantly, suggesting that combination therapy with creatine and CoQ10 can increase PL synthesis and recycling, decrease PL release into
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randomized, double-blind clinical study investigated and evaluated the efficacy of 10 g creatine daily combined with minocycline in early-stage PD patients. That study showed that PD progression in the creatine treatment group was reduced by approximately 50% after one year of treatment and that the tolerance of the treatment regimen was excellent [15]. Another creatine supplementation trial demonstrated neuroprotective features in cellular and animal models of neurodegenerative diseases, including PD [16]. In accordance with the above results, our results have shown that combination therapy with creatine and CoQ10 could delay the decline of cognitive function in PD-MCI patients. However, the results for the creatine protective effect were inconsistent. A pilot study of early PD patients has demonstrated that no difference was evident in UPDRS scores when comparing creatine treatment to placebo for two years [17]. The Neuroprotection Exploratory Trials of PD (NET-PD), sponsored by the National Institute of Neurological Disorders and Stroke (NINDS), initially found no evidence for futility in the use of creatine therapy [18]. Subsequently, PD patients were randomized to creatine or placebo treatments and were followed for a long duration (i.e., 5–7 years). The study utilized a global statistical test (GST) consisting of five clinical rating scales to assess the disease progression and to potentially provide higher power to test the hypothesis [19]. However, according to the NET-PD website, an interim analysis revealed evidence for futility. Interestingly, recent a study utilizing proton magnetic resonance spectroscopy (H-MRS) revealed that patients with PD had significantly lower levels of the ratio of Nacetyl aspartate to creatine (NAA/Cr) within the anterior cingulate cortex (ACC) compared to age-matched controls, findings that have been correlated with cognitive decline, suggesting that neuronal integrity within the ACC may play a critical role in the pathophysiology underlying the related neuropsychiatric features of executive dysfunction [20]. Moreover, another H-MRS study has shown that PD is associated with widespread alterations of increased creatine and higher creatine values in PD samples may reflect greater neuronal energy expenditure early in the disease process that is compensatory in nature [21]. Hence, the protective effects of creatine in PD and PD-MCI patients have to be explored further. It is well acknowledged that reactive oxygen species (ROS) production and the resulting oxidative stress from mitochondrial dysfunction play roles in PD etiology and progression. CoQ10 promotes oxidative phosphorylation responses and protects the integrity of biological membranes. The main action of CoQ10 is to transmit electrons
the central nervous system, and exert neuroprotective effects. The treatment effects of creatine and CoQ10 were considered to be associated with the following factors [2, 29– 32]: (1) stabilized mitochondrial oxidative phosphorylation function, improved energy metabolism, increased mitochondrial complex I activity, decreased free radical production, and protection against oxidative stress damage; (2) inhibition of the loss of tyrosine hydroxylase-containing neurons in the substantia nigra pars compacta and aggregation of α-synuclein in the substantia nigra neurons; (3) stabilized MPT pores, decreased MPT permeability, apoptosis inhibition, prevention of CoQ10 loss from the respiratory chain, oxidative phosphorylation inhibition, loss of mitochondrial membrane potential, and increased MPT permeability induced by oxidative stress and calcium overload; (4) facilitation of energy conversion in the mitochondria by the interconversion between creatine and creatine phosphate, stabilized ATP synthesis, regulation of the ATP-ADP ratio, and prevention of ATPase functional overinhibition; (5) a decrease in the neuronal damage induced by excitotoxin and environmental toxins; and (6) reduction in membrane PL dam-
age caused by oxidative stress and facilitation of PL resynthesis. The exact mechanisms of these factors still await further studies. In summary, PL metabolism impairment plays an important role in the molecular pathology of cognitive impairment in PD patients. As important active components in mitochondrial energy metabolism and antioxidants, creatine and CoQ10 have adjuvant therapy functions in PD-associated cognitive impairment; they have the potential to become new neuroprotective agents in the treatment of PD-MCI to delay disease progression. It is possible that the combination of creatine and CoQ10 could become a new disease-modifying method for treating PD and PD-MCI. The sample size in this study was small; therefore, the long-term efficacy and the influences of different doses of creatine and CoQ10 on PD and PDMCI still require further in-depth studies.
Conflicts of Interest/Disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication.
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