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Review

Coenzyme Q10 and Parkinsonian Syndromes: A Systematic Review

by
Félix Javier Jiménez-Jiménez
1,*,
Hortensia Alonso-Navarro
1,
Elena García-Martín
2 and
José A. G. Agúndez
2
1
Section of Neurology, Hospital Universitario del Sureste, Ronda del Sur 10, E28500 Arganda del Rey, Spain
2
ARADyAL Instituto de Salud Carlos III, University Institute of Molecular Pathology Biomarkers, Universidad de Extremadura, E10071 Cáceres, Spain
*
Author to whom correspondence should be addressed.
J. Pers. Med. 2022, 12(6), 975; https://doi.org/10.3390/jpm12060975
Submission received: 20 May 2022 / Revised: 10 June 2022 / Accepted: 11 June 2022 / Published: 15 June 2022
Browse Figures
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Abstract

:
Coenzyme Q10 (CoQ10) has an important role as an antioxidant. Being that oxidative stress is one of the mechanisms involved in the pathogenesis of Parkinson’s disease (PD) and other neurodegenerative diseases, several studies addressed the concentrations of CoQ10 in the different tissues of patients with PD and other parkinsonian syndromes (PS), trying to elucidate their value as a marker of these diseases. Other studies addressed the potential therapeutic role of CoQ10 in PD and PS. We underwent a systematic review and a meta-analysis of studies measuring tissue CoQ10 concentrations which shows that, compared with controls, PD patients have decreased CoQ10 levels in the cerebellar cortex, platelets, and lymphocytes, increased total and oxidized CoQ10 levels in the cerebrospinal fluid and a non-significant trend toward decreased serum/plasma CoQ10 levels. Patients with multiple system atrophy (MSA) showed decreased CoQ10 levels in the cerebellar cortex, serum/plasma, cerebrospinal fluid, and skin fibroblasts. Patients with Lewy body dementia (LBD) showed decreased cerebellar cortex CoQ10, and those with progressive supranuclear palsy (PSP) had decreased CoQ10 levels in the cerebrospinal fluid. A previous meta-analysis of studies addressing the therapeutic effects of CoQ10 in PD showed a lack of improvement in patients with early PD. Results of the treatment with CoQ10 in PSP should be considered preliminary. The potential role of CoQ10 therapy in the MSA and selected groups of PD patients deserves future studies.

1. Introduction

Coenzyme Q10 (CoQ10, Figure 1), which is also known as ubiquinone, is a 1,4-benzoquinone that is present in the majority of tissues in the human body. It is an important component of the electron transport chain in the mitochondria, participating in the generation of cellular energy through oxidative phosphorylation. In tissues, CoQ10 can be present in three redox states: fully oxidized (ubiquinone), partially oxidized (semiquinone or ubisemiquinone), and fully reduced (ubiquinol). Together with mitochondria, CoQ10 is present in the endoplasmic reticulum, Golgi apparatus, lysosomes, and peroxisomes. CoQ10 has important antioxidant actions (both by scavenging free radicals and by the regeneration of other antioxidants, such as alpha-tocopherol or ascorbate acid), giving protection to cells against oxidative stress processes [1,2].
Because oxidative stress is one of the most important pathogenetic mechanisms of Parkinson’s disease (PD) and other neurodegenerative disorders [3,4], and because of the role of CoQ10 as an antioxidant, both the study of CoQ10 concentrations in different tissues of patients diagnosed with PD and/or other parkinsonian syndromes and the potential therapeutic role of CoQ10 in these diseases, have been the matter of several publications over the last two decades. The aim of this systematic review and meta-analysis is to analyze the results of studies addressing the tissular concentrations of CoQ10 in patients diagnosed with parkinsonian syndromes compared to healthy controls and the results of therapeutic trials of CoQ10 in PD and other causes of parkinsonism.

2. Methods

2.1. Search Strategy and Criteria for Eligibility of Studies

A literature search using several well-known databases (PubMed, EMBASE, Web of Science (WOS) Main Collection) from 1966 until 4 May 2022, was performed. The term “coenzyme Q10” was crossed with “Parkinson’s disease” (356, 924, and 303 items were found in PubMed, EMBASE, and WOS, respectively), “parkinsonism” (403, 183, and 39 items were found in PubMed, EMBASE, and WOS, respectively), parkinsonian syndromes (223, 7, and 6 items were found in PubMed, EMBASE, and WOS, respectively), “multiple system atrophy” (36, 125, and 56 items were found in PubMed, EMBASE, and WOS, respectively), “Lewy body dementia” (8, 39, and 10 items were found in PubMed, EMBASE, and WOS, respectively), “Lewy body disease” (8, 62, and 24 items were found in PubMed, EMBASE, and WOS, respectively), “progressive supranuclear palsy” (31, 66, and 9 items were found in PubMed, EMBASE, and WOS, respectively), and “corticobasal degeneration” (4, 28, and 5 items were found in PubMed, EMBASE, and WOS, respectively). A total of 1054 references were retrieved by the whole search and examined one by one, and then those that were strictly related to the proposed topics, without language restrictions, were selected, excluding the duplicated articles and abstracts. The flowcharts for the selection of eligible studies—following the PRISMA guidelines [5]—analyzing tissue CoQ10 concentrations in patients with several types of parkinsonian syndrome and controls, and therapeutic trials with CoQ10 in parkinsonian syndromes, are plotted in Figure 2.

2.2. Selection of Studies and Methodology for the Meta-Analyses

Meta-analyses of those observational eligible studies that assessed the concentrations of CoQ10 in tissues were performed. The first author, year of publication, country, study design, and quantitative measures were extracted, and the risk of bias was analyzed by using the Newcastle–Ottawa Scale [6]. Data from selected studies analyzing the tissular concentrations of CoQ10 in patients diagnosed with PD compared to controls, patients diagnosed with multiple system atrophy (MSA) compared to controls, and patients with Lewy body dementia (LBD), progressive supranuclear palsy (PSP), and cortical basal degeneration (CBD) compared to healthy controls are summarized, respectively, in Table 1, Table 2 and Table 3. The plasma/serum and CSF levels of coenzyme Q10 were converted to nmol/mL, and brain tissue levels to pmol/mL, when necessary. The meta-analyses followed the PRISMA [5] (Table S1) and MOOSE guidelines [7] (Table S2) and were carried out by using the R software package meta [8]. We applied the random-effects model because of the high heterogeneity across studies, and we used the inverse variance method for the meta-analytical procedure, the DerSimonian-Laird as an estimator for Tau2, the Jackson method for the confidence interval of Tau2 and Tau, and the Hedges’ g (bias-corrected standardized mean difference). We calculated the statistical power to detect differences in mean values (alpha = 0.05) for the pooled samples when stated in the text.

3. Results

3.1. Studies Assessing Tissular CoQ10 Concentrations

3.1.1. Parkinson’s Disease

Serum/Plasma

Matsubara et al. [28] reported decreased serum CoQ10 levels in PD patients. However, the comparison group was composed of patients with cerebral infarction instead of healthy controls. The pooled results of the seven studies assessing the serum or plasma total CoQ10 levels in PD patients compared with controls [9,10,11,12,13,14,15], did not show significant differences in this value between the two groups (Table 1, Figure 3a), as was the case with the two studies assessing the serum or plasma CoQ10 corrected to cholesterol levels (Table 1, Figure 3b) [9,14]. However, the serum/plasma oxidized CoQ10/total CoQ10 ratio was found to be significantly higher in PD patients compared with controls in two of these studies (Table 1, Figure 3c) [11,13]. Two studies showed a lack of differences in the serum/plasma oxidized CoQ10 and in the reduced CoQ10 concentrations between PD patients and controls [11,14], although there were substantial differences in these values between these studies.

Blood Cells

Two studies showed decreased CoQ10 concentrations in platelets [16] and lymphocytes [17], respectively, from patients with PD compared with healthy controls (Table 1).

Cerebrospinal Fluid (CSF)

According to two studies, PD patients showed increased total [18,19] and oxidized [18] CSF CoQ10 concentrations (Table 1).

Brain

The pooled data from three studies [20,21,22] showed decreased CoQ10 levels in the cerebellar cortex of PD patients in comparison with controls (Table 1, Figure 4), while concentrations in the cerebral cortex [20,21], striatum [20], and substantia nigra [20] did not differ significantly between the two groups (Table 1).

Skin Fibroblasts

Del Hoyo et al. [23] reported similar CoQ10 concentrations in skin fibroblasts from PD patients and controls (Table 1).
The pooled data from the three studies, addressing serum/plasma total CoQ10 concentrations [14,15,24], showed a decrease in this value in patients with MSA compared with controls (Table 2, Figure 5). There have been reported decreased CoQ10 concentrations in the CSF [19], cerebellum cortex [21,22], and skin fibroblasts [25] from MSA patients (Table 2), although the pooled data from studies assessing cerebellum cortex CoQ10 levels did not reach statistical significance. In contrast, the cerebral cortex [21,22] and striatum [21] CoQ10 levels were similar in MSA and controls (Table 2).

3.1.2. Other Parkinsonian Syndromes

The results of studies addressing CoQ10 concentrations in patients with other parkinsonian syndromes, compared with healthy controls, are summarized in Table 3. In summary, patients with Lewy body dementia (DLB) showed similar CoQ10 concentrations to those of the control in serum/plasma [26,27], and in the cerebral cortex [21], but lower CoQ10 concentrations in the cerebellum cortex [21]. Patients diagnosed with progressive supranuclear palsy (PSP) showed decreased CSF CoQ10 levels [19], and patients with cortical basal degeneration showed normal cerebral cortex CoQ10 levels [21].

3.2. Studies Assessing Therapeutic Response to CoQ10 Administration

3.2.1. Parkinson’s Disease

The results of the 10 eligible studies addressing the therapeutic response of CoQ10 administration in patients with PD [29,30,31,32,33,34,35,36,37,38] are summarized in Table 4. One of these studies used an open-label design [29], while the others were randomized clinical placebo-controlled trials [30]. CoQ10 was generally well-tolerated, according to the four studies assessing adverse effects [32,33,34,35,36]. Despite five of these studies showing a mild improvement in motor scales in PD patients [30,31,35,36,38], three meta-analyses [39,40,41], one of them including eight randomized clinical trials [41], concluded that CoQ10 was not superior to the placebo in improving motor symptoms.
The study by Yoritaka et al. [38] showed a significant improvement in motor symptoms of PD patients suffering from the “wearing-off” phenomenon, and Li et al. [37] described a positive effect of concomitant CoQ10 and creatine therapy on cognitive impairment, assessed by the Montreal Cognitive Assessment (MoCA). However, these results are based on a small size series.
Mitsui et al. [42] reported the effects of the treatment with CoQ10 1200 mg/day in a patient diagnosed with familial MSA, in an advanced stage, related to the compound heterozygous nonsense (R387X) and missense (V393A) mutations in the COQ2 gene. The administration of CoQ10 resulted in increased serum and CSF total CoQ10 concentrations, the increased cerebral metabolic ratio of the oxygen measured by 15O2 positron emission tomography (PET), and led to stability in several clinical scores (Barthel Index, Scale for the Assessment and Rating of Ataxia—SARA, International Cooperative Ataxia Rating Scale—ICARS, and the Unified Multiple System Atrophy Rating Scale—UMSARS) during 3 years of follow-up.

3.2.2. Progressive Supranuclear Palsy

Two randomized clinical trials studied the effects of CoQ10 in patients diagnosed with PSP. Stamelou et al. [43], in a 6-week, monocenter, double-blind, randomized, placebo-controlled, phase II trial, including 21 clinically probable PSP patients assigned to a liquid nanodispersion of CoQ10 (doses of 5 mg/kg/day) or placebo, showed a mild improvement in a Frontal Assessment Battery and in the total scores of the PSP rating scale (PSPRS) in those assigned to CoQ10, while there were no significant changes in the UPDRS and the Mini-Mental State Examination (MMSE). They did not describe the relevant adverse effects. As should be expected, plasma levels of CoQ10 increased in the treated, but not untreated patients. In patients receiving CoQ10 compared to those receiving the placebo, the ratio of high-energy phosphates to low-energy phosphates (adenosine-triphosphate to adenosine-diphosphate, and phosphocreatine to unphosphorylated creatine) increased significantly in the occipital lobe and showed a consistent trend towards an increase in the basal ganglia. For this reason, the authors suggested a possible disease-modifying neuroprotective of CoQ10.
In contrast, Apetauerova et al. [44], in a one-year, investigator-initiated, multicenter, randomized, placebo-controlled, double-blind clinical trial involving 61 patients diagnosed with PSP assigned to CoQ10 (2400 mg/day) or a placebo, found no significant differences between the two study groups in PSPRS (although there was a non-significant trend toward a slower decline in the CoQ10 group), UPDRS, activities of daily living (ADL), MMSE, the 39-item Parkinson’s Disease Questionnaire (PDQ-39), and the 36-item Short-Form Health Survey (SF-36). Despite CoQ10 being well-tolerated, 41% of participants withdrew from the study for different reasons.

4. Discussion and Conclusions

The possible role of CoQ10 in the pathogenesis, or its value as a diagnostic marker of PD and other parkinsonian syndromes, has not been definitively established. In the case of PD, the pooled analyses of studies measuring CoQ10 concentrations in the brain tissues [20,21,22], showed a significant decrease in the cerebellum cortex of PD patients (Table 1, Figure 4), which was likely related to the concentrations found in the larger control group of one of these studies [21], while CoQ10 concentrations in the striatum, substantia nigra, and cerebral cortex were similar in PD patients and controls. Studies in platelets [16] and lymphocytes [17] showed a consistent decrease in CoQ10 concentrations, while in the CSF, both the total [18,19] and oxidized CoQ10 levels [18] were found to be increased in PD patients. The pooled data of the seven studies assessing serum/plasma CoQ10 levels [9,10,11,12,13,14,15] showed a non-significant trend toward lower concentrations in PD patients compared with controls (Table 1, Figure 3a), while the percentage of oxidized vs. total CoQ10 was increased in PD (Table 1). One study showed a surprisingly very high percentage of oxidized CoQ10, which was related to the easy oxidation of the reduced to oxidized CoQ10 from the moment of sample extraction because precautions were not taken to prevent this oxidation [14]. Finally, CoQ10 levels in the skin fibroblasts were similar in PD patients and controls [23].
In MSA, CoQ10 concentrations were found to be decreased in the cerebellar cortex in two studies (19, 20)—although the results of the pooled data did not reach statistical significance (Table 2)—in the serum/plasma [14,15,24], CSF [19], and skin fibroblasts [25]. Patients with LBD showed decreased cerebellar CoQ10 [21] and patients with PSP showed decreased CoQ10 concentrations [19] in single studies.
Due to their antioxidant actions, it was proposed that CoQ10 administration could be a potential protective therapy in PD and other neurodegenerative diseases [45,46]. Moreover, the administration of CoQ10 has shown neuroprotective effects in several models of experimental parkinsonism:
(a)
CoQ10 or idebenone (an analog of CoQ10) attenuates the loss of striatal dopamine and dopaminergic axons, induced by 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) administration in rodents [47,48,49,50] and in monkeys [51].
(b)
In rats, both the coadministration of CoQ10 and creatine [52] or CoQ10 and nicotinamide [53] have shown additive neuroprotective effects against striatal dopamine depletion after MPTP administration.
(c)
In rats injected with 6-hydroxydopamine (6-OHDA), the coadministration of CoQ10 and a mir-149sp mimic [54], or of CoQ10 and bone marrow stromal cells (BMSC) [55], improves motor symptoms and prevents dopaminergic damage.
(d)
CoQ10 administration was also able to prevent iron-induced apoptosis in cultured human dopaminergic (SK-N-SH) neurons, in metallothionein gene-manipulated mice, and in alpha-synuclein knockout (alpha-synko) mice [56].
(e)
CoQ10 administration can prevent neurodegeneration and behavioral deterioration in rodents exposed to several toxins causing experimental parkinsonism, such as the pesticides paraquat [57,58], dichlorvos [59], and rotenone [60,61], and showed neuroprotective effects against rotenone in primary rat mesencephalic cultures [62] and human neuroblastoma cells [63]. Interestingly, the exposure of human neuroblastoma SH-SY5Y cells to commonly used organophosphate compounds, such as dichlorvos, methyl-parathion (parathion), and chlorpyrifos (CPF), induces an important decrease in CoQ10 levels and complex II + III activity—both related to a decrease in neuronal cell viability. In this model, CoQ10 supplementation can modestly although significantly increase complex II + III activity [64].
(f)
CoQ10 supplementation (with or without the concomitant treatment of levodopa) has shown a protective effect against chlorpromazine-induced parkinsonism in mice, including a reduction in mortality and catalepsy, an increase in dopamine levels, and a decrease in oxidative stress [65]. Similarly, CoQ10 improved the forced swimming test, locomotor activity test, catalepsy, muscle coordination, and akinesia test, and reduced the dopamine depletion in haloperidol-induced parkinsonism in rats [66].
However, CoQ10 had not shown neuroprotective effects in a Drosophila DJ-1 model of PD [67]. Moreover, idebenone can induce apoptotic death cells in human neuroblastoma cells [68]. On the other hand, MPTP and its metabolite 1-methyl-4-phenyl-2,3-dihydropyridinium (MPDP+) are also able to induce a reduction in CoQ10, and a reduction in CoQ10 promotes the conversion of MPDP+ to the active neurotoxin 1-methyl-4-phenylpiridinium (MPP+) and increases its neurotoxicity [69].
Several studies analyzed the effects of CoQ10 administration on serum/plasma and CSF CoQ10 levels. Lönnrot et al. [70] described a significant increase in the plasma CoQ10 concentrations, but a lack of changes in the CSF CoQ10 concentrations in five healthy individuals after oral supplementation with ascorbic acid and CoQ10. Shults et al. [71], described an increase in plasma CoQ10 concentrations in 17 subjects after the administration of an escalating dosage of coenzyme Q10 (1200, 1800, 2400, and 3000 mg/day) with a stable dosage of vitamin E (alpha-tocopherol) 1200 IU/day, reaching the maximum plasma concentration with 2400 mg/day. Nukui et al. [72] reported, both in a double-blind, placebo-controlled study involving 46 healthy volunteers humans and in an acute, single-dose administration study in rats, that the administration of a water-soluble type of CoQ10 reached considerably higher serum CoQ10 concentrations than conventional CoQ10.
Despite the possible beneficial effects of CoQ10 administration, its good absorption, the lack of important adverse effects, and the improvement in PD symptoms suggested by several studies [30,31,35,36,38], data from meta-analyses of randomized clinical trials did not suggest the general usefulness of this therapy in patients with PD [39,40,41]. Several biochemical studies suggest the presence of CoQ10 deficiency in MSA, but the possible role of this compound in the treatment of MSA has not been explored yet. Although short-term use of CoQ10 treatment in PSP showed promising effects [43], the results of a randomized clinical trial involving a small series of patients showed no beneficial effects [44].
Despite all these data, the improvement in motor symptoms reported in a small series of patients with PD and the “wearing-off” phenomenon under CoQ10 therapy [38], and the improvement in cognitive impairment in patients treated with the combination of CoQ10 and creatine [37] suggest that CoQ10 could be useful in selected patients, and the role of personalized medicine could be important. In this regard, Seet et al. [73], in a preliminary study involving 16 PD patients treated with different doses of CoQ10, described that patients who experienced a significant short-term reduction in the UPDRS score had lower baseline plasma ubiquinol and decreased F2-isoprostanes (CoQ10 and F2-isoprostanes increased significantly at a 2400 mg/day dosage of CoQ10), suggesting that the therapeutic response should depend on the baseline levels of these two compounds.
Moreover, a recent double-blind randomized, phase II, placebo-controlled study using an omics-based strategy with CoQ10 has been recently proposed [74]. In this study, the assignation to a treatment group should be done after the stratification by the so-called “mitochondrial risk burden” in homozygous or compound heterozygous Parkin/PINK1 mutation carriers (P++), heterozygous Parkin/PINK1 mutation carriers (P+), and “omics” positive (omics+) and “omics” negative PD patients (omics-), those being omics+ with the highest and those who are omics- with the lowest cumulative burden of common genetic variants in genes that are related to mitochondrial function. Changes in the motor subscore of UPDRS should be the primary endpoint, and the appearance of motor fluctuations and non-motor symptoms in the 31P-magnetic resonance spectroscopy (31P-MRS) imaging results, and changes in structural and functional brain anatomy (MRI), should be the secondary endpoints.med-con
In summary, according to the current data, the possible value of the treatment with CoQ10 in parkinsonian syndromes could deserve further studies, at least in selected subgroups of patients with PD and in patients diagnosed with MSA and PSP.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/jpm12060975/s1. Table S1. PRISMA Checklist. Table S2. MOOSE Checklist.

Author Contributions

F.J.J.-J.: Conceptualization, Methodology, Investigation, Validation, Formal analysis, Writing—original draft, Writing—review and editing, Project administration. H.A.-N.: Conceptualization, Methodology, Investigation, Validation, Formal analysis, Writing—original draft, Writing—review and editing, Project administration. E.G.-M.: Conceptualization, Methodology, Investigation, Validation, Formal analysis, Writing—original draft, Writing—review and editing, Project administration, Obtaining funding. J.A.G.A.: Conceptualization, Methodology, Investigation, Validation, Formal analysis, Writing—original draft, Writing—review and editing, Project administration, Obtaining funding. All authors have read and agreed to the published version of the manuscript.

Funding

The work at the authors’ laboratory is supported in part by Grants RETICS RD16/0006/0004 (ARADyAL), PI18/00540 and PI21/01683 from Fondo de Investigación Sanitaria, Instituto de Salud Carlos III, Madrid, Spain and IB20134 and GR21073 from Junta de Extremadura, Mérida, Spain. This study was partially funded with FEDER funds.

Institutional Review Board Statement

Not applicable because this is a review article.

Informed Consent Statement

Not applicable because this is a review article.

Data Availability Statement

All data related to the current study, intended for reasonable use, is available from J.A.G. Agúndez (University Institute of Molecular Pathology Biomarkers, University of Extremadura -UNEx ARADyAL Instituto de Salud Carlos III, Av/de la Universidad S/N, E10071 Cáceres. Spain) and F.J. Jiménez-Jiménez (Section of Neurology, Hospital del Sureste, Arganda del Rey, Madrid, Spain).

Acknowledgments

We recognize the efforts of the personnel at the Library of Hospital Universitario del Sureste, Arganda del Rey, who retrieved an important number of papers for us.

Conflicts of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Figure 1. Chemical structure of coenzyme Q10.
Figure 1. Chemical structure of coenzyme Q10.
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Figure 2. PRISMA Flowchart for the studies assessing tissue concentrations of coenzyme Q10 in parkinsonian syndromes, and for therapeutic trials with CoQ10 in parkinsonian syndromes.
Figure 2. PRISMA Flowchart for the studies assessing tissue concentrations of coenzyme Q10 in parkinsonian syndromes, and for therapeutic trials with CoQ10 in parkinsonian syndromes.
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Figure 3. Meta-analyses of studies assessing serum/plasma total CoQ10 levels [7,8,9,10,11,12,13], serum/plasma CoQ10 corrected to cholesterol levels (b) [7,12], and serum/plasma oxidized CoQ10/total CoQ10 ratio (c) in PD patients compared with controls [9,11].
Figure 3. Meta-analyses of studies assessing serum/plasma total CoQ10 levels [7,8,9,10,11,12,13], serum/plasma CoQ10 corrected to cholesterol levels (b) [7,12], and serum/plasma oxidized CoQ10/total CoQ10 ratio (c) in PD patients compared with controls [9,11].
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Figure 4. Meta-analyses of studies assessing CoQ10 concentrations in the cerebellar cortex of PD patients and controls [18,19,20].
Figure 4. Meta-analyses of studies assessing CoQ10 concentrations in the cerebellar cortex of PD patients and controls [18,19,20].
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Figure 5. Meta-analyses of studies assessing serum/plasma total CoQ10 levels, serum/plasma total CoQ10 concentrations in MSA patients and controls [12,13,22].
Figure 5. Meta-analyses of studies assessing serum/plasma total CoQ10 levels, serum/plasma total CoQ10 concentrations in MSA patients and controls [12,13,22].
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Table
Table 1. Coenzyme Q10 Concentrations in Several Tissues from Parkinson’s Disease (PD) Patients and Healthy Controls (HC).
Table 1. Coenzyme Q10 Concentrations in Several Tissues from Parkinson’s Disease (PD) Patients and Healthy Controls (HC).
TissueAuthor, Year [Ref]ParameterPD NPD Mean ± SD
(Except % in *) 		HC NHC Mean ± SDDifference in Means (95% C.I.), p
Serum/plasmaJiménez-Jiménez et al., 2000 [9]Total CoQ10 (nmol/L)331157 ± 344311219 ± 42462.00 (−130.39 to 254.39); 0.522
Buhmann et al., 2004 [10]Total CoQ10 (nmol/L)40990 ± 62024530 ± 290−460.00 (−729.67 to −190.32); 0.001
Sohmiya et al., 2004 [11]Total CoQ10 (nmol/L)36613.3 ± 16029748.7 ± 224135.40 (40.11 to 230.69); 0.006
Bolner et al., 2006 [12]Total CoQ10 (nmol/L)44814.28 ± 750.5721 1004.24 ± 772.58189.96 (−211.60 to 591.52); 0.348
Gorgone et al., 2012 [13]Total CoQ10 (nmol/L)82713.49 ± 187.6460871.01 ± 162.16157.52 (97.95 to 217.09); <0.001
Kasai et al. 2016 [14]Total CoQ10 (nmol/L)20740.8 ± 377.218985.3 ± 939.4244.50 (−217.59 to 706.59); 0.290
Du et al., 2018 [15]Total CoQ10 (nmol/L)301640.13 ± 419.80301838.58 ± 481.41198.45 (−34.98 to 431.88); 0.094
TOTAL SERIESTotal CoQ10 (nmol/L)285906.01 ± 531.192131025.65 ± 592.90Random-effects model p = 0.234
Jiménez-Jiménez et al., 2000 [9]Total CoQ10/cholesterol335.03 ± 1.50315.30 ± 1.8402.7 (−0.57 to 1.11); 0.521
Kasai et al. 2016 [14]Total CoQ10/cholesterol204.07 ± 1.84185.92 ± 5.881.85 (−0.47 to 4.17); 0.115
TOTAL SERIESTotal CoQ10/cholesterol534.67 ± 1.69495.53 ± 3.80Random-effects model p = 0.197
Sohmiya et al., 2004 [11]% Oxidized/total CoQ10364.7 ± 1.8293.4 ± 0.9−1.30 (−2.03 to −0.57); <0.001
Gorgone et al., 2012 [13]% Oxidized/total CoQ10825.5 ± 0.9603.8 ± 0.9−1.70 (−2.00 to −1.40); <0.001
TOTAL SERIES% Oxidized/total CoQ101185.26 ± 1.29893.67 ± 0.9Random-effects model p = 0.006
Sohmiya et al., 2004 [11]Oxidized CoQ10 (nmol/L)3628.3 ± 10.52924.7 ± 8.3−3.60 (−8.38 to 1.18); 0.137
Kasai et al. 2016 [14]Oxidized CoQ10 (nmol/L)20644.2 ± 382.418900.2 ± 890.6256.00 (−186.86 to 698.86); 0.249
Sohmiya et al., 2004 [11]Reduced CoQ10 (nmol/L)36585 ± 15529724 ± 219139.00 (46.17 to 231.83); 0.004
Kasai et al. 2016 [14]Reduced CoQ10 (nmol/L)2096.6 ± 118.21885.2 ± 66.6−11.40 (−75.52 to 52.72); 0.721
PlateletsGötz et al., 2000 [16]Total CoQ10 (ng/109 platelets)2080.6 ± 5.91993.7 ± 5.113.10 (9.51 to 16.69); <0.001
Götz et al., 2000 [16]Reduced CoQ10 (ng/109 platelets)2010.3 ± 2.41920.3 ± 3.210.00 (8.17 to 11.83); <0.001
Götz et al., 2000 [16]Oxidized CoQ10 (ng/109 platelets)2070.3 ± 4.81973.5 ± 4.73.20 (0.07 to 6.33); 0.045
Götz et al., 2000 [16]Reduced/oxidizedCoQ10200.15 ± 0.04190.32 ± 0.070.17 (0.13 to 0.21); <0.001
Götz et al., 2000 [16]Reduced/total CoQ10 200.11 ± 0.02190.21 ± 0.030.10 (0.08 to 0.12); <0.001
LymphocytesMischley et al., 2012 [17] *% of patients with CoQ10 deficiency *2232–36% 888–9% p = 0.0012–0.006 (according to authors data)
CSFIsobe et al., 2007 [18]Oxidized CoQ10 (nmol/L)205.2 ± 1.5172.9 ± 1.3−2.30 (−3.25 to −1.35); <0.001
Isobe et al., 2007 [18]Reduced CoQ10 (nmol/L)200.7 ± 0.6170.8 ± 0.70.10 (−0.33 to 0.53); 0.643
Isobe et al., 2007 [18]Oxidized/total CoQ10200.803 ± 0.179170.682 ± 0.204−0.12 (−0.25 to 0.01); 0.063
Compta et al., 2018 [19]Total CoQ10 (nmol/L)1554.39 ± 7.161536.02 ± 7.20−18.37 (−23.74 to −13.00); < 0.001
Brain
StriatumHargreaves et al. 2008 [20]Total CoQ10 (pmol/mg protein)20188.6 ± 51.420214.3 ± 64.325.70 (−11.56 to 62.96); 0.171
Substantia nigraHargreaves et al. 2008 [20]Total CoQ10 (pmol/mg protein)8102.9 ± 42.98120.0 ± 4.317.10 (−15.59 to 49.79); 0.281
Cerebellum cortexHargreaves et al. 2008 [20]Total CoQ10 (pmol/mg protein)25107.1 ± 34.325124.3 ± 47.117.20 (−6.23 to 40.63); 0.147
Schottlaender et al., 2016 [21]Total CoQ10 (pmol/mg protein)7262.47 ± 28.8437241.87 ± 57.70−2.06 (−65.95 to 24.75); 0.365
Barca et al., 2016 [22]Total CoQ10 (pmol/mg protein)9132.2 ± 8.4712113.1 ± 7.16−19.10 (−26.24 to −11.96); <0.001
TOTAL SERIES Total CoQ10 (pmol/mg protein) 41139.14 ± 64.49 74181.27 ± 78.20 Random-effects model
p = 0.03358
Cerebral cortexHargreaves et al. 2008 [20]Total CoQ10 (pmol/mg protein)13128.6 ± 61.413218.6 ± 55.790.00 (42.55 to 137.45); 0.0007
Schottlaender et al., 2016 [21]Total CoQ10 (pmol/mg)7276.02 ± 71.3737259.39 ± 107.09−16.63 (−102.09 to 68.84); 0.697
TOTAL SERIES Total CoQ10 (pmol/mg) 20180.20 ± 99.89 50248.78 ± 97.53 Random-effects model
p = 0.143
Skin fibroblastsDel Hoyo et al., 2010 [23]Total CoQ10/CS201.16 ± 0.33190.97 ± 0.25−0.19 (−0.38 to 0.00); 0.051
Del Hoyo et al., 2010 [23]Reduced CoQ10/CS200.41 ± 0.16190.34 ± 0.11−0.07 (−0.16 to 0.02); 0.122
Del Hoyo et al., 2010 [23]Oxidized CoQ10/CS200.75 ± 0.26190.63 ± 0.23−0.12 (−0.28 to 0.04); 0.136
Del Hoyo et al., 2010 [23]Total CoQ10/mg protein2086.27 ± 29.071971.86 ± 26.38−14.41 (−32.45 to 3.63); 0.114
Del Hoyo et al., 2010 [23]Reduced CoQ10/mg protein2024.50 ± 7.381924.50 ± 7.380.00 (−4.79 to 4.79); 1.000
Del Hoyo et al., 2010 [23]Oxidized CoQ10/mg protein2056.49 ± 25.201947.31 ± 23.50−9.18 (−25.01 to 6.65); 0.248
Del Hoyo et al., 2010 [23]Oxidized CoQ10/Reduced CoQ10200.60 ± 0.27190.62 ± 0.270.02 (−0.16 to 0.20); 0.818
* Expressed in % of patients with CoQ10 defficiency.
Table
Table 2. Coenzyme Q10 Concentrations in Several Tissues from Patients with Multisystem Atrophy (MSA) and Healthy Controls (HC).
Table 2. Coenzyme Q10 Concentrations in Several Tissues from Patients with Multisystem Atrophy (MSA) and Healthy Controls (HC).
TissueAuthor, Year [Ref]ParameterMSA NMSA Mean ± SDHC NHC Mean ± SDDifference in Means (95% C.I.), p
Serum/plasmaKasai et al. 2016 [14]Total CoQ10 (nmol/L)18593.2 ± 222.618985.3 ± 939.4392.10 (−70.34 to 854.54); 0.094
Mitsui et al., 2016 [24]Total CoQ10 (nmol/L)44590.71 ± 254.8239833.95 ± 664.69243.24 (28.09 to 458.39); 0.027
Du et al., 2018 [15]Total CoQ10 (nmol/L)301640.13 ± 419.80301858.38 ± 481.41218.25 (−15.18 to 451.68); 0.066
TOTAL SERIES Total CoQ10 (nmol/L) 92933.40 ± 583.47 871218.52 ± 817.98 Random-effects model
p = 0.001
Kasai et al. 2016 [14]Total CoQ10/cholesterol183.04 ± 1.23185.92 ± 5.882.88 (0.00 to 5.76); 0.050
Kasai et al. 2016 [14]Oxidized CoQ10 (nmol/L)18520.7 ± 202.818900.2 ± 890.6379.50 (−58.02 to 817.02); 0.087
Kasai et al. 2016 [14]Reduced CoQ10 (nmol/L)1872.4 ± 34.11885.2 ± 66.612.80 (17.64 to 48.64); 0.473
CSFCompta et al., 2018 [19]Total CoQ10 (nmol/L)2026.63 ± 3.701536.02 ± 7.10 9.37 (5.61 to 13.13); <0.0001
Brain
Cerebellum cortexSchottlaender et al., 2016 [21]Total CoQ10 (pmol/mg)20169.30 ± 49.7137241.87 ± 57.7072.57 (41.94 to 103.20); <0.001
Barca et al., 2016 [22]Total CoQ10 (pmol/mg)1268.1 ± 10.0312113.1 ± 7.1645.00 (37.62 to 52.38); <0.001
TOTAL SERIESTotal CoQ10 (pmol/mg)32131.35 ± 63.4749 210.33 ± 75.09 Random-effects model
p = 0.0977
Cerebral cortex frontal Schottlaender et al., 2016 [21] Total CoQ10 (pmol/mg)20260.44 ± 70.2237259.39 ± 107.09−1.05 (−54.43 to 52.33); 0.969
Cerebral cortex occipitalBarca et al., 2016 [22]Total CoQ10 (nmol/mg protein)10277.1 ± 29.739267.3 ± 21.88−9.80 (−35.32 to 15.72); 0.429
StriatumBarca et al., 2016 [22]Total CoQ10 (nmol/mg protein)7244.2 ± 27.167230.8 ± 28.62−13.40 (−45.89 to 10.09); 0.387
Skin fibroblastsMonzio Compagnoni et al., 2010 [25]Total CoQ10 (pg/mg protein)1427.83 ± 1.44645.22 ± 3.4817.39 (15.13 to 19.65); <0.001
Table
Table 3. Coenzyme Q10 Concentrations in Several Tissues from Patients with Lewy Body Dementia (LBD), Progressive Supranuclear Palsy, and Cortical Basal Degeneration Compared with Healthy Controls (HC).
Table 3. Coenzyme Q10 Concentrations in Several Tissues from Patients with Lewy Body Dementia (LBD), Progressive Supranuclear Palsy, and Cortical Basal Degeneration Compared with Healthy Controls (HC).
Lewy Body Dementia (LBD)
TissueAuthor, Year [Ref]ParameterLBD NLBD Mean ± SD HC NHC Mean ± SDDifference in Means (95% C.I.), p
Serum/plasmaMolina et al., 2002 [26]Total CoQ10 (nmol/L)18960.6 ± 359.1201205.2 ± 362.2244.60 (6.90 to 482.30); 0.044
Gironi et al. 2011 [27]Total CoQ10 (nmol/L)7645.17 ± 29066622.12 ± 227.14−23.05 (−207.81 to 161.71); 0.804
TOTAL SERIESTotal CoQ10 (nmol/L)25872.28 ± 365.0586757.72 ± 360.79Random-effects model: p = 0.409
Molina et al., 2002 [7]Total CoQ10/cholesterol184.67 ± 1.75205.05 ± 1.520.38 (−0.70 to 1.46); 0.478
Brain
Cerebellum cortexSchottlaender et al., 2016 [21]Total CoQ10 (pmol/mg)20169.30 ± 49.7137241.87 ± 57.7072.57 (41.94 to 103.20); <0.001
Cerebral cortex frontal Schottlaender et al., 2016 [21] Total CoQ10 (pmol/mg)20260.44 ± 70.2237259.39 ± 107.09−1.05 (−54.43 to 52.33); 0.969
Progressive Supranuclear Palsy (PSP)
TissueAuthor, Year [Ref]ParameterPSP NPSP Mean ± SDHC NHC Mean ± SDDifference in Means (95% C.I.), p
CSFCompta et al., 2018 [19]Total CoQ10 (nmol/L)1047.67 ± 4.051536.02 ± 7.10 −11.65 (−16.79 to −6.51); 0.0001
Cortical Basal Degeneration (CBD)
TISSUEAuthor, Year [Ref]ParameterCBD NCBD Mean ± SDHC NHC Mean ± SDDifference in Means (95% C.I.), p
Cerebellum cortexSchottlaender et al., 2016 [21]Total CoQ10 (pmol/mg)15271.18 ± 76.2137241.87 ± 57.70−29.31 (−68.31 to 9.69); 0.137
Table
Table 4. Studies describing the effects of levodopa and dopamine agonists in patients with RBD.
Table 4. Studies describing the effects of levodopa and dopamine agonists in patients with RBD.
Authors, Year [Ref]Study SettingType of StudyMain FindingsLevel of Evidence (Quality Score)
Strijks et al., 1997 [29]10 patients diagnosed with PD. Dosage of 200 mg/day. Assessment of motor performance with UPDRS and motor test.3 months open-label study
  • Lack of improvement in PD motor symptoms.
II (NA)
Shults et al., 2002 [30]Eighty subjects with early PD not requiring treatment for their disability. Dosages of 300, 600, or 1200 mg/day
Evaluation with the UPDRS at the screening, baseline, and 1-, 4-, 8-, 12-, and 16-month visits. Follow-up of 16 months or until disability requiring treatment with levodopa. 		Multicenter, randomized, parallel-group, placebo-controlled,
double-blind, dosage-ranging trial.
  • Significantly lower increase in UPDRS scores during follow-up in patients assigned to CoQ10 therapy, especially with the highest doses.
I (>50%)
Müller et al., 2003 [31]Twenty-eight treated and stable PD patients. Dosage of 360 mg/day for 4 weeks.
Scoring of PD symptoms, and visual function using the Farnsworth–Munsell 100 Hue test (FMT).		Monocenter, parallel-group, placebo-controlled, double-blind trial
  • Mild symptomatic benefit on PD symptoms in patients assigned to CoQ10 therapy.
  • Better improvement in FMT performance in patients assigned to CoQ10 therapy.
I (>50%)
NINDS NET-PD Investigators 2007 [32]Seventy-one untreated early PD patients assigned to CoQ10 therapy (2400 mg/day), 71 to GPI-1485, and 71 to placebo.
Measurement of change in total UPDRS scores and subscores, Hoehn & Yahr staging, and Schwabb & England scale scores, either at the time requiring symptomatic therapy or at 12 months.		Randomized, double-blind, calibrated futility clinical
trial
  • The primary outcome measure (change in total UPDRS scores over 1 year) did not differ significantly between the 3 treatment groups.
  • Changes in Hoehn & Yahr staging, and Schwabb & England scale scores did not differ significantly between the 3 treatment groups.
  • CoQ10 was well-tolerated. The percentages of withdrawal because of adverse effects were 8%, 11%, and 10%, respectively, for CoQ10, GPI-1485, and placebo.
I (>50%)
Storch et al., 2007 [33]One hundred thirty-one patients with PD without motor fluctuations and a stable antiparkinsonian treatment.
Treatment with placebo or nanoparticular CoQ10 (100 mg 3 times a day, equivalent to 1200 mg/day of standard formulation) for 3 months.
The stratification criterion was levodopa treatment.
Evaluation with the UPDRS (sum score of parts II and III) at baseline, 1, 2, and 3 months at each visit monthly. 		Multicenter, randomized, double-blind, placebo-controlled, stratified,
parallel-group, single-dose trial.
  • The mean changes of the sum UPDRS parts II/III score did not differ significantly between the placebo and CoQ10 groups (−3.69 and −3.33)
  • No secondary outcome measure showed a significant change between the placebo group and the CoQ10 group.
  • The frequency and quality of adverse events are similar in both treatment groups.
I (>50%)
Parkinson Study Group QE3 Investigators [34]Six hundred patients diagnosed with PD (from 67 hospitals in the USA) in the previous 5 years, free of dopaminergic therapy in the previous 3 months, with Hoehn & Yahr stage of 2.5 or less.
Two hundred were assigned to CoQ10 1200 mg/day, 200 to CoQ10 2400 mg/day and 200 to placebo. All patients were taking vitamin E 1200 IU/day.
Evaluation at 16 months from baseline or until a disability requiring dopaminergic treatment.
The study was powered to detect a 3-point difference between active treatment and placebo.		Phase III randomized, placebo-controlled,
double-blind clinical trial
  • At study termination, both active treatment groups showed slight adverse trends relative to placebo.
  • Adjusted mean changes (worsening) in total UPDRS scores from baseline to final visit did not differ between the 3 study groups.
  • Treatments were well-tolerated with no safety concerns.
I (>50%)
Jie et al., 2014 [35]Eighty-eight patients diagnosed with PD and treated with levodopa.
Forty-four were assigned to CoQ10 375–750 mg/day, and 44 to placebo
Evaluation with the Webster Scale at baseline and 3 months		Monocenter, randomized, placebo-controlled,
double-blind clinical trial
  • Significant improvement in UPDRS Webster Scale scores in the group of patients treated with CoQ10.
  • Lack of significant adverse effects.
I (>50%)
Wang et al., 2014 [36]Thirty-nine patients diagnosed with PD under conventional therapy.
Twenty-one were assigned to CoQ10 450 or 1200 mg/day, and 18 to placebo as add-on therapy
Evaluation with the UPDRS III and Webster Scale at baseline and 36 weeks		Monocenter, randomized, placebo-controlled,
double-blind clinical trial
  • Significant improvement in UPDRS III and Webster Scale scores in the group of patients treated with CoQ10 1200 mg/day (but not of the patients treated with CoQ10 450 mg/day) compared with the placebo group.
I (>50%)
Li et al., 2015 [37]Seventy-five patients diagnosed with PD and MCI.
Random assignation to treatment with CoQ10 100 mg b.i.d. and creatine 5 mg b.i.d. or to placebo.
Evaluation with the UPDRS part III, and MoCa at 12 and 18 months. 		Phase III randomized, placebo-controlled,
double-blind clinical trial
  • Non-significant differences in UPDRS III scores between the 2 study groups at 12 and 18 months.
  • Significantly lower worsening in the MoCA scores in patients assigned to CoQ10 plus creatine.
I (>50%)
Yoritaka et al., 2015 [38]Twenty-six patients with PD experiencing
wearing off (group A) and 22 early PD patients without levodopa (with or without a dopamine agonist, group B).
Treatment with 300 mg/day of ubiquinol-10 or placebo for 48 weeks (Group A, 14 ubiquinol-10, 12 placeboes) or 96 weeks (Group B, 14 ubiquinol-10, 8 placeboes).		Randomized, double-blind, placebo-controlled, parallel-group pilot trial
  • Significant improvement in UPDRS scores in patients treated with ubiquinol-10 compared with placebo in group A.
  • Lack of significant changes in UPDRS scores in patients treated with ubiquinol-10 compared with placebo in group B.
I (>50%)
MoCA: Montreal Cognitive Assessment, PD: Parkinson’s disease, UPDRS: Unified Parkinson’s disease rating scale.
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Jiménez-Jiménez, F.J.; Alonso-Navarro, H.; García-Martín, E.; Agúndez, J.A.G. Coenzyme Q10 and Parkinsonian Syndromes: A Systematic Review. J. Pers. Med. 2022, 12, 975. https://doi.org/10.3390/jpm12060975

AMA Style

Jiménez-Jiménez FJ, Alonso-Navarro H, García-Martín E, Agúndez JAG. Coenzyme Q10 and Parkinsonian Syndromes: A Systematic Review. Journal of Personalized Medicine. 2022; 12(6):975. https://doi.org/10.3390/jpm12060975

Chicago/Turabian Style

Jiménez-Jiménez, Félix Javier, Hortensia Alonso-Navarro, Elena García-Martín, and José A. G. Agúndez. 2022. "Coenzyme Q10 and Parkinsonian Syndromes: A Systematic Review" Journal of Personalized Medicine 12, no. 6: 975. https://doi.org/10.3390/jpm12060975

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