Coenzyme Q10 and Parkinsonian Syndromes: A Systematic Review

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.


Introduction
Coenzyme Q 10 (CoQ 10 , Figure 1), which is also known as ubiquinone, is a 1,4benzoquinone 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, CoQ 10 can be present in three redox states: fully oxidized (ubiquinone), partially oxidized (semiquinone or ubisemiquinone), and fully reduced (ubiquinol). Together with mitochondria, CoQ 10 is present in the endoplasmic reticulum, Golgi apparatus, lysosomes, and peroxisomes. CoQ 10 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 CoQ 10 as an antioxidant, both the study of CoQ 10 concentrations in different tissues of patients diagnosed with PD and/or other parkinsonian syndromes and the potential therapeutic role of CoQ 10 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 CoQ 10 in patients diagnosed with parkinsonian syndromes compared to healthy controls and the results of therapeutic trials of CoQ 10 in PD and other causes of parkinsonism.

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 Q 10 " 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 CoQ 10 concentrations in patients with several types of parkinsonian syndrome and controls, and therapeutic trials with CoQ 10 in parkinsonian syndromes, are plotted in Figure 2.

Selection of Studies and Methodology for the Meta-Analyses
Meta-analyses of those observational eligible studies that assessed the concentrations of CoQ 10 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 CoQ 10 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 Tables 1-3. 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 Tau 2 , the Jackson method for the confidence interval of Tau 2 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.    Matsubara et al. [28] reported decreased serum CoQ 10 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 CoQ 10 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 CoQ 10 corrected to cholesterol levels (Table 1, Figure 3b) [9,14]. However, the serum/plasma oxidized CoQ 10 /total CoQ 10 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 CoQ 10 and in the reduced CoQ 10 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 CoQ 10 concentrations in platelets [16] and lymphocytes [17], respectively, from patients with PD compared with healthy controls (Table 1).

Skin Fibroblasts
Del Hoyo et al. [23] reported similar CoQ 10 concentrations in skin fibroblasts from PD patients and controls ( Table 1).
The pooled data from the three studies, addressing serum/plasma total CoQ 10 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 CoQ 10 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 CoQ 10 levels did not reach statistical significance. In contrast, the cerebral cortex [21,22] and striatum [21] CoQ 10 levels were similar in MSA and controls (Table 2).

Other Parkinsonian Syndromes
The results of studies addressing CoQ 10 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 CoQ 10 concentrations to those of the control in serum/plasma [26,27], and in the cerebral cortex [21], but lower CoQ 10 concentrations in the cerebellum cortex [21]. Patients diagnosed with progressive supranuclear palsy (PSP) showed decreased CSF CoQ 10 levels [19], and patients with cortical basal degeneration showed normal cerebral cortex CoQ 10 levels [21].

Parkinson's Disease
The results of the 10 eligible studies addressing the therapeutic response of CoQ 10 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 placebocontrolled trials [30]. CoQ 10 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 CoQ 10 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 CoQ 10 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 CoQ 10 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 CoQ 10 resulted in increased serum and CSF total CoQ 10 concentrations, the increased cerebral metabolic ratio of the oxygen measured by 15

Progressive Supranuclear Palsy
Two randomized clinical trials studied the effects of CoQ 10 in patients diagnosed with PSP. Stamelou et al. [43], in a 6-week, monocenter, double-blind, randomized, placebocontrolled, 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 CoQ 10 , 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 CoQ 10 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 CoQ 10 being well-tolerated, 41% of participants withdrew from the study for different reasons.

Discussion and Conclusions
The possible role of CoQ 10 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 CoQ 10 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 CoQ 10 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 CoQ 10 concentrations, while in the CSF, both the total [18,19] and oxidized CoQ 10 levels [18] were found to be increased in PD patients. The pooled data of the seven studies assessing serum/plasma CoQ 10 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 CoQ 10 was increased in PD (Table 1). One study showed a surprisingly very high percentage of oxidized CoQ 10 , which was related to the easy oxidation of the reduced to oxidized CoQ 10 from the moment of sample extraction because precautions were not taken to prevent this oxidation [14]. Finally, CoQ 10 levels in the skin fibroblasts were similar in PD patients and controls [23].
In MSA, CoQ 10 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 CoQ 10 [21] and patients with PSP showed decreased CoQ 10 concentrations [19] in single studies.
Due to their antioxidant actions, it was proposed that CoQ 10 administration could be a potential protective therapy in PD and other neurodegenerative diseases [45,46]. Moreover, the administration of CoQ 10 has shown neuroprotective effects in several models of experimental parkinsonism: (a) CoQ 10 or idebenone (an analog of CoQ 10 ) 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 CoQ 10 and creatine [52] or CoQ 10 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 CoQ 10 and a mir-149sp mimic [54], or of CoQ 10 and bone marrow stromal cells (BMSC) [55], improves motor symptoms and prevents dopaminergic damage. (d) CoQ 10 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) CoQ 10 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 CoQ 10 levels and complex II + III activity-both related to a decrease in neuronal cell viability. In this model, CoQ 10 supplementation can modestly although significantly increase complex II + III activity [64].
(f) CoQ 10 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, CoQ 10 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, CoQ 10 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-2,3dihydropyridinium (MPDP + ) are also able to induce a reduction in CoQ 10 , and a reduction in CoQ 10 promotes the conversion of MPDP + to the active neurotoxin 1-methyl-4phenylpiridinium (MPP+) and increases its neurotoxicity [69].
Several studies analyzed the effects of CoQ 10 administration on serum/plasma and CSF CoQ 10 levels. Lönnrot et al. [70] described a significant increase in the plasma CoQ 10 concentrations, but a lack of changes in the CSF CoQ 10 concentrations in five healthy individuals after oral supplementation with ascorbic acid and CoQ 10. Shults et al. [71], described an increase in plasma CoQ 10 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, singledose administration study in rats, that the administration of a water-soluble type of CoQ 10 reached considerably higher serum CoQ 10 concentrations than conventional CoQ 10 .
Despite the possible beneficial effects of CoQ 10 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 CoQ 10 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 CoQ 10 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 CoQ 10 therapy [38], and the improvement in cognitive impairment in patients treated with the combination of CoQ 10 and creatine [37] suggest that CoQ 10 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 CoQ 10 , described that patients who experienced a significant short-term reduction in the UPDRS score had lower baseline plasma ubiquinol and decreased F2-isoprostanes (CoQ 10 and F2-isoprostanes increased significantly at a 2400 mg/day dosage of CoQ 10 ), 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 CoQ 10 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 31 P-magnetic resonance spectroscopy ( 31 P-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 CoQ 10 in parkinsonian syndromes could deserve further studies, at least in selected subgroups of patients with PD and in patients diagnosed with MSA and PSP.