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Figure.
Plasma Levels of Coenzyme Q10 (CoQ10) in Patients With Multiple System Atrophy (MSA) and Controls
Plasma Levels of Coenzyme Q10 (CoQ10) in Patients With Multiple System Atrophy (MSA) and Controls

Plasma levels of CoQ10 obtained from individual patients with MSA and control are plotted. Open circles indicate the plasma levels of CoQ10 obtained from patients with MSA and controls carrying the V393A mutation in COQ2. The long and short horizontal bars represent the mean and SD, respectively. The mean plasma level of CoQ10 in patients with MSA was significantly lower than that in controls (Mann-Whitney test, P = .01).

Table.  
Characteristics of Participants
Characteristics of Participants
1.
Gilman  S, Wenning  GK, Low  PA,  et al.  Second consensus statement on the diagnosis of multiple system atrophy.  Neurology. 2008;71(9):670-676.PubMedGoogle ScholarCrossref
2.
Multiple-System Atrophy Research Collaboration.  Mutations in COQ2 in familial and sporadic multiple-system atrophy.  N Engl J Med. 2013;369(3):233-244.PubMedGoogle ScholarCrossref
3.
Ashby  MN, Kutsunai  SY, Ackerman  S, Tzagoloff  A, Edwards  PA.  COQ2 is a candidate for the structural gene encoding para-hydroxybenzoate.  J Biol Chem. 1992;267(6):4128-4136.PubMedGoogle Scholar
4.
Littarru  GP, Tiano  L.  Bioenergetic and antioxidant properties of coenzyme Q10: recent developments.  Mol Biotechnol. 2007;37(1):31-37.PubMedGoogle ScholarCrossref
5.
Jeon  BS, Farrer  MJ, Bortnick  SF; Korean Canadian Alliance on Parkinson’s Disease and Related Disorders.  Mutant COQ2 in multiple-system atrophy.  N Engl J Med. 2014;371(1):80.PubMedGoogle ScholarCrossref
6.
Chen  YP, Zhao  B, Cao  B,  et al.  Mutation scanning of the COQ2 gene in ethnic Chinese patients with multiple-system atrophy.  Neurobiol Aging. 2015;36(2):1222.e7-1222.e11.PubMedGoogle ScholarCrossref
7.
Lin  CH, Tan  EK, Yang  CC, Yi  Z, Wu  RM.  COQ2 gene variants associate with cerebellar subtype of multiple system atrophy in Chinese.  Mov Disord. 2015;30(3):436-437.PubMedGoogle ScholarCrossref
8.
Wen  XD, Li  HF, Wang  HX, Ni  W, Dong  Y, Wu  ZY.  Mutation analysis of COQ2 in Chinese patients with cerebellar subtype of multiple system atrophy.  CNS Neurosci Ther. 2015;21(8):626-630.PubMedGoogle ScholarCrossref
9.
Zhao  Q, Yang  X, Tian  S, An  R, Zheng  J, Xu  Y.  Association of the COQ2 V393A variant with risk of multiple system atrophy in East Asians.  Neurol Sci. 2016;37(3):423-430.PubMedGoogle ScholarCrossref
10.
Yamashita  S, Yamamoto  Y.  Simultaneous detection of ubiquinol and ubiquinone in human plasma as a marker of oxidative stress.  Anal Biochem. 1997;250(1):66-73.PubMedGoogle ScholarCrossref
11.
Kaikkonen  J, Nyyssönen  K, Tuomainen  TP, Ristonmaa  U, Salonen  JT.  Determinants of plasma coenzyme Q10 in humans.  FEBS Lett. 1999;443(2):163-166.PubMedGoogle ScholarCrossref
12.
Kasai  T, Tokuda  T, Ohmichi  T,  et al.  Serum levels of coenzyme Q10 in patients with multiple system atrophy.  PLoS One. 2016;11(1):e0147574.PubMedGoogle ScholarCrossref
13.
Schottlaender  LV, Bettencourt  C, Kiely  AP,  et al.  Coenzyme Q10 levels are decreased in the cerebellum of multiple-system atrophy patients.  PLoS One. 2016;11(2):e0149557.PubMedGoogle ScholarCrossref
14.
Frackowiak  RS, Lenzi  GL, Jones  T, Heather  JD.  Quantitative measurement of regional cerebral blood flow and oxygen metabolism in man using 15O and positron emission tomography.  J Comput Assist Tomogr. 1980;4(6):727-736.PubMedGoogle ScholarCrossref
15.
Yoritaka  A, Kawajiri  S, Yamamoto  Y,  et al.  Randomized, double-blind, placebo-controlled pilot trial of reduced coenzyme Q10 for Parkinson’s disease.  Parkinsonism Relat Disord. 2015;21(8):911-916.PubMedGoogle ScholarCrossref
16.
Sohmiya  M, Tanaka  M, Suzuki  Y, Tanino  Y, Okamoto  K, Yamamoto  Y.  An increase of oxidized coenzyme Q-10 occurs in the plasma of sporadic ALS patients.  J Neurol Sci. 2005;228(1):49-53.PubMedGoogle ScholarCrossref
17.
Yamagishi  K, Ikeda  A, Moriyama  Y,  et al; CIRCS Investigators.  Serum coenzyme Q10 and risk of disabling dementia.  Atherosclerosis. 2014;237(2):400-403.PubMedGoogle ScholarCrossref
Original Investigation
August 2016

Plasma Coenzyme Q10 Levels in Patients With Multiple System Atrophy

Author Affiliations
  • 1Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
 

Copyright 2016 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.

JAMA Neurol. 2016;73(8):977-980. doi:10.1001/jamaneurol.2016.1325
Abstract

Importance  Multiple system atrophy (MSA) is an intractable neurodegenerative disease characterized by autonomic failure in addition to various combinations of parkinsonism, cerebellar ataxia, and pyramidal dysfunction. It has recently been reported that functionally impaired variants of COQ2, which encodes an essential enzyme in the biosynthetic pathway of coenzyme Q10 (CoQ10), are associated with MSA. However, little is known about the role of CoQ10 in the pathogenesis of MSA.

Objective  To compare the levels of plasma CoQ10 in patients with MSA with those in age-, sex-, and COQ2 genotype–matched controls.

Design, Setting, and Participants  We enrolled 44 Japanese patients with MSA and 39 Japanese controls from September 1, 2012, to December 31, 2015. Patients with MSA were diagnosed on the basis of the second consensus criteria by at least 2 neurologists. Plasma CoQ10 levels were measured by high-performance liquid chromatography with electrochemical detection. Sanger sequencing of COQ2 was performed to determine the COQ2 genotypes. Multiple logistic regression analysis was performed to determine the association between MSA and the plasma CoQ10 level.

Main Outcomes and Measures  Plasma CoQ10 levels in patients with MSA were compared with those in controls after adjusting for age, sex, and COQ2 genotype.

Results  Among 44 patients with MSA (mean [SD] age, 63.7 [8.3] years) and 39 controls (mean [SD] age, 60.3 [13.0] years), the mean (SD) plasma level of CoQ10 in patients with MSA was lower than that in controls (0.51 [0.22] vs 0.72 [0.42] µg/mL; P = .01) (difference between medians: −0.14; 95% CI, –0.25 to –0.03). The mean (SD) plasma levels of CoQ10 in patients with the cerebellar variant of MSA and those with the parkinsonian variant of MSA were 0.58 (0.19) and 0.49 (0.26) µg/mL, respectively. After adjusting for age, sex, and COQ2 genotype, the levels of plasma CoQ10 were significantly associated with MSA (95% CI, 0.10; range, 0.02 to 0.66) (P = .02).

Conclusions and Relevance  Our data showed decreased levels of plasma CoQ10 in patients with MSA regardless of the COQ2 genotype, supporting a hypothesis that supplementation with CoQ10 is beneficial for patients with MSA.

Introduction

Multiple system atrophy (MSA) is a progressive neurodegenerative disease clinically characterized by autonomic failure in addition to various combinations of parkinsonism, cerebellar ataxia, and pyramidal dysfunction.1 Whole-genome sequence analysis in combination with linkage analysis has recently revealed homozygous or compound heterozygous mutations in COQ2 (OMIM 609825) in 2 of 6 multiplex families with MSA.2 The COQ2 genotype encodes parahydroxybenzoate-polyprenyl transferase, an essential enzyme involved in the biosynthesis of coenzyme Q10 (CoQ10),3 which is a lipophilic molecule that functions as an essential carrier in electron transport in the mitochondrial respiratory chain and as an endogenous antioxidant.4 Levels of CoQ10 in frozen brain tissues and lymphoblastoid cell lines from patients with MSA carrying homozygous (M128V-V393A/M128V-V393A) and compound heterozygous mutations (R387X/V393A) were substantially lower than those from controls.2 It was also demonstrated that functionally impaired variants of COQ2 were associated with the risk of developing MSA.2 Several subsequent case-control association studies in East Asia have consistently shown that the carrier frequency of V393A in COQ2 is higher in patients with MSA than in controls.2,5-9 On the basis of these findings, a question is raised regarding the potential role of CoQ10 insufficiency in the pathophysiologic development of MSA. Nevertheless, thus far, little has been known about levels of plasma CoQ10 in patients with MSA carrying either COQ2 mutations or no mutations. In this study, we aimed to evaluate the levels of plasma CoQ10 in patients with MSA to substantiate a hypothesis that CoQ10 insufficiency underlies development of MSA.

Box Section Ref ID

Key Points

  • Question Are there any associations of plasma levels of coenzyme Q10 with multiple system atrophy?

  • Findings In this case-control study that included 44 cases and 39 controls, the mean plasma coenzyme Q10 level in patients with multiple system atrophy was lower than that in controls. After adjusting for age, sex, and COQ2 genotype, the association of plasma coenzyme Q10 levels with multiple system atrophy was significant.

  • Meaning Our data suggest that low levels of plasma coenzyme Q10 may play a role in the pathogenesis of multiple system atrophy.

Methods
Participants

We enrolled 44 Japanese patients with MSA and 39 Japanese control participants from a pool of outpatient clinics at The University of Tokyo Hospital from September 1, 2012, to December 31, 2015. Controls were recruited mainly from spouses of the patients presenting to the clinics. Patients with MSA were diagnosed on the basis of the second consensus criteria by at least 2 neurologists (J.M. and T.M.).1 Individuals in the control group were free of neurologic diseases. Exclusion criteria for all participants were dyslipidemia, hypothyroidism, hyperthyroidism, severe liver or kidney disease, tube feeding, and any history of intake of ubiquinone, ubiquinol, idebenone, or statins during the 3 months before this study. All participants provided written informed consent. The study was approved by The University of Tokyo Ethics Committee.

Measurement of Plasma CoQ10 Level and Sequencing of COQ2

All plasma samples were prepared using BD Biosciences Vacutainer CPT tubes with sodium heparin (BD Biosciences), followed by centrifugation within 2 hours of blood collection and storage at −80°C until analysis. Plasma levels of CoQ10 were measured by high-performance liquid chromatography with electrochemical detection10 and conducted at the Japan Institute for the Control of Aging by Nikken SEIL Co, Ltd. The person conducting the measurements was blinded to the case or control status of the participants. Sanger sequencing of all of the exons and splice sites of COQ2 was performed as previously described.2

Statistical Analysis

Continuous variables are presented as mean (SD). Fisher exact tests and t tests were used to compare the demographic features of patients with MSA and controls. Linear regression analysis was carried out to determine the correlation of the levels of CoQ10 with disease duration. The Kruskal-Wallis test was used to determine the differences in the levels of CoQ10 between subgroups classified according to gait status (ambulatory, ambulatory with assistance, or wheelchair dependent). The Mann-Whitney test was used to determine the differences in the levels of CoQ10 between patients with MSA and controls. Multiple logistic regression analysis was used to calculate the significance of the difference in levels of CoQ10 between patients with MSA and controls by using level of CoQ10, age, sex, and COQ2 genotype as independent variables. All statistical tests were 2-sided, with P < .05 considered significant. For the statistical analyses, we used GraphPad Prism, version 5.0.4 (GraphPad Software, Inc) and R, version 2.15.3 (http://www.r-project.org/).

Results

Baseline data are presented in the Table. There was no significant difference in the mean (SD) age of patients with MSA (63.7 [8.3] years) and that of controls (60.3 [13.0] years). Similarly, we found no significant difference in the sex distribution, which was reported to be associated with the plasma CoQ10 level.11 The mean (SD) duration of disease was 3.3 (2.5) years. Twenty-six patients had the cerebellar variant of MSA and 18 had the parkinsonian variant. Among the 44 patients with MSA, 26 were ambulatory; 9 required mobility aids, such as a cane or a walker; and 9 were wheelchair dependent. Three of the 44 patients with MSA (6.8%) and 3 of the 39 controls (7.7%) carried the heterozygous V393A variant in COQ2. No variants other than V393A were found in COQ2.

Linear regression analysis between the plasma level of CoQ10 and the duration of disease did not show a significant correlation (P = .23). The Kruskal-Wallis test further showed that the plasma level of CoQ10 was not associated with the gait status (ambulatory, ambulatory with assistance, or wheelchair dependent) (P = .32).

The mean (SD) plasma level of CoQ10 in patients with MSA was significantly lower than that in controls (0.51 [0.22] vs 0.72 [0.42] µg/mL; P = .01) (difference between medians: −0.14; 95% CI, –0.25 to –0.03) (Figure). The mean (SD) plasma levels of CoQ10 in patients with the cerebellar variant of MSA and those with the parkinsonian variant of MSA were 0.58 (0.19) and 0.49 (0.26) µg/mL, respectively.

Multiple logistic regression analysis with plasma level of CoQ10, age, sex, and COQ2 genotype as the independent variables revealed that only plasma CoQ10 level was significantly associated with MSA (95% CI, 0.10; range, 0.02 to 0.66) (P = .02). The plasma levels of CoQ10 in the 3 patients with MSA carrying V393A in COQ2 were 0.31, 0.31, and 0.54 µg/mL; levels in the 3 controls carrying V393A were 0.51, 0.72, and 0.89 µg/mL.

Even if the 3 patients with MSA and 3 controls carrying V393A in COQ2 were excluded, multiple logistic regression analysis revealed that only the plasma level of CoQ10 was significantly associated with MSA (95% CI, 0.14; range, 0.03 to 0.83) (P = .03). Although there was a trend that the plasma levels of CoQ10 in patients carrying V393A were lower than those not carrying V393A, the mean (SD) plasma level of CoQ10 in the 3 patients with MSA carrying V393A in COQ2 (0.39 [0.13] µg/mL) did not differ significantly compared with the mean (SD) plasma level of CoQ10 in the patients with MSA without the COQ2 mutation (0.52 [0.23] µg/mL; P = .33), presumably owing to the small sample size.

Discussion

After adjusting for age, sex, and COQ2 genotype, we found that the patients with MSA had significantly lower plasma levels of CoQ10 than the controls in this study. Lower plasma levels of CoQ10 were observed not only in the patients with MSA carrying COQ2 mutation but also in those not carrying the mutation. This finding strongly supports a notion that CoQ10 insufficiency plays a role in the pathogenesis of MSA even in the patients not carrying the COQ2 mutations, although the mechanisms underlying the decreased plasma levels of CoQ10 in those not carrying COQ2 mutations remain to be elucidated.

A recent study measuring serum levels of CoQ10 in 18 patients with MSA and 18 controls also showed that CoQ10 levels that were corrected on the basis of serum cholesterol levels (because cholesterol levels influence CoQ10 levels by creating a conjugated form in blood) were significantly lower in the patients with MSA than in controls.12 The COQ2 genotypes were not determined in this study. Moreover, a study on the levels of CoQ10 in frozen autopsied cerebellar tissues revealed significantly decreased levels of CoQ10 in the autopsy-proven MSA cases compared with levels in controls or in patients with other neurodegenerative diseases (dementia with Lewy bodies, Parkinson disease, corticobasal degeneration, and cerebellar degeneration).13 These patients with MSA reportedly did not carry mutations in COQ2.

The mechanisms underlying the decreased levels of CoQ10 in plasma or the cerebellum in patients with MSA, particularly in those without COQ2 mutations, remain to be elucidated. However, these findings indicate that CoQ10 insufficiency is likely involved in the pathogenesis of MSA.

Several limitations of the study need to be addressed. First, this was a case-control study; therefore, data should be interpreted with caution because we did not investigate the longitudinal effects of the plasma level of CoQ10 on the development of MSA. Second, plasma levels of CoQ10 do not directly reflect the mitochondrial respiratory chain activities or conditions of oxidative stress in the brain. Further in vivo studies, such as measurement of the cerebral metabolic consumption of oxygen,14 would be required to characterize mitochondrial respiratory chain activities in the brain. Third, many confounders other than age, sex, COQ2 genotype, and intake of ubiquinone, ubiquinol, idebenone, or statins remained unadjusted. For example, several confounders, including serum cholesterol, γ-glutamyltransferase, and triglyceride levels; 4-day alcohol consumption; intensity of conditioning exercise; and dietary nutrients have been reported to be determinants of plasma CoQ10 levels.11 Fourth, we are uncertain whether the low plasma levels of CoQ10 are specific to patients with MSA. In this regard, however, it was reported that the mean plasma level of CoQ10 in 64 Japanese patients with Parkinson disease was 0.75 µg/mL15 and was 0.78 µg/mL in 20 Japanese patients with amyotrophic lateral sclerosis.16 The mean serum level of CoQ10 in 65 Japanese patients with cognitive impairments was reported to be 0.63 µg/mL17 and was 0.64 µg/mL in 20 Japanese patients with Parkinson disease.12 All of these CoQ10 levels were similar to the mean (SD) plasma level of CoQ10 in the controls in our study (0.72 [0.42] µg/mL). Comparable levels of CoQ10 in controls were reported in these previous stidies.12,16 Finally, the SDs were relatively large compared with the differences between groups in this study, presumably owing to the small sample size. Larger case-control studies will be needed to confirm our findings. Since only a limited number of cases and controls carrying COQ2 variants were included in our study, inclusion of a sufficiently large number of cases and controls carrying COQ2 variants will be needed to address the correlation between plasma levels of CoQ10 and presence of COQ2 variants.

Conclusions

Our data suggest that low plasma levels of CoQ10 may play a role in the pathogenesis of MSA and may increase the risk of MSA. Prospective cohort studies are warranted to determine the longitudinal effects of plasma levels of CoQ10 on the development of MSA. Furthermore, future clinical trials of supplementation with CoQ10 in patients with MSA are required to confirm our hypothesis.

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Article Information

Accepted for Publication: March 28, 2016.

Corresponding Author: Shoji Tsuji, MD, PhD, Department of Neurology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo 113-8655, Japan (tsuji@m.u-tokyo.ac.jp).

Published Online: June 27, 2016. doi:10.1001/jamaneurol.2016.1325.

Author Contributions: Drs Mitsui and Tsuji had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Mitsui, Tsuji.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Mitsui, Matsukawa, Yasuda, Tsuji.

Critical revision of the manuscript for important intellectual content: Ishiura, Tsuji.

Statistical analysis: Mitsui, Tsuji.

Obtained funding: Tsuji.

Administrative, technical, or material support: Tsuji.

Study supervision: Tsuji.

Conflict of Interest Disclosures: None reported.

Funding/Support: This study was supported in part by KAKENHI (grant-in-aid for Scientific Research on Innovative Areas [22129001 and 22129002]) (Dr Tsuji), and a grant-in-aid for Scientific Research (C) (Dr Mitsui) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and a grant-in-aid (H26-Itaku[Nan]-Ippan-006) from the Ministry of Health, Welfare and Labour of Japan (Dr Tsuji).

Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

References
1.
Gilman  S, Wenning  GK, Low  PA,  et al.  Second consensus statement on the diagnosis of multiple system atrophy.  Neurology. 2008;71(9):670-676.PubMedGoogle ScholarCrossref
2.
Multiple-System Atrophy Research Collaboration.  Mutations in COQ2 in familial and sporadic multiple-system atrophy.  N Engl J Med. 2013;369(3):233-244.PubMedGoogle ScholarCrossref
3.
Ashby  MN, Kutsunai  SY, Ackerman  S, Tzagoloff  A, Edwards  PA.  COQ2 is a candidate for the structural gene encoding para-hydroxybenzoate.  J Biol Chem. 1992;267(6):4128-4136.PubMedGoogle Scholar
4.
Littarru  GP, Tiano  L.  Bioenergetic and antioxidant properties of coenzyme Q10: recent developments.  Mol Biotechnol. 2007;37(1):31-37.PubMedGoogle ScholarCrossref
5.
Jeon  BS, Farrer  MJ, Bortnick  SF; Korean Canadian Alliance on Parkinson’s Disease and Related Disorders.  Mutant COQ2 in multiple-system atrophy.  N Engl J Med. 2014;371(1):80.PubMedGoogle ScholarCrossref
6.
Chen  YP, Zhao  B, Cao  B,  et al.  Mutation scanning of the COQ2 gene in ethnic Chinese patients with multiple-system atrophy.  Neurobiol Aging. 2015;36(2):1222.e7-1222.e11.PubMedGoogle ScholarCrossref
7.
Lin  CH, Tan  EK, Yang  CC, Yi  Z, Wu  RM.  COQ2 gene variants associate with cerebellar subtype of multiple system atrophy in Chinese.  Mov Disord. 2015;30(3):436-437.PubMedGoogle ScholarCrossref
8.
Wen  XD, Li  HF, Wang  HX, Ni  W, Dong  Y, Wu  ZY.  Mutation analysis of COQ2 in Chinese patients with cerebellar subtype of multiple system atrophy.  CNS Neurosci Ther. 2015;21(8):626-630.PubMedGoogle ScholarCrossref
9.
Zhao  Q, Yang  X, Tian  S, An  R, Zheng  J, Xu  Y.  Association of the COQ2 V393A variant with risk of multiple system atrophy in East Asians.  Neurol Sci. 2016;37(3):423-430.PubMedGoogle ScholarCrossref
10.
Yamashita  S, Yamamoto  Y.  Simultaneous detection of ubiquinol and ubiquinone in human plasma as a marker of oxidative stress.  Anal Biochem. 1997;250(1):66-73.PubMedGoogle ScholarCrossref
11.
Kaikkonen  J, Nyyssönen  K, Tuomainen  TP, Ristonmaa  U, Salonen  JT.  Determinants of plasma coenzyme Q10 in humans.  FEBS Lett. 1999;443(2):163-166.PubMedGoogle ScholarCrossref
12.
Kasai  T, Tokuda  T, Ohmichi  T,  et al.  Serum levels of coenzyme Q10 in patients with multiple system atrophy.  PLoS One. 2016;11(1):e0147574.PubMedGoogle ScholarCrossref
13.
Schottlaender  LV, Bettencourt  C, Kiely  AP,  et al.  Coenzyme Q10 levels are decreased in the cerebellum of multiple-system atrophy patients.  PLoS One. 2016;11(2):e0149557.PubMedGoogle ScholarCrossref
14.
Frackowiak  RS, Lenzi  GL, Jones  T, Heather  JD.  Quantitative measurement of regional cerebral blood flow and oxygen metabolism in man using 15O and positron emission tomography.  J Comput Assist Tomogr. 1980;4(6):727-736.PubMedGoogle ScholarCrossref
15.
Yoritaka  A, Kawajiri  S, Yamamoto  Y,  et al.  Randomized, double-blind, placebo-controlled pilot trial of reduced coenzyme Q10 for Parkinson’s disease.  Parkinsonism Relat Disord. 2015;21(8):911-916.PubMedGoogle ScholarCrossref
16.
Sohmiya  M, Tanaka  M, Suzuki  Y, Tanino  Y, Okamoto  K, Yamamoto  Y.  An increase of oxidized coenzyme Q-10 occurs in the plasma of sporadic ALS patients.  J Neurol Sci. 2005;228(1):49-53.PubMedGoogle ScholarCrossref
17.
Yamagishi  K, Ikeda  A, Moriyama  Y,  et al; CIRCS Investigators.  Serum coenzyme Q10 and risk of disabling dementia.  Atherosclerosis. 2014;237(2):400-403.PubMedGoogle ScholarCrossref
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