Effect of Metabolic Syndrome on Parkinson's Disease: A Systematic Review

Souza, Ana Patrícia da Silva; Barros, Waleska Maria Almeida; Silva, José Maurício Lucas; Silva, Mariluce Rodrigues Marques; Silva, Ana Beatriz Januário; Fernandes, Matheus Santos de Sousa; Santos, Maria Eduarda Rodrigues Alves dos; Silva, Mayara Luclécia da; Carmo, Taciane Silva do; Silva, Roberta Karlize Pereira; Silva, Karollainy Gomes da; Souza, Sandra Lopes de; Souza, Viviane de Oliveira Nogueira

doi:10.6061/clinics/2021/e3379

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REVIEW ARTICLE • Clinics 76 • 2021 • https://doi.org/10.6061/clinics/2021/e3379 copy

Effect of Metabolic Syndrome on Parkinson's Disease: A Systematic Review

Authorship SCIMAGO INSTITUTIONS RANKINGS

Evidence shows that metabolic syndrome (MS) is associated with a greater risk of developing Parkinson's disease (PD) because of the increase in oxidative stress levels along with other factors such as neuroinflammation and mitochondrial dysfunction. However, because some studies have reported that MS is associated with a lower risk of PD, the relationship between MS and PD should be investigated. This study aimed to investigate the effect of MS on PD. Two authors searched five electronic databases, namely, MEDLINE, PubMed, Scopus, PsycINFO, Web of Science, and Science Direct, for relevant articles between September and October 2020. After screening the title and abstract of all articles, 34 articles were selected for full-text review. Finally, 11 articles meeting the eligibility criteria were included in the study. The quality of articles was critically evaluated using the Joanna Briggs Institute. Overall, we evaluated data from 23,586,349 individuals (including healthy individuals, with MS and PD) aged 30 years or more. In cohort studies, the follow-up period varied between 2 and 30 years. MS contributed considerably to the increase in the incidence of PD. In addition, obesity, a component of MS, alone can increase the probability of developing neurodegenerative diseases. However, despite few studies on MS and PD, changes in cognitive function and more rapid progression of PD disease has been documented in patients with MS using methods commonly used in research.

Metabolic Syndrome; Parkinson Disease; Vascular Risk Factors

Study, year, Country, Study design	Sample (number, sex, age or mean age)	Objective	Methods	Data collection instruments	Diagnosis of MS and related component	Results: biochemical parameters	Results: anthropometric variables	Main Results
Roh et al. (⁷7. Roh JH, Lee S, Yoon JH. Metabolic Syndrome and Parkinson’s Disease Incidence: A Nationwide Study Using Propensity Score Matching. Metab Syndr Relat Disord. 2021;19(1):1-7. https://doi.org/10.1089/met.2020.0060 https://doi.org/10.1089/met.2020.0060... ) South Korea Cohort study	N= 314.737 56.1% M 85,530 individuals with MS and 85,530 individuals without MS ↑ 40 years old	To investigate the effect of MS on the incidence of PD	Analysis of data from the National health service database. (NHIS-HealS) (2002-2015)	Secondary data	Joint Interim Statement (JIS)	↓ HDL ↑ PD incidence ↓ Correlation between HDL and PD risk observed in men ↑ TG associated with the incidence of PD in individuals in general ↑ Fasting glucose associated with ↑ PD incidence in individuals in general	↑ WC was not associated with the incidence of PD in individuals in general.	Average follow-up period: 7.23 years 819 (0.48%) individuals developed PD ↑ Incidence among individuals with MS ↑ Hypertensive 1.34 incidence of PD in both sexes ↑ Incidence of PD increased with the number of components of MS
Thaler et al. (¹⁸18. Thaler A, Shenhar-Tsarfaty S, Shaked Y, Gurevich T, Omer N, Bar-Shira A, et al. Metabolic syndrome does not influence the phenotype of LRRK2 and GBA related Parkinson’s disease. Sci Rep. 2020;10(1):9329. https://doi.org/10.1038/s41598-020-66319-9 https://doi.org/10.1038/s41598-020-66319... ) Israel Cross-sectional study	N=562 M and F 104 individuals with idiopathic PD, 40 individuals with LRRK2 -PD, 70 individuals with GBA-PD, 196 healthy carriers, 55 individuals with LRRK2 -PNM and 97 individuals with GBA -PNM	To evaluate the effect of MS on the phenotype of LRRK2 and PD GBA and on the prevalence of prodromal characteristics among individuals at risk for PD	Genetic tests for the G2019S mutation in the LRRK2 gene and for the AJ GBA mutations; laboratory tests; Information; cognitive, motor, olfactory and affective functions.	MDS-UPDRS; MoCA, BDI; NMSQ; SCOPA-AUT; RBDO; UPSIT. Demographic data; PAN; Blood analysis of HbA1c, TG and HDL levels.	Change in 3 of the 5 components: fasting glucose levels, BP, BMI, HDL, and TG.	LRRK2 -PD ↑ TG levels and pre-diabetes rates. LRRK2 -PNM TG levels PNM with probability rates for prodromal PD. ↑ 50% had frequencies of hypertriglyceridemia and pre-diabetes. Pre-diabetes associated with age and UPDRS-III scores accounting for 38.8% of the variance. The probability ratio for conversion to PD in 10 (3%) individuals was >80% (non-carriers: 4 individuals, GBA-PNM: 3 individuals, and LRRK2-NMC: 3 individuals).		Groups with PD and PNM did not differ in the number of metabolic components 70 PD patients (32.7%) with MS. This group was older and had a longer diagnosis time. 94 (27.2%) PNM with MS. Hypertension was associated with age and sex M was responsible for 35.7% of the variance. Individuals with MS did not have a high risk of developing PD.
van den Heuvel et al. (²²22. van den Heuvel LL, du Plessis S, Stalder T, Acker D, Kirschbaum C, Carr J, et al. Hair glucocorticoid levels in Parkinson’s disease. Psychoneuroendocrinology. 2020;117:104704. https://doi.org/10.1016/j.psyneuen.2020.104704 https://doi.org/10.1016/j.psyneuen.2020.... ) South Africa />Case-control study	56 F (25 pcts F with PD and 31 controls) aged 45 to 78 years	To examine the association of PD diagnosis, clinical characteristics, and risk of PD-CVD (as defined by the MS) with the levels of GC (cortisol and cortisone) in hair.	Analysis of hair samples, representing a 3-month retrospective window of GC levels using tandem mass chromatography liquid chromatography.	Glycemia, TG, HDL, HbA1c; LDL, total blood cholesterol. Sociodemographic data, MINI, UPDRS, H&I, NMSS; PSS-10; WHO STEPS; GPAQ.	Joint Interim Statement(JIS)	↑ Capillary cortisone in PD patients than in controls. Levels of cortisone in hair in unadjusted analysis were associated with the number of criteria for MS, use of antihypertensive medication, WHR, known CVD and use of aspirin, and a tendency to demonstrate significance for HDL-C.		Prevalence of MS in Pcts with PD was 56.0% and that in control individuals was 25.8%. Non-motor symptoms of PD (mood anhedonia and anxiety) were associated with capillary cortisone levels. No significant interactions were found between PD and MS based on the GC levels in hair.
Yoo et al. (¹⁵15. Yoo D, Kim R, Jung YJ, Han K, Shin CM, Lee JY. Serum gamma-glutamyltransferase activity and Parkinson’s disease risk in men and women. Sci Rep. 2020;10(1):1258. https://doi.org/10.1038/s41598-020-58306-x https://doi.org/10.1038/s41598-020-58306... ) South Korea Cohort study	N=6,098,405 F and M >40 years old	To assess the association between the serum GGT level and PD risk. Analyze the possible interaction between the GGT level and obesity or MS	National Health Insurance Service (NHIS) database	Secondary data	Change in 3 of the 5 components or use of antihypertensive, hypoglycemic, or hypolipemic medication.	-	Factors associated with the serum GGT level were age, low income, BMI, current smoking, light to moderate alcohol consumption, exercise, DM, hypertension, dyslipidemia, chronic kidney disease, and MS	Average follow-up period was 6.4 years. DP developed in 20,895 (0.34%) individuals (M: 9,512 and F: 11,383) ↓ PD incidence was low in ↑ M, whereas ↑ high in F according to GGT activity ↑ Obesity and MS are the risk factors for PD in both sexes. A sub additive interaction was found between the serum GGT level and obesity in women.
Nam et al. (⁶6. Nam GE, Kim SM, Han K, Kim NH, Chung HS, Kim JW, et al. Metabolic syndrome and risk of Parkinson disease: A nationwide cohort study. PLoS Med. 2018;15(8):e1002640. https://doi.org/10.1371/journal.pmed.1002640 https://doi.org/10.1371/journal.pmed.100... ) South Korea Cohort study	N=17,163,560 age ≥40 years Individuals with MS: 58.1 years Individuals without MS: 51.9 years	To investigate the association of MS and its components with the development of PD in the South Korean population using large cohort data.	Analysis of NHIS data from January 1, 2009, to December 31, 2012 and follow-up of pcts up to 31 December 2015.	Secondary data	National Cholesterol Education Program Adult Treatment Panel III.	Pcts with 3 MS components at ↑ 31% PD risk, and those with all 5 components at ↑ 66% risk compared with those without any component	MS group had higher mean BMI, WC, BP, glucose level, serum total cholesterol level, TG level, and LDL-C level. Individuals with abdominal obesity or hypertriglyceridemia had approximately 13% PD risk.	Average follow-up period was 5.3 years. 44,205 incident cases of PD. ↑ Individuals with MS (n=5,848,508) had a higher risk of PD than individuals without MS (n=11,315,052). Each component of MS was positively associated with the risk of PD. Positive correlation was found between the incidence of PD and the number of components of MS.
Peng et al. (¹⁶16. Peng Z, Dong S, Tao Y, Huo Y, Zhou Z, Huang W, et al. Metabolic syndrome contributes to cognitive impairment in patients with Parkinson’s disease. Parkinsonism Relat Disord. 2018;55:68-74. https://doi.org/10.1016/j.parkreldis.2018.05.013 https://doi.org/10.1016/j.parkreldis.201... ) China Cohort study	N=787 60 years. Individuals with PD divided into three groups: PD-CN, PD-CCL and PDD. 249 individuals with PD and MS at the beginning of the study divided into 3 subgroups according to the treatment of each component of MS: untreated pcts, pcts who received treatment for some components, and pcts who received treatments for all components.	To investigate the effect of MS on cognitive impairment in PD.	Physical and neurological examinations, blood analysis and neuroimaging. MS incidence assessed based on medical records or doctors' assessment. Annual monitoring for 5 years.	UPDRS, MMSE, RAVLT, Doppler ultrasonography, computed tomography angiography, magnetic resonance imaging	National Cholesterol Education Program's Adult Treatment Panel III.	↑ Individuals with PD-CCL and those with PDD had high levels of hypertension, glucose, and ↑ hypertriglyceridemia than individuals with PD-CN. Associations between BP, glucose, TG, and PDD. BP and glucose levels were associated with the main cognitive domains; TG level was associated with executive function, language, memory, and visuospatial function; HDL-C level was associated with memory and visuospatial functions.	Individuals with PD-CCL and those with PDD were significantly older and had higher BMI, UPDRS 3 scores, H&Y stage, systolic and diastolic BP, glucose level, total cholesterol level, and TG level as well as longer duration of PD. Still had lower education level (<6 years), lacunar infarction, white matter lesions, and MS than those with PD-CN	At 5 years, 255 (32.4%) individuals were diagnosed with PD-CCL and 105 (13.3%) individuals were diagnosed with PDD. MS was associated with PD-CCL. MS was associated with the main cognitive domains in Pcts with PDD. Incidence of PD-CCL and PDD was higher in individuals with MS than in those without MS Pcts treated for some or all of the major components of MS had a ↓ lower risk of PDD than patients with untreated MS.
Oxenkrug et al. (¹⁹19. Oxenkrug G, van der Hart M, Roeser J, Summergrad P. Peripheral Tryptophan - Kynurenine Metabolism Associated with Metabolic Syndrome is Different in Parkinson’s and Alzheimer’s Diseases. Endocrinol Diabetes Metab J. 2017;1(4):http://researchopenworld.com/wp-content/uploads/2017/11/EDMJ-2017-113-Gregory-F-Oxenkrug-USA.pdf http://researchopenworld.com/wp-content/... ) United States of America (USA) Cross-sectional study	7 F pcts with PD and 11 M pcts with PD (age range: 50 to 74 years). 12 F pcts with probable AD and 8 M pcts with probable AD (age range: 60 to 75 years). 24 healthy individuals matched for age and gender (12 F and 12 M).	To compare peripheral quinurenines in AD and PD with an emphasis on quinurenines associated with MS (i.e., KYNA, ANA, 3-HK, and XA)	Analysis of blood samples collected after overnight fasting.	Analysis of Trp, Kyn, ANA, KYNA, and 3-HK using high performance liquid chromatography coupled with mass spectrometry, MMSE		N/S differences in plasma concentrations of Trp, Kyn, and all Kyn metabolites were found in untreated patients and patients treated with L-DOPA.		In Pcts with PD, ↓ Trp concentrations and the reason Kyn: Trp, Kyn, ANA and KYNA ↑ than in the control. Concentrations of 3-HK in Pcts with PD were below the sensitivity limit of the method. In Pcts with AD, the serum ANA concentrations were approximately ↑ 3 times higher and KYNA concentrations were approximately ↓ 40% more than those in control individuals.
Leehey et al. (²⁰20. Leehey M, Luo S, Sharma S, Wills AA, Bainbridge JL, Wong PS, et al. Association of metabolic syndrome and change in Unified Parkinson’s Disease Rating Scale scores. Neurology. 2017;89(17):1789-94. https://doi.org/10.1212/WNL.0000000000004572 https://doi.org/10.1212/WNL.000000000000... ) USA Cross-sectional study	N=1022 M and F 2 groups: Individual with MS (N=396, mean age 63.9 years) over the 3 years of the study and individuals without evidence of MS (N=626, mean age 59.9 years) over the 3 years.	To compare the progression of PD between individuals with MS during the first 3 years of the trial and individuals with no evidence of MS.	Secondary analysis of patient data from the NET-DP LS study 1. The changes in the UPDRS and SDMT scores from randomization to 3 years were compared.	UPDRS, SDMT	National Cholesterol Education Program Adult Treatment Panel III (modified).	-	-	Pcts with older MS: propensity to be of the sex M (75.3% versus 57.0%), and ↑ an average level of uric acid. In Pcts with MS there was an ↑ additional 0.6- (0.2) units per year in the total UPDRS and ↑ 0.5- (0.2) units in the motor UPDRS scores compared with participants without MS. N/S changes in SDMT scores.
Doiron et al. (¹⁷17. Doiron M, Langlois M, Dupré N, Simard M. The influence of vascular risk factors on cognitive function in early Parkinson’s disease. Int J Geriatr Psychiatry. 2018;33(2):288-97. https://doi.org/10.1002/gps.4735 https://doi.org/10.1002/gps.4735... ) Canada Cohort study	367 pcts (≥50 years old) with PD at baseline and 310 pcts at 24-month follow-up.	To investigate hypertension, dyslipidemia, DM, and BMI as possible risk factors for cognitive impairment in a large cohort of untreated patients with PD and without dementia.	Clinical and neurological examinations, biological sampling, neuropsychological assessments, and neuroimaging. Participants reassessed approximately after 24 months.	UPDRS, GDS, Girl, LNS, SDMT, HVLT-R, BJLO, total blood cholesterol, LDL, HDL, and TG.	Hypertension, DM, Obesity	HDL was correlated with BJLO performance at baseline	BMI was associated only with the verbal fluency Z score at 24 months.	Hypertension was the most prevalent comorbidity in 35.4% of the individuals at baseline and 41.1% of the individuals at follow-up. Time of hypertension and pulse pressure were associated with worse cognitive outcomes. Longer history of hypertension and ↑ higher pulse pressure were associated with impaired verbal episodic memory and semantic verbal fluency. Other vascular risk factors were not associated with cognitive outcomes.
Laudisio et al. (²¹21. Laudisio A, Lo Monaco MR, Vetrano DL, Pisciotta MS, Bentivoglio AR, Bernabei R, et al. Association of metabolic syndrome with falls in patients with Parkinson’s disease. Clin Nutr. 2017;36(2):559-63. https://doi.org/10.1016/j.clnu.2016.02.004 https://doi.org/10.1016/j.clnu.2016.02.0... ) Italy Cross-sectional study	N=194 Elderly individuals with PD (IM 73 years old) treated at a geriatric hospital at the Catholic University of Rome.	To evaluate the association between MS and occurrence of falls in patients with PD.	Recorded the history and number of falls in the last year.	ADL; IADLs; GDS; MMSE, UPDRS, MNA, dual energy X-rays Absorptiometry, Portable dynamometer, Tinetti, 24-h BP recording.	National Cholesterol Education Program Adult Treatment Panel III.	N/S associations were noted between the occurrence of falls and any of the components of SM.	-	91 (47%) participants reported falls. MS was diagnosed in 44 (23%) participants. Severity of PD according to the UPDRS did not differ significantly according to the diagnosis of MS. SM was associated with less falls.
Sääksjärvi et al. (⁹9. Sääksjärvi K, Knekt P, Männistö S, Lyytinen J, Heliövaara M. Prospective study on the components of metabolic syndrome and the incidence of Parkinson’s disease. Parkinsonism Relat Disord. 2015;21(10):1148-55. https://doi.org/10.1016/j.parkreldis.2015.07.017 https://doi.org/10.1016/j.parkreldis.201... ) Finland Cohort study	6641 aged 30-79 years and without PD at baseline (1978-1980)	To investigate whether MS or its components, or serum total cholesterol, can predict the incidence of PD in a prospective cohort.	Based on the Mini-Finland Health Survey conducted from 1978 to 1980. Anthropometric, biochemical blood analyses were performed.	HDL, TG, Glycemia, and total cholesterol in the blood. 25-hydroxy vit D serum by radioimmunoassay	Harmonized definition of the metabolic syndrome	↑ Serum TG and fasting plasma glucose predicted ↓ risk of PD, even after excluding the first 10 years of follow-up. PA, HDL, or total cholesterol do not predict PD risk.	↑ Risk suggestive of PD observed in overweight individuals	During 30-year follow-up (1978-2007), 89 incident cases of PD were recorded. MS predicted the risk of PD up to 50%.

Studies	Q1	Q2	Q3	Q4	Q5	Q6	Q7	Q8	Q9	Q10	Q11
(7)	Y	Y	Y	Y	Y	Y	Y	Y	U	U	Y
(15)	Y	Y	Y	Y	Y	Y	Y	Y	U	U	Y
(6)	Y	Y	Y	Y	Y	Y	Y	Y	U	U	Y
(16)	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y
(17)	Y	Y	Y	Y	Y	Y	Y	Y	Y	U	Y
(9)	Y	Y	Y	Y	U	Y	Y	Y	Y	Y	Y

Studies	Q1	Q2	Q3	Q4	Q5	Q6	Q7	Q8
(18)	Y	Y	Y	Y	Y	Y	Y	Y
(19)	U	U	Y	Y	U	U	U	U
(20)	Y	Y	Y	Y	Y	Y	Y	Y
(21)	Y	Y	Y	Y	Y	Y	Y	Y

Studies	Q1	Q2	Q3	Q4	Q5	Q6	Q7	Q8	Q9	Q10
(22)	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y

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[1] *Corresponding author. E-mail: patricia-asb@hotmail.com