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Assessing the association between white matter lesions and Parkinson’s disease

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Abstract

Background

The association between white matter (WM) lesions and Parkinson’s disease (PD) was not fully established. We therefore applied Mendelian randomization (MR) analyses to identify the causal effect between white matter lesions and PD.

Methods

We performed a bidirectional two-sample Mendelian randomization (MR) study to investigate the association between three WM phenotypes—white matter hyperintensities (WMH, N = 18,381), fractional anisotropy (FA, N = 17,673), and mean diffusivity (MD, N = 17,467)—with PD (N = 482,730) using summary statistics from genome-wide association studies (GWAS). The inverse variance weighted (IVW), weighted median, MR-Egger, and MR-PRESSO methods were used to evaluate the causal estimate.

Results

Significant evidence was suggested that higher MD was associated with a higher PD risk (OR = 1.049, 95% CI = 1.018–1.081, p = 0.022) when the outlier was removed using MR-PRESSO method. Moreover, genetically predicted PD was associated with a lower WMH load (IVW β = − 0.047, 95% CI = − 0.085 to − 0.009, p = 0.016) and a higher FA (β = 0.185, 95% CI = 0.021–0.349, p = 0.027). No evidence of pleiotropy was found using MR-Egger intercept.

Conclusion

Our findings provided genetic support that white matter microstructural integrity lesions might increase the risk of PD. However, genetically predicted PD was potentially associated with a lower load of white matter lesions.

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Data availability

Data of the present study are publicly available and may also be available from the corresponding author upon request.

References

  1. Postuma RB, Berg D, Stern M, Poewe W, Olanow CW, Oertel W, Obeso J, Marek K, Litvan I, Lang AE, Halliday G, Goetz CG, Gasser T, Dubois B, Chan P, Bloem BR, Adler CH, Deuschl G (2015) MDS clinical diagnostic criteria for Parkinson’s disease. Mov Disord 30(12):1591–1601

    Article  PubMed  Google Scholar 

  2. de Lau LM, Breteler MM (2006) Epidemiology of Parkinson’s disease. Lancet Neurol 5(6):525–535

    Article  PubMed  Google Scholar 

  3. Wirdefeldt K, Adami HO, Cole P, Trichopoulos D, Mandel J (2011) Epidemiology and etiology of Parkinson’s disease: a review of the evidence. Eur J Epidemiol 26(Suppl 1):S1-58

    Article  PubMed  Google Scholar 

  4. Wardlaw JM, Smith C, Dichgans M (2019) Small vessel disease: mechanisms and clinical implications. Lancet Neurol 18(7):684–696

    Article  PubMed  Google Scholar 

  5. Pozorski V, Oh JM, Okonkwo O, Krislov S, Barzgari A, Theisen F, Sojkova J, Bendlin BB, Johnson SC, Gallagher CL (2019) Cross-sectional and longitudinal associations between total and regional white matter hyperintensity volume and cognitive and motor function in Parkinson’s disease. Neuroimage Clin 23:101870

    Article  PubMed  PubMed Central  Google Scholar 

  6. Linortner P, McDaniel C, Shahid M, Levine TF, Tian L, Cholerton B, Poston KL (2020) White matter hyperintensities related to Parkinson’s disease executive function. Mov Disord Clin Pract 7(6):629–638

    Article  PubMed  PubMed Central  Google Scholar 

  7. Chiang PL, Chen HL, Lu CH, Chen PC, Chen MH, Yang IH, Tsai NW, Lin WC (2017) White matter damage and systemic inflammation in Parkinson’s disease. BMC Neurosci 18(1):48

    Article  PubMed  PubMed Central  Google Scholar 

  8. Gallagher C, Bell B, Bendlin B, Palotti M, Okonkwo O, Sodhi A, Wong R, Buyan-Dent L, Johnson S, Willette A, Harding S, Ninman N, Kastman E, Alexander A (2013) White matter microstructural integrity and executive function in Parkinson’s disease. J Int Neuropsychol Soc 19(3):349–354

    Article  PubMed  PubMed Central  Google Scholar 

  9. Piccini P, Pavese N, Canapicchi R, Paoli C, Del Dotto P, Puglioli M, Rossi G, Bonuccelli U (1995) White matter hyperintensities in Parkinson’s disease. Clinical correlations Arch Neurol 52(2):191–194

    Article  CAS  PubMed  Google Scholar 

  10. Fukui T, Sato Y, Ichikawa H, Takeuchi T, Sugita K, Tsukagoshi H (1995) Evaluation of influential factors of cognitive impairments in idiopathic Parkinson’s disease. Eur Neurol 35(2):86–92

    Article  CAS  PubMed  Google Scholar 

  11. Beyer MK, Aarsland D, Greve OJ, Larsen JP (2006) Visual rating of white matter hyperintensities in Parkinson’s disease. Mov Disord 21(2):223–229

    Article  PubMed  Google Scholar 

  12. Burton EJ, McKeith IG, Burn DJ, Firbank MJ, O’Brien JT (2006) Progression of white matter hyperintensities in Alzheimer disease, dementia with Lewy bodies, and Parkinson disease dementia: a comparison with normal aging. Am J Geriatr Psychiatry 14(10):842–849

    Article  PubMed  Google Scholar 

  13. de Schipper LJ, Hafkemeijer A, Bouts M, van der Grond J, Marinus J, Henselmans JML, van Hilten JJ (2019) Age- and disease-related cerebral white matter changes in patients with Parkinson’s disease. Neurobiol Aging 80:203–209

    Article  PubMed  Google Scholar 

  14. Walker VM, Davey Smith G, Davies NM, Martin RM (2017) Mendelian randomization: a novel approach for the prediction of adverse drug events and drug repurposing opportunities. Int J Epidemiol 46(6):2078–2089

    Article  PubMed  PubMed Central  Google Scholar 

  15. Davies NM, Holmes MV, Davey Smith G (2018) Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians. BMJ 362:k601

    Article  PubMed  PubMed Central  Google Scholar 

  16. Persyn E, Hanscombe KB, Howson JMM, Lewis CM, Traylor M, Markus HS (2020) Genome-wide association study of MRI markers of cerebral small vessel disease in 42,310 participants. Nat Commun 11(1):2175

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Nalls MA, Blauwendraat C, Vallerga CL, Heilbron K, Bandres-Ciga S, Chang D, Tan M, Kia DA, Noyce AJ, Xue A, Bras J, Young E, von Coelln R, Simón-Sánchez J, Schulte C, Sharma M, Krohn L, Pihlstrøm L, Siitonen A, Iwaki H, Leonard H, Faghri F, Gibbs JR, Hernandez DG, Scholz SW, Botia JA, Martinez M, Corvol JC, Lesage S, Jankovic J, Shulman LM, Sutherland M, Tienari P, Majamaa K, Toft M, Andreassen OA, Bangale T, Brice A, Yang J, Gan-Or Z, Gasser T, Heutink P, Shulman JM, Wood NW, Hinds DA, Hardy JA, Morris HR, Gratten J, Visscher PM, Graham RR, Singleton AB (2019) Identification of novel risk loci, causal insights, and heritable risk for Parkinson’s disease: a meta-analysis of genome-wide association studies. Lancet Neurol 18(12):1091–1102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Shim H, Chasman DI, Smith JD, Mora S, Ridker PM, Nickerson DA, Krauss RM, Stephens M (2015) A multivariate genome-wide association analysis of 10 LDL subfractions, and their response to statin treatment, in 1868 Caucasians. PLoS ONE 10(4):e0120758

    Article  PubMed  PubMed Central  Google Scholar 

  19. Chen L, Yang H, Li H, He C, Yang L, Lv G (2022) Insights into modifiable risk factors of cholelithiasis: a Mendelian randomization study. Hepatology 75(4):785–796

    Article  CAS  PubMed  Google Scholar 

  20. Burgess S, Butterworth A, Thompson SG (2013) Mendelian randomization analysis with multiple genetic variants using summarized data. Genet Epidemiol 37(7):658–665

    Article  PubMed  PubMed Central  Google Scholar 

  21. Bowden J, Davey Smith G, Burgess S (2015) Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int J Epidemiol 44(2):512–525

    Article  PubMed  PubMed Central  Google Scholar 

  22. Bowden J, Davey Smith G, Haycock PC, Burgess S (2016) Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator. Genet Epidemiol 40(4):304–314

    Article  PubMed  PubMed Central  Google Scholar 

  23. Verbanck M, Chen CY, Neale B, Do R (2018) Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet 50(5):693–698

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Burgess S, Thompson SG (2017) Interpreting findings from Mendelian randomization using the MR-Egger method. Eur J Epidemiol 32(5):377–389

    Article  PubMed  PubMed Central  Google Scholar 

  25. Kim HJ, Kim SJ, Kim HS, Choi CG, Kim N, Han S, Jang EH, Chung SJ, Lee CS (2013) Alterations of mean diffusivity in brain white matter and deep gray matter in Parkinson’s disease. Neurosci Lett 550:64–68

    Article  CAS  PubMed  Google Scholar 

  26. Muñoz Maniega S, Chappell FM, Valdés Hernández MC, Armitage PA, Makin SD, Heye AK, Thrippleton MJ, Sakka E, Shuler K, Dennis MS, Wardlaw JM (2017) Integrity of normal-appearing white matter: Influence of age, visible lesion burden and hypertension in patients with small-vessel disease. J Cereb Blood Flow Metab 3(2):644–656

    Article  Google Scholar 

  27. Song SK, Sun SW, Ju WK, Lin SJ, Cross AH, Neufeld AH (2003) Diffusion tensor imaging detects and differentiates axon and myelin degeneration in mouse optic nerve after retinal ischemia. Neuroimage 20(3):1714–1722

    Article  PubMed  Google Scholar 

  28. Zhao Z, Nelson AR, Betsholtz C, Zlokovic BV (2015) Establishment and Dysfunction of the Blood-Brain Barrier. Cell 163(5):1064–1078

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Nelson AR, Sweeney MD, Sagare AP (1862) Zlokovic BV (2016) Neurovascular dysfunction and neurodegeneration in dementia and Alzheimer’s disease. Biochim Biophys Acta 5:887–900

    Google Scholar 

  30. Al-Bachari S, Naish JH, Parker GJM, Emsley HCA, Parkes LM (2020) Blood-brain barrier leakage is increased in Parkinson’s disease. Front Physiol 11:593026

    Article  PubMed  PubMed Central  Google Scholar 

  31. Song IU, Lee JE, Kwon DY, Park JH, Ma HI (2017) Parkinson’s disease might increase the risk of cerebral ischemic lesions. Int J Med Sci 14(4):319–322

    Article  PubMed  PubMed Central  Google Scholar 

  32. Butt A, Kamtchum-Tatuene J, Khan K, Shuaib A, Jickling GC, Miyasaki JM, Smith EE, Camicioli R (2021) White matter hyperintensities in patients with Parkinson’s disease: a systematic review and meta-analysis. J Neurol Sci 426:117481

    Article  PubMed  Google Scholar 

  33. Jacobsson SO, Fowler CJ (1999) Dopamine and glutamate neurotoxicity in cultured chick telencephali cells: effects of NMDA antagonists, antioxidants and MAO inhibitors. Neurochem Int 34(1):49–62

    Article  CAS  PubMed  Google Scholar 

  34. Korten A, Lodder J, Vreeling F, Boreas A, van Raak L, Kessels F (2001) Stroke and idiopathic Parkinson’s disease: does a shortage of dopamine offer protection against stroke? Mov Disord 16(1):119–123

    Article  CAS  PubMed  Google Scholar 

  35. Busto R, Harik SI, Yoshida S, Scheinberg P, Ginsberg MD (1985) Cerebral norepinephrine depletion enhances recovery after brain ischemia. Ann Neurol 18(3):329–336

    Article  CAS  PubMed  Google Scholar 

  36. Espay AJ, LeWitt PA, Kaufmann H (2014) Norepinephrine deficiency in Parkinson’s disease: the case for noradrenergic enhancement. Mov Disord 29(14):1710–1719

    Article  CAS  PubMed  Google Scholar 

  37. Burgess S, Davies NM, Thompson SG (2016) Bias due to participant overlap in two-sample Mendelian randomization. Genet Epidemiol 40(7):597–608

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank all the Hugh Markus group and International Parkinson’s Disease Genomics Consortium for making the summary data publicly available, and we are grateful for all the investigators and participants who contributed to those studies.

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Authors and Affiliations

  1. Medical School of Chinese PLA, Beijing, China

    Yahui Zhu, Zhengqing He, Wenxiu Yu & Xusheng Huang

  2. Department of Neurology, the First Medical Center, Chinese PLA General Hospital, Beijing, China

    Yahui Zhu, Rongrong Du, Zhengqing He, Xinyuan Pang, Wenxiu Yu & Xusheng Huang

  3. College of Medicine, Nankai University, Tianjin, China

    Rongrong Du & Xinyuan Pang

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  1. Yahui Zhu
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Contributions

Conceptualization: Xusheng Huang; methodology: Yahui Zhu, Rongrong Du, Zhengqing He; formal analysis and investigation: Yahui Zhu, Rongrong Du, Zhengqing He, Xinyuan Pang, Wenxiu Yu; writing — original draft preparation: Yahui Zhu; writing — review and editing: Xusheng Huang; resources: Yahui Zhu; supervision: Xusheng Huang.

Corresponding author

Correspondence to Xusheng Huang.

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Ethical approval

In the original GWAS, studies on WM MRI markers and PD were approved by the institutional review board and informed consent was obtained from all the patients. In this study, we only used summary data and no additional participant ethical consent was required.

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The authors declare no competing interests.

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Zhu, Y., Du, R., He, Z. et al. Assessing the association between white matter lesions and Parkinson’s disease. Neurol Sci 44, 897–903 (2023). https://doi.org/10.1007/s10072-022-06494-x

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