Skip to main content
SpringerLink
Log in

Genetic Factors Influencing the Development and Treatment of Cognitive Impairment and Psychosis in Parkinson’s Disease

  • Chapter
  • First Online:
Book cover Psychiatry and Neuroscience Update

  • 1052 Accesses

Abstract

Parkinson’s disease (PD) is a neurodegenerative disease in which both genetic and environmental factors play significant roles. In addition to increasing the risk of developing PD, gene mutations might also influence the phenotypical characteristics of the disease, including the development of cognitive impairment and psychosis. For instance, mutations of the GBA gene, which encodes the enzyme γ-glucocerebrosidase, have been related to cognitive impairment or dementia and visual hallucinations. Interest in the APOE gene, which encodes the apolipoprotein E, stems from the finding of increased Alzheimer’s disease risk in carriers of APOE ε4 alleles. In a cohort of 390 PD patients, APOE ε4 allele carriers showed significantly increased cognitive decline during the 2-year follow-up period. Mutations of the LRRK2 gene, which encodes the leucine-rich repeat kinase 2, have been related to a lower risk of cognitive impairment and dementia and lower scores for apathy and hallucinations. PD patients with mutations in the BDNF, COMT, PARP4, and MTCL1 genes showed increased risk of cognitive impairment, dementia, and visual hallucinations, but these results have not been replicated yet. Hallucinations have also been related to mutations in the cholecystokinin CCK gene. These findings suggest that gene mutations may be important determinants of cognitive impairment and psychosis in PD and highlight promising targets for new therapeutic approaches.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Pringsheim T, Jette N, Frolkis A, et al. The prevalence of Parkinson’s disease: a systematic review and meta-analysis. Mov Disord. 2014;29:1583–90.

    Article  Google Scholar 

  2. Chaudhuri KR, Schapira AH. Non-motor symptoms of Parkinson’s disease: dopaminergic pathophysiology and treatment. Lancet Neurol. 2009;8:464–74.

    Article  CAS  Google Scholar 

  3. Hornykiewicz O. Dopamine (3-hydroxytyramine) and brain function. Pharmacol Rev. 1966;18:925–64.

    CAS  PubMed  Google Scholar 

  4. Fahn S. The history of dopamine and levodopa in the treatment of Parkinson’s disease. Mov Disord. 2008;23(Suppl 3):S497–508.

    Article  Google Scholar 

  5. Soto C. Unfolding the role of protein misfolding in neurodegenerative diseases. Nat Rev Neurosci. 2003;4:49–60.

    Article  CAS  Google Scholar 

  6. Poewe W, Gauthier S, Aarsland D, et al. Diagnosis and management of Parkinson’s disease dementia. Int J Clin Pract. 2008;62:1581–7.

    Article  CAS  Google Scholar 

  7. Aarsland D, Marsh L, Schrag A. Neuropsychiatric symptoms in Parkinson’s disease. Mov Disord. 2009;24:2175–86.

    Article  Google Scholar 

  8. Buter TC, Van Den Hout A, Matthews FE, et al. Dementia and survival in Parkinson disease: a 12-year population study. Neurology. 2008;70:1017–22.

    Article  CAS  Google Scholar 

  9. Akbar U, Friedman JH. Recognition and treatment of neuropsychiatric disturbances in Parkinson’s disease. Expert Rev Neurother. 2015;15:1053–65.

    Article  CAS  Google Scholar 

  10. Factor SA, Feustel PJ, Friedman JH, et al. Longitudinal outcome of Parkinson’s disease patients with psychosis. Neurology. 2003;60:1756–61.

    Article  CAS  Google Scholar 

  11. Lill CM. Genetics of Parkinson’s disease. Mol Cell Probes. 2016;30:386–96.

    Article  CAS  Google Scholar 

  12. Klein C, Westenberger A. Genetics of Parkinson’s disease. Cold Spring Harb Perspect Med. 2012;2:a008888.

    Article  Google Scholar 

  13. Polymeropoulos MH, Lavedan C, Leroy E, et al. Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science. 1997;276:2045–7.

    Article  CAS  Google Scholar 

  14. Bekris LM, Mata IF, Zabetian CP. The genetics of Parkinson disease. J Geriatr Psychiatry Neurol. 2010;23:228–42.

    Article  Google Scholar 

  15. Marras C, Lang A, Van De Warrenburg BP, et al. Nomenclature of genetic movement disorders: recommendations of the international Parkinson and movement disorder society task force. Mov Disord. 2016;31:436–57.

    Article  Google Scholar 

  16. Spillantini MG, Schmidt ML, Lee VM, et al. Alpha-synuclein in Lewy bodies. Nature. 1997;388:839–40.

    Article  CAS  Google Scholar 

  17. Bendor JT, Logan TP, Edwards RH. The function of alpha-synuclein. Neuron. 2013;79:1044–66.

    Article  CAS  Google Scholar 

  18. Brettschneider J, Del Tredici K, Lee VM, et al. Spreading of pathology in neurodegenerative diseases: a focus on human studies. Nat Rev Neurosci. 2015;16:109–20.

    Article  CAS  Google Scholar 

  19. Walsh DM, Selkoe DJ. A critical appraisal of the pathogenic protein spread hypothesis of neurodegeneration. Nat Rev Neurosci. 2016;17:251–60.

    Article  CAS  Google Scholar 

  20. Paisan-Ruiz C, Jain S, Evans EW, et al. Cloning of the gene containing mutations that cause PARK8-linked Parkinson’s disease. Neuron. 2004;44:595–600.

    Article  CAS  Google Scholar 

  21. Zimprich A, Biskup S, Leitner P, et al. Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron. 2004;44:601–7.

    Article  CAS  Google Scholar 

  22. Healy DG, Falchi M, O’sullivan SS, et al. Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson’s disease: a case-control study. Lancet Neurol. 2008;7:583–90.

    Article  CAS  Google Scholar 

  23. Ross OA, Soto-Ortolaza AI, Heckman MG, et al. Association of LRRK2 exonic variants with susceptibility to Parkinson’s disease: a case-control study. Lancet Neurol. 2011;10:898–908.

    Article  CAS  Google Scholar 

  24. Webber PJ, West AB. LRRK2 in Parkinson’s disease: function in cells and neurodegeneration. FEBS J. 2009;276:6436–44.

    Article  CAS  Google Scholar 

  25. Nalls MA, Pankratz N, Lill CM, et al. Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson’s disease. Nat Genet. 2014;46:989–93.

    Article  CAS  Google Scholar 

  26. Goker-Alpan O, Schiffmann R, Lamarca ME, et al. Parkinsonism among Gaucher disease carriers. J Med Genet. 2004;41:937–40.

    Article  CAS  Google Scholar 

  27. Sidransky E, Nalls MA, Aasly JO, et al. Multicenter analysis of glucocerebrosidase mutations in Parkinson’s disease. N Engl J Med. 2009;361:1651–61.

    Article  CAS  Google Scholar 

  28. Nalls MA, Escott-Price V, Williams NM, et al. Genetic risk and age in Parkinson’s disease: continuum not stratum. Mov Disord. 2015;30:850–4.

    Article  CAS  Google Scholar 

  29. Pihlstrom L, Morset KR, Grimstad E, et al. A cumulative genetic risk score predicts progression in Parkinson’s disease. Mov Disord. 2016;31:487–90.

    Article  Google Scholar 

  30. Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science. 2002;297:353–6.

    Article  CAS  Google Scholar 

  31. Mawuenyega KG, Sigurdson W, Ovod V, et al. Decreased clearance of CNS beta-amyloid in Alzheimer’s disease. Science. 2010;330:1774.

    Article  CAS  Google Scholar 

  32. Siderowf A, Xie SX, Hurtig H, et al. CSF amyloid {beta} 1-42 predicts cognitive decline in Parkinson disease. Neurology. 2010;75:1055–61.

    Article  CAS  Google Scholar 

  33. Deleidi M, Maetzler W. Protein clearance mechanisms of alpha-synuclein and amyloid-Beta in lewy body disorders. Int J Alzheimers Dis. 2012;2012:391438.

    PubMed  PubMed Central  Google Scholar 

  34. Brockmann K, Lerche S, Dilger SS, et al. SNPs in Abeta clearance proteins: lower CSF Abeta1-42 levels and earlier onset of dementia in PD. Neurology. 2017;89:2335–40.

    Article  CAS  Google Scholar 

  35. Garai K, Verghese PB, Baban B, et al. The binding of apolipoprotein E to oligomers and fibrils of amyloid-beta alters the kinetics of amyloid aggregation. Biochemistry. 2014;53:6323–31.

    Article  CAS  Google Scholar 

  36. Deane R, Sagare A, Hamm K, et al. apoE isoform-specific disruption of amyloid beta peptide clearance from mouse brain. J Clin Invest. 2008;118:4002–13.

    Article  CAS  Google Scholar 

  37. Tsuang D, Leverenz JB, Lopez OL, et al. APOE epsilon4 increases risk for dementia in pure synucleinopathies. JAMA Neurol. 2013;70:223–8.

    Article  Google Scholar 

  38. Schrag A, Siddiqui UF, Anastasiou Z, et al. Clinical variables and biomarkers in prediction of cognitive impairment in patients with newly diagnosed Parkinson’s disease: a cohort study. Lancet Neurol. 2017;16:66–75.

    Article  CAS  Google Scholar 

  39. Mata IF, Leverenz JB, Weintraub D, et al. APOE, MAPT, and SNCA genes and cognitive performance in Parkinson disease. JAMA Neurol. 2014;71:1405–12.

    Article  Google Scholar 

  40. Factor SA, Steenland NK, Higgins DS, et al. Disease-related and genetic correlates of psychotic symptoms in Parkinson’s disease. Mov Disord. 2011;26:2190–5.

    Article  Google Scholar 

  41. Goetz CG, Burke PF, Leurgans S, et al. Genetic variation analysis in Parkinson disease patients with and without hallucinations: case-control study. Arch Neurol. 2001;58:209–13.

    Article  CAS  Google Scholar 

  42. Kachergus J, Mata IF, Hulihan M, et al. Identification of a novel LRRK2 mutation linked to autosomal dominant parkinsonism: evidence of a common founder across European populations. Am J Hum Genet. 2005;76:672–80.

    Article  CAS  Google Scholar 

  43. Thaler A, Ash E, Gan-Or Z, et al. The LRRK2 G2019S mutation as the cause of Parkinson’s disease in Ashkenazi Jews. J Neural Transm (Vienna). 2009;116:1473–82.

    Article  CAS  Google Scholar 

  44. Mirelman A, Heman T, Yasinovsky K, et al. Fall risk and gait in Parkinson’s disease: the role of the LRRK2 G2019S mutation. Mov Disord. 2013;28:1683–90.

    Article  CAS  Google Scholar 

  45. Srivatsal S, Cholerton B, Leverenz JB, et al. Cognitive profile of LRRK2-related Parkinson’s disease. Mov Disord. 2015;30:728–33.

    Article  CAS  Google Scholar 

  46. Kalia LV, Lang AE, Hazrati LN, et al. Clinical correlations with Lewy body pathology in LRRK2-related Parkinson disease. JAMA Neurol. 2015;72:100–5.

    Article  Google Scholar 

  47. Somme JH, Molano Salazar A, Gonzalez A, et al. Cognitive and behavioral symptoms in Parkinson’s disease patients with the G2019S and R1441G mutations of the LRRK2 gene. Parkinsonism Relat Disord. 2015;21:494–9.

    Article  Google Scholar 

  48. Neumann J, Bras J, Deas E, et al. Glucocerebrosidase mutations in clinical and pathologically proven Parkinson’s disease. Brain. 2009;132:1783–94.

    Article  Google Scholar 

  49. Goker-Alpan O, Lopez G, Vithayathil J, et al. The spectrum of parkinsonian manifestations associated with glucocerebrosidase mutations. Arch Neurol. 2008;65:1353–7.

    Article  Google Scholar 

  50. Seto-Salvia N, Pagonabarraga J, Houlden H, et al. Glucocerebrosidase mutations confer a greater risk of dementia during Parkinson’s disease course. Mov Disord. 2012;27:393–9.

    Article  CAS  Google Scholar 

  51. Brockmann K, Srulijes K, Hauser AK, et al. GBA-associated PD presents with nonmotor characteristics. Neurology. 2011;77:276–80.

    Article  CAS  Google Scholar 

  52. Oeda T, Umemura A, Mori Y, et al. Impact of glucocerebrosidase mutations on motor and nonmotor complications in Parkinson’s disease. Neurobiol Aging. 2015;36:3306–13.

    Article  CAS  Google Scholar 

  53. Mata IF, Leverenz JB, Weintraub D, et al. GBA variants are associated with a distinct pattern of cognitive deficits in Parkinson’s disease. Mov Disord. 2016;31:95–102.

    Article  CAS  Google Scholar 

  54. Davis MY, Johnson CO, Leverenz JB, et al. Association of GBA mutations and the E326K polymorphism with motor and cognitive progression in Parkinson disease. JAMA Neurol. 2016;73:1217–24.

    Article  Google Scholar 

  55. Jesus S, Huertas I, Bernal-Bernal I, et al. GBA variants influence motor and non-motor features of Parkinson’s disease. PLoS One. 2016;11:e0167749.

    Article  Google Scholar 

  56. Cilia R, Tunesi S, Marotta G, et al. Survival and dementia in GBA-associated Parkinson’s disease: the mutation matters. Ann Neurol. 2016;80:662–73.

    Article  CAS  Google Scholar 

  57. Mata IF, Johnson CO, Leverenz JB, et al. Large-scale exploratory genetic analysis of cognitive impairment in Parkinson’s disease. Neurobiol Aging. 2017;56:211 e211–7.

    Article  Google Scholar 

  58. Caspell-Garcia C, Simuni T, Tosun-Turgut D, et al. Multiple modality biomarker prediction of cognitive impairment in prospectively followed de novo Parkinson disease. PLoS One. 2017;12:e0175674.

    Article  Google Scholar 

  59. Fujii C, Harada S, Ohkoshi N, et al. Association between polymorphism of the cholecystokinin gene and idiopathic Parkinson’s disease. Clin Genet. 1999;56:394–9.

    Article  CAS  Google Scholar 

  60. Wang J, Si YM, Liu ZL, et al. Cholecystokinin, cholecystokinin-A receptor and cholecystokinin-B receptor gene polymorphisms in Parkinson’s disease. Pharmacogenetics. 2003;13:365–9.

    Article  CAS  Google Scholar 

  61. Goldman JG, Goetz CG, Berry-Kravis E, et al. Genetic polymorphisms in Parkinson disease subjects with and without hallucinations: an analysis of the cholecystokinin system. Arch Neurol. 2004;61:1280–4.

    PubMed  Google Scholar 

  62. Lautner R, Insel PS, Skillback T, et al. Preclinical effects of APOE epsilon4 on cerebrospinal fluid Abeta42 concentrations. Alzheimers Res Ther. 2017;9:87.

    Article  Google Scholar 

  63. Emre M, Aarsland D, Brown R, et al. Clinical diagnostic criteria for dementia associated with Parkinson’s disease. Mov Disord. 2007;22:1689–707; quiz 1837.

    Article  Google Scholar 

  64. Zahodne LB, Fernandez HH. Pathophysiology and treatment of psychosis in Parkinson’s disease: a review. Drugs Aging. 2008;25:665–82.

    Article  CAS  Google Scholar 

  65. Moore SF, Barker RA. Predictors of Parkinson’s disease dementia: towards targeted therapies for a heterogeneous disease. Parkinsonism Relat Disord. 2014;20(Suppl 1):S104–7.

    Article  Google Scholar 

  66. Goedert M. NEURODEGENERATION. Alzheimer’s and Parkinson’s diseases: the prion concept in relation to assembled Abeta, tau, and alpha-synuclein. Science. 2015;349:1255555.

    Article  Google Scholar 

  67. Lerche S, Schulte C, Srulijes K, et al. Cognitive impairment in Glucocerebrosidase (GBA)-associated PD: not primarily associated with cerebrospinal fluid Abeta and Tau profiles. Mov Disord. 2017;32:1780–3.

    Article  CAS  Google Scholar 

  68. Jindal H, Bhatt B, Sk S, et al. Alzheimer disease immunotherapeutics: then and now. Hum Vaccin Immunother. 2014;10:2741–3.

    Article  Google Scholar 

  69. Schliebs R. Basal forebrain cholinergic dysfunction in Alzheimer’s disease – interrelationship with beta-amyloid, inflammation and neurotrophin signaling. Neurochem Res. 2005;30:895–908.

    Article  CAS  Google Scholar 

  70. Perez-Lloret S, Barrantes FJ. Deficits in cholinergic neurotransmission and their clinical correlates in Parkinson’s disease. NPJ Park Dis. 2016;2:16001–12.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Cardiology Research, National Scientific and Technological Research Council-University of Buenos Aires, (CONICET-ININCA), Buenos Aires, Argentina

    Santiago Perez-Lloret

  2. Genda Genetics and Molecular Biology Laboratory, Buenos Aires, Argentina

    Viviana Bernath

  3. Laboratory of Molecular Neurobiology, Biomedical Research Institute, UCA-CONICET, Faculty of Medical Sciences, Buenos Aires, Argentina

    Francisco J. Barrantes

Authors
  1. Santiago Perez-Lloret
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Viviana Bernath
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Francisco J. Barrantes
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Santiago Perez-Lloret .

Editor information

Editors and Affiliations

  1. Cathedra of Psychopathology, Catholic University of Argentina, Mendoza, Argentina

    Pascual Ángel Gargiulo

  2. Laboratory of Neurosciences and Experimental Psychology, Area of Pharmacology, Department of Pathology, National University of Cuyo, Council of Scientific and Technological Research (CONICET), Mendoza, Argentina

    Humberto Luis Mesones Arroyo

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Perez-Lloret, S., Bernath, V., Barrantes, F.J. (2019). Genetic Factors Influencing the Development and Treatment of Cognitive Impairment and Psychosis in Parkinson’s Disease. In: Gargiulo, P., Mesones Arroyo, H. (eds) Psychiatry and Neuroscience Update . Springer, Cham. https://doi.org/10.1007/978-3-319-95360-1_29

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-95360-1_29

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-95359-5

  • Online ISBN: 978-3-319-95360-1

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation