The Genetic Basis of Cognitive Impairment and Dementia in Parkinson's Disease

Overview

Journal Front Psychiatry

Specialty Psychiatry

Date 2016 Jun 1

PMID 27242557

Citations 22

Authors

Lucy M Collins

Caroline H Williams-Gray

Affiliations

Soon will be listed here.

Abstract

Cognitive dysfunction is a common feature of Parkinson's disease (PD) with mild cognitive impairment affecting around a quarter of patients in the early stages of their disease, and approximately half developing dementia by 10 years from diagnosis. However, the pattern of cognitive impairments and their speed of evolution vary markedly between individuals. While some of this variability may relate to extrinsic factors and comorbidities, inherited genetic heterogeneity is also known to play an important role. A number of common genetic variants have been identified, which contribute to cognitive function in PD, including variants in catechol-O-methyltransferase, microtubule-associated protein tau, and apolipoprotein E. Furthermore, rarer mutations in glucocerebrosidase and α-synuclein and are strongly associated with dementia risk in PD. This review explores the functional impact of these variants on cognition in PD and discusses how such genotype-phenotype associations provide a window into the mechanistic basis of cognitive heterogeneity in this disorder. This has consequent implications for the development of much more targeted therapeutic strategies for cognitive symptoms in PD.

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References

Kasten M, Kertelge L, Bruggemann N, van der Vegt J, Schmidt A, Tadic V . Nonmotor symptoms in genetic Parkinson disease. Arch Neurol. 2010; 67(6):670-6. DOI: 10.1001/archneurol.67.6.670. View

Farrer L, Cupples L, Haines J, Hyman B, Kukull W, Mayeux R . Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA. 1997; 278(16):1349-56. View

Williams-Gray C, Goris A, Foltynie T, Brown J, Maranian M, Walton A . Prevalence of the LRRK2 G2019S mutation in a UK community based idiopathic Parkinson's disease cohort. J Neurol Neurosurg Psychiatry. 2006; 77(5):665-7. PMC: 2117467. DOI: 10.1136/jnnp.2005.085019. View

Chartier-Harlin M, Dachsel J, Vilarino-Guell C, Lincoln S, Lepretre F, Hulihan M . Translation initiator EIF4G1 mutations in familial Parkinson disease. Am J Hum Genet. 2011; 89(3):398-406. PMC: 3169825. DOI: 10.1016/j.ajhg.2011.08.009. View

Marras C, Schule B, Schuele B, Munhoz R, Rogaeva E, Langston J . Phenotype in parkinsonian and nonparkinsonian LRRK2 G2019S mutation carriers. Neurology. 2011; 77(4):325-33. PMC: 3140802. DOI: 10.1212/WNL.0b013e318227042d. View

Blasi G, Mattay V, Bertolino A, Elvevag B, Callicott J, Das S . Effect of catechol-O-methyltransferase val158met genotype on attentional control. J Neurosci. 2005; 25(20):5038-45. PMC: 6724859. DOI: 10.1523/JNEUROSCI.0476-05.2005. View

Goker-Alpan O, Stubblefield B, Giasson B, Sidransky E . Glucocerebrosidase is present in α-synuclein inclusions in Lewy body disorders. Acta Neuropathol. 2010; 120(5):641-9. PMC: 3352317. DOI: 10.1007/s00401-010-0741-7. View

Klein C, Westenberger A . Genetics of Parkinson's disease. Cold Spring Harb Perspect Med. 2012; 2(1):a008888. PMC: 3253033. DOI: 10.1101/cshperspect.a008888. View

Foltynie T, Brayne C, Robbins T, Barker R . The cognitive ability of an incident cohort of Parkinson's patients in the UK. The CamPaIGN study. Brain. 2003; 127(Pt 3):550-60. DOI: 10.1093/brain/awh067. View

10.

Myers A, Pittman A, Zhao A, Rohrer K, Kaleem M, Marlowe L . The MAPT H1c risk haplotype is associated with increased expression of tau and especially of 4 repeat containing transcripts. Neurobiol Dis. 2006; 25(3):561-70. DOI: 10.1016/j.nbd.2006.10.018. View

11.

Puschmann A, Ross O, Vilarino-Guell C, Lincoln S, Kachergus J, Cobb S . A Swedish family with de novo alpha-synuclein A53T mutation: evidence for early cortical dysfunction. Parkinsonism Relat Disord. 2009; 15(9):627-32. PMC: 2783246. DOI: 10.1016/j.parkreldis.2009.06.007. View

12.

Williams-Gray C, Mason S, Evans J, Foltynie T, Brayne C, Robbins T . The CamPaIGN study of Parkinson's disease: 10-year outlook in an incident population-based cohort. J Neurol Neurosurg Psychiatry. 2013; 84(11):1258-64. DOI: 10.1136/jnnp-2013-305277. View

13.

Tsuang D, Leverenz J, Lopez O, Hamilton R, Bennett D, Schneider J . APOE ε4 increases risk for dementia in pure synucleinopathies. JAMA Neurol. 2013; 70(2):223-8. PMC: 3580799. DOI: 10.1001/jamaneurol.2013.600. View

14.

Aarsland D, Zaccai J, Brayne C . A systematic review of prevalence studies of dementia in Parkinson's disease. Mov Disord. 2005; 20(10):1255-63. DOI: 10.1002/mds.20527. View

15.

Seto-Salvia N, Pagonabarraga J, Houlden H, Pascual-Sedano B, Dols-Icardo O, Tucci A . Glucocerebrosidase mutations confer a greater risk of dementia during Parkinson's disease course. Mov Disord. 2011; 27(3):393-9. DOI: 10.1002/mds.24045. View

16.

Egan M, Goldberg T, Kolachana B, Callicott J, Mazzanti C, Straub R . Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. Proc Natl Acad Sci U S A. 2001; 98(12):6917-22. PMC: 34453. DOI: 10.1073/pnas.111134598. View

17.

Goldman-Rakic P, Muly 3rd E, Williams G . D(1) receptors in prefrontal cells and circuits. Brain Res Brain Res Rev. 2000; 31(2-3):295-301. DOI: 10.1016/s0165-0173(99)00045-4. View

18.

Bonifati V, Rizzu P, van Baren M, Schaap O, Breedveld G, Krieger E . Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science. 2002; 299(5604):256-9. DOI: 10.1126/science.1077209. View

19.

Nalls M, Pankratz N, Lill C, Do C, Hernandez D, Saad M . Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease. Nat Genet. 2014; 46(9):989-93. PMC: 4146673. DOI: 10.1038/ng.3043. View

20.

Compta Y, Pereira J, Rios J, Ibarretxe-Bilbao N, Junque C, Bargallo N . Combined dementia-risk biomarkers in Parkinson's disease: a prospective longitudinal study. Parkinsonism Relat Disord. 2013; 19(8):717-24. DOI: 10.1016/j.parkreldis.2013.03.009. View