Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Cognitive decline in Parkinson disease

Key Points

  • The full spectrum of cognitive impairment, from subjective cognitive decline to dementia, has been observed in Parkinson disease (PD)

  • Mild cognitive impairment in PD usually progresses to dementia, but can be stable and even revert in some patients

  • The aetiology of cognitive impairment in PD has not been fully elucidated, but limbic and cortical Lewy body pathology seems to be the main cause

  • Amyloid plaque pathology also contributes to cognitive decline in PD, and amyloid pathology detected by cerebrospinal fluid analysis and imaging can predict subsequent dementia

  • Other probable mechanisms include genetics, synaptic pathology, neurotransmitter changes and inflammation

  • Cholinesterase inhibitors have symptomatic effects, but no disease-modifying treatments are available to reduce the risk of dementia in PD

Abstract

Dementia is a frequent problem encountered in advanced stages of Parkinson disease (PD). In recent years, research has focused on the pre-dementia stages of cognitive impairment in PD, including mild cognitive impairment (MCI). Several longitudinal studies have shown that MCI is a harbinger of dementia in PD, although the course is variable, and stabilization of cognition — or even reversal to normal cognition — is not uncommon. In addition to limbic and cortical spread of Lewy pathology, several other mechanisms are likely to contribute to cognitive decline in PD, and a variety of biomarker studies, some using novel structural and functional imaging techniques, have documented in vivo brain changes associated with cognitive impairment. The evidence consistently suggests that low cerebrospinal fluid levels of amyloid-β42, a marker of comorbid Alzheimer disease (AD), predict future cognitive decline and dementia in PD. Emerging genetic evidence indicates that in addition to the APOE*ε4 allele (an established risk factor for AD), GBA mutations and SCNA mutations and triplications are associated with cognitive decline in PD, whereas the findings are mixed for MAPT polymorphisms. Cognitive enhancing medications have some effect in PD dementia, but no convincing evidence that progression from MCI to dementia can be delayed or prevented is available, although cognitive training has shown promising results.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Amyloid-β PET scans in Parkinson disease dementia.
Figure 2: Overview of risk factors for Parkinson disease dementia.

Similar content being viewed by others

References

  1. Sauerbier, A., Jenner, P., Todorova, A. & Chaudhuri, K. R. Non motor subtypes and Parkinson's disease. Parkinsonism Relat. Disord. 22 (Suppl. 1), S41–S46 (2016).

    Article  PubMed  Google Scholar 

  2. Svenningsson, P., Westman, E., Ballard, C. & Aarsland, D. Cognitive impairment in patients with Parkinson's disease: diagnosis, biomarkers, and treatment. Lancet Neurol. 11, 697–707 (2012).

    Article  PubMed  Google Scholar 

  3. Erro, R. et al. Do subjective memory complaints herald the onset of mild cognitive impairment in Parkinson disease? J. Geriatr. Psychiatry Neurol. 27, 276–281 (2014).

    Article  PubMed  Google Scholar 

  4. Emre, M. et al. Clinical diagnostic criteria for dementia associated with Parkinson's disease. Mov. Disord. 22, 1689–1707 (2007).

    Article  PubMed  Google Scholar 

  5. Litvan, I. et al. Diagnostic criteria for mild cognitive impairment in Parkinson's disease: Movement Disorder Society Task Force guidelines. Mov. Disord. 27, 349–356 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Pedersen, K. F., Larsen, J. P., Tysnes, O. B. & Alves, G. Prognosis of mild cognitive impairment in early Parkinson disease: the Norwegian ParkWest study. JAMA Neurol. 70, 580–586 (2013).

    Article  PubMed  Google Scholar 

  7. Williams-Gray, C. H. et al. The distinct cognitive syndromes of Parkinson's disease: 5 year follow-up of the CamPaIGN cohort. Brain 132, 2958–2969 (2009).

    Article  PubMed  Google Scholar 

  8. Williams-Gray, C. H. et al. The CamPaIGN study of Parkinson's disease: 10-year outlook in an incident population-based cohort. J. Neurol. Neurosurg. Psychiatry 84, 1258–1264 (2013).

    Article  PubMed  Google Scholar 

  9. Santangelo, G. et al. Mild cognitive impairment in newly diagnosed Parkinson's disease: a longitudinal prospective study. Parkinsonism Relat. Disord. 21, 1219–1226 (2015).

    Article  PubMed  Google Scholar 

  10. Pigott, K. et al. Longitudinal study of normal cognition in Parkinson disease. Neurology 85, 1276–1282 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Williams-Gray, C. H., Hampshire, A., Robbins, T. W., Owen, A. M. & Barker, R. A. Catechol O-methyltransferase Val158Met genotype influences frontoparietal activity during planning in patients with Parkinson's disease. J. Neurosci. 27, 4832–4838 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kehagia, A. A., Barker, R. A. & Robbins, T. W. Cognitive impairment in Parkinson's disease: the dual syndrome hypothesis. Neurodegener. Dis. 11, 79–92 (2013).

    Article  PubMed  Google Scholar 

  13. Wood, K.-L. et al. Different PD-MCI criteria and risk of dementia in Parkinson's disease: 4-year longitudinal study. NPJ Parkinsons Dis. 2, 15027 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Chahine, L. M. et al. Cognition in individuals at risk for Parkinson's: Parkinson associated risk syndrome (PARS) study findings. Mov. Disord. 31, 86–94 (2016).

    Article  CAS  PubMed  Google Scholar 

  15. Postuma, R. B. et al. MDS clinical diagnostic criteria for Parkinson's disease. Mov. Disord. 30, 1591–1601 (2015).

    Article  PubMed  Google Scholar 

  16. Marras, C. & Chaudhuri, K. R. Nonmotor features of Parkinson's disease subtypes. Mov. Disord. 31, 1095–1102 (2016).

    Article  CAS  PubMed  Google Scholar 

  17. Chaudhuri, K. R. & Sauerbier, A. Parkinson disease: unravelling the nonmotor mysteries of Parkinson disease. Nat. Rev. Neurol. 12, 10–11 (2016).

    Article  CAS  PubMed  Google Scholar 

  18. Aarsland, D., Andersen, K., Larsen, J. P., Lolk, A. & Kragh-Sorensen, P. Prevalence and characteristics of dementia in Parkinson disease: an 8-year prospective study. Arch. Neurol. 60, 387–392 (2003).

    Article  PubMed  Google Scholar 

  19. Anang, J. B. et al. Predictors of dementia in Parkinson disease: a prospective cohort study. Neurology 83, 1253–1260 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  20. ffytche, D. H. et al. Risk factors for early psychosis in PD: insights from the Parkinson's Progression Markers Initiative. J. Neurol. Neurosurg. Psychiatry (in press).

  21. Halliday, G. M., Leverenz, J. B., Schneider, J. S. & Adler, C. H. The neurobiological basis of cognitive impairment in Parkinson's disease. Mov. Disord. 29, 634–650 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Braak, H. et al. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol. Aging 24, 197–211 (2003).

    Article  PubMed  Google Scholar 

  23. Compta, Y. et al. Lewy- and Alzheimer-type pathologies in Parkinson's disease dementia: which is more important? Brain 134, 1493–1505 (2011).

    Article  PubMed  Google Scholar 

  24. Howlett, D. R. et al. Regional multiple pathology scores are associated with cognitive decline in Lewy body dementias. Brain Pathol. 25, 401–408 (2015).

    Article  CAS  PubMed  Google Scholar 

  25. Irwin, D. J., Lee, V. M. & Trojanowski, J. Q. Parkinson's disease dementia: convergence of α-synuclein, tau and amyloid-β pathologies. Nat. Rev. Neurosci. 14, 626–636 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Ballard, C. et al. Differences in neuropathologic characteristics across the Lewy body dementia spectrum. Neurology 67, 1931–1934 (2006).

    Article  CAS  PubMed  Google Scholar 

  27. Terry, R. D. et al. Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment. Ann. Neurol. 30, 572–580 (1991).

    Article  CAS  PubMed  Google Scholar 

  28. Pienaar, I. S., Burn, D., Morris, C. & Dexter, D. Synaptic protein alterations in Parkinson's disease. Mol. Neurobiol. 45, 126–143 (2012).

    Article  CAS  PubMed  Google Scholar 

  29. Bellucci, A. et al. Review: Parkinson's disease: from synaptic loss to connectome dysfunction. Neuropathol. Appl. Neurobiol. 42, 77–94 (2016).

    Article  CAS  PubMed  Google Scholar 

  30. Schulz-Schaeffer, W. J. The synaptic pathology of α-synuclein aggregation in dementia with Lewy bodies, Parkinson's disease and Parkinson's disease dementia. Acta Neuropathol. 120, 131–143 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Whitfield, D. R. et al. Assessment of ZnT3 and PSD95 protein levels in Lewy body dementias and Alzheimer's disease: association with cognitive impairment. Neurobiol. Aging 35, 2836–2844 (2014).

    Article  CAS  PubMed  Google Scholar 

  32. Bereczki, E. et al. Synaptic proteins predict cognitive decline in Alzheimer's disease and Lewy body dementia. Alzheimers Dement. 12, 1149–1158 (2016).

    Article  PubMed  Google Scholar 

  33. Wellington, H. et al. Increased CSF neurogranin concentration is specific to Alzheimer disease. Neurology 86, 829–835 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Bereczki, E. et al. Synaptic proteins in CSF relate to Parkinson`s disease stage markers. NPJ Parkinsons Dis. 3, 7 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Kulisevsky, J. Role of dopamine in learning and memory: implications for the treatment of cognitive dysfunction in patients with Parkinson's disease. Drugs Aging 16, 365–379 (2000).

    Article  CAS  PubMed  Google Scholar 

  36. Shimada, H. et al. Mapping of brain acetylcholinesterase alterations in Lewy body disease by PET. Neurology 73, 273–278 (2009).

    Article  CAS  PubMed  Google Scholar 

  37. Ehrt, U., Broich, K., Larsen, J. P., Ballard, C. & Aarsland, D. Use of drugs with anticholinergic effect and impact on cognition in Parkinson's disease: a cohort study. J. Neurol. Neurosurg. Psychiatry 81, 160–165 (2010).

    Article  PubMed  Google Scholar 

  38. Ye, Z. et al. Predicting beneficial effects of atomoxetine and citalopram on response inhibition in Parkinson's disease with clinical and neuroimaging measures. Hum. Brain Mapp. 37, 1026–1037 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  39. Varrone, A. et al. 5-HT1B receptor imaging and cognition: a positron emission tomography study in control subjects and Parkinson's disease patients. Synapse 69, 365–374 (2015).

    Article  CAS  PubMed  Google Scholar 

  40. Vorovenci, R. J. & Antonini, A. The efficacy of oral adenosine A2A antagonist istradefylline for the treatment of moderate to severe Parkinson's disease. Expert Rev. Neurother. 15, 1383–1390 (2015).

    Article  CAS  PubMed  Google Scholar 

  41. Ko, W. K. et al. An evaluation of istradefylline treatment on Parkinsonian motor and cognitive deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated macaque models. Neuropharmacology 110, 48–58 (2016).

    Article  CAS  PubMed  Google Scholar 

  42. Gatt, A. P. et al. Dementia in Parkinson's disease is associated with enhanced mitochondrial complex I deficiency. Mov. Disord. 31, 352–359 (2016).

    Article  CAS  PubMed  Google Scholar 

  43. Cagin, U. et al. Mitochondrial retrograde signaling regulates neuronal function. Proc. Natl Acad. Sci. USA 112, E6000–E6009 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Rocha, N. P. et al. Plasma levels of soluble tumor necrosis factor receptors are associated with cognitive performance in Parkinson's disease. Mov. Disord. 29, 527–531 (2014).

    Article  CAS  PubMed  Google Scholar 

  45. Fan, Z. et al. Influence of microglial activation on neuronal function in Alzheimer's and Parkinson's disease dementia. Alzheimers Dement. 11, 608–621.e7 (2015).

    Article  PubMed  Google Scholar 

  46. Lindqvist, D. et al. Cerebrospinal fluid inflammatory markers in Parkinson's disease — associations with depression, fatigue, and cognitive impairment. Brain Behav. Immun. 33, 183–189 (2013).

    Article  CAS  PubMed  Google Scholar 

  47. Aviles-Olmos, I., Limousin, P., Lees, A. & Foltynie, T. Parkinson's disease, insulin resistance and novel agents of neuroprotection. Brain 136, 374–384 (2013).

    Article  PubMed  Google Scholar 

  48. Petrou, M. et al. Diabetes, gray matter loss, and cognition in the setting of Parkinson disease. Acad. Radiol. 23, 577–581 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Leverenz, J. B. et al. Cerebrospinal fluid biomarkers and cognitive performance in non-demented patients with Parkinson's disease. Parkinsonism Relat. Disord. 17, 61–64 (2011).

    Article  PubMed  Google Scholar 

  50. Lim, N. S. et al. Plasma EGF and cognitive decline in Parkinson's disease and Alzheimer's disease. Ann. Clin. Transl. Neurol. 3, 346–355 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Baek, J. H. et al. Unfolded protein response is activated in Lewy body dementias. Neuropathol. Appl. Neurobiol. 42, 352–365 (2015).

    Article  CAS  PubMed  Google Scholar 

  52. Bajic, N., Jenner, P., Ballard, C. G. & Francis, P. T. Proteasome inhibition leads to early loss of synaptic proteins in neuronal culture. J. Neural Transm. (Vienna) 119, 1467–1476 (2012).

    Article  CAS  Google Scholar 

  53. Paul, G. et al. Safety and tolerability of intracerebroventricular PDGF-BB in Parkinson's disease patients. J. Clin. Invest. 125, 1339–1346 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Collins, L. M. & Williams-Gray, C. H. The genetic basis of cognitive impairment and dementia in Parkinson's disease. Front. Psychiatry 7, 89 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Healy, D. G. et al. Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson's disease: a case–control study. Lancet Neurol. 7, 583–590 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Srivatsal, S. et al. Cognitive profile of LRRK2-related Parkinson's disease. Mov. Disord. 30, 728–733 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Shanker, V. et al. Mood and cognition in leucine-rich repeat kinase 2 G2019S Parkinson's disease. Mov. Disord. 26, 1875–1880 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  58. Ben Sassi, S. et al. Cognitive dysfunction in Tunisian LRRK2 associated Parkinson's disease. Parkinsonism Relat. Disord. 18, 243–246 (2012).

    Article  PubMed  Google Scholar 

  59. Belarbi, S. et al. LRRK2 G2019S mutation in Parkinson's disease: a neuropsychological and neuropsychiatric study in a large Algerian cohort. Parkinsonism Relat. Disord. 16, 676–679 (2010).

    Article  PubMed  Google Scholar 

  60. Nichols, W. C. et al. Genetic screening for a single common LRRK2 mutation in familial Parkinson's disease. Lancet 365, 410–412 (2005).

    CAS  PubMed  Google Scholar 

  61. Goldwurm, S. et al. LRRK2 G2019S mutation and Parkinson's disease: a clinical, neuropsychological and neuropsychiatric study in a large Italian sample. Parkinsonism Relat. Disord. 12, 410–419 (2006).

    Article  PubMed  Google Scholar 

  62. Alcalay, R. N. et al. Self-report of cognitive impairment and mini-mental state examination performance in PRKN, LRRK2, and GBA carriers with early onset Parkinson's disease. J. Clin. Exp. Neuropsychol. 32, 775–779 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  63. Aasly, J. O. et al. Clinical features of LRRK2-associated Parkinson's disease in central Norway. Ann. Neurol. 57, 762–765 (2005).

    Article  CAS  PubMed  Google Scholar 

  64. Chartier-Harlin, M. C. et al. α-Synuclein locus duplication as a cause of familial Parkinson's disease. Lancet 364, 1167–1169 (2004).

    Article  CAS  PubMed  Google Scholar 

  65. Somme, J. H. et al. Initial neuropsychological impairments in patients with the E46K mutation of the α-synuclein gene (PARK 1). J. Neurol. Sci. 310, 86–89 (2011).

    Article  CAS  PubMed  Google Scholar 

  66. Seidel, K. et al. First appraisal of brain pathology owing to A30P mutant alpha-synuclein. Ann. Neurol. 67, 684–689 (2010).

    Article  CAS  PubMed  Google Scholar 

  67. Puschmann, A. et al. A Swedish family with de novo α-synuclein A53T mutation: evidence for early cortical dysfunction. Parkinsonism Relat. Disord. 15, 627–632 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  68. Mata, I. F. et al. APOE. MAPT, and SNCA genes and cognitive performance in Parkinson disease. JAMA Neurol. 71, 1405–1412 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  69. Guella, I. et al. α-Synuclein genetic variability: a biomarker for dementia in Parkinson disease. Ann. Neurol. 79, 991–999 (2016).

    Article  CAS  PubMed  Google Scholar 

  70. Alcalay, R. N. et al. Cognitive performance of GBA mutation carriers with early-onset PD: the CORE-PD study. Neurology 78, 1434–1440 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Setó- Salvia, N. et al. Glucocerebrosidase mutations confer a greater risk of dementia during Parkinson's disease course. Mov. Disord. 27, 393–399 (2012).

    Article  CAS  Google Scholar 

  72. Winder-Rhodes, S. E. et al. Glucocerebrosidase mutations influence the natural history of Parkinson's disease in a community-based incident cohort. Brain 136, 392–399 (2013).

    Article  PubMed  Google Scholar 

  73. Chahine, L. M. et al. Clinical and biochemical differences in patients having Parkinson disease with versus without GBA mutations. JAMA Neurol. 70, 852–858 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  74. Oeda, T. et al. Impact of glucocerebrosidase mutations on motor and nonmotor complications in Parkinson's disease. Neurobiol. Aging 36, 3306–3313 (2015).

    Article  CAS  PubMed  Google Scholar 

  75. Mata, I. F. et al. GBA variants are associated with a distinct pattern of cognitive deficits in Parkinson's disease. Mov. Disord. 31, 95–102 (2016).

    Article  CAS  PubMed  Google Scholar 

  76. Liu, G. et al. Specifically neuropathic Gaucher's mutations accelerate cognitive decline in Parkinson's. Ann. Neurol. 80, 674–685 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Cilia, R. et al. Survival and dementia in GBA-associated Parkinson's disease: the mutation matters. Ann. Neurol. 80, 662–673 (2016).

    Article  CAS  PubMed  Google Scholar 

  78. Williams-Gray, C. H. et al. Apolipoprotein E genotype as a risk factor for susceptibility to and dementia in Parkinson's disease. J. Neurol. 256, 493–498 (2009).

    Article  CAS  PubMed  Google Scholar 

  79. Morley, J. F. et al. Genetic influences on cognitive decline in Parkinson's disease. Mov. Disord. 27, 512–518 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Paul, K. C. et al. APOE. MAPT, and COMT and Parkinson's disease susceptibility and cognitive symptom progression. J. Parkinsons Dis. 6, 349–359 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Mengel, D. et al. Apolipoprotein E ε4 does not affect cognitive performance in patients with Parkinson's disease. Parkinsonism Relat. Disord. 29, 112–116 (2016).

    Article  PubMed  Google Scholar 

  82. Federoff, M., Jimenez-Rolando, B., Nalls, M. A. & Singleton, A. B. A large study reveals no association between APOE and Parkinson's disease. Neurobiol. Dis. 46, 389–392 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Desikan, R. S. et al. Genetic overlap between Alzheimer's disease and Parkinson's disease at the MAPT locus. Mol. Psychiatry 20, 1588–1595 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Nombela, C. et al. Genetic impact on cognition and brain function in newly diagnosed Parkinson's disease: ICICLE-PD study. Brain 137, 2743–2758 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  85. Winder-Rhodes, S. E. et al. Association between MAPT haplotype and memory function in patients with Parkinson's disease and healthy aging individuals. Neurobiol. Aging 36, 1519–1528 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Chung, S. J. et al. Genomic determinants of motor and cognitive outcomes in Parkinson's disease. Parkinsonism Relat. Disord. 18, 881–886 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  87. Andreassen, O. A. et al. Genetic pleiotropy between multiple sclerosis and schizophrenia but not bipolar disorder: differential involvement of immune-related gene loci. Mol. Psychiatry 20, 207–214 (2015).

    Article  CAS  PubMed  Google Scholar 

  88. Mollenhauer, B. et al. Biological confounders for the values of cerebrospinal fluid proteins in Parkinson's disease and related disorders. J. Neurochem. 139 (Suppl. 1), 290–317 (2016).

    Article  CAS  PubMed  Google Scholar 

  89. Lin, C. H. & Wu, R. M. Biomarkers of cognitive decline in Parkinson's disease. Parkinsonism Relat. Disord. 21, 431–443 (2015).

    Article  CAS  PubMed  Google Scholar 

  90. Skogseth, R. E. et al. Associations between cerebrospinal fluid biomarkers and cognition in early untreated Parkinson's disease. J. Parkinsons Dis. 5, 783–792 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Stav, A. L. et al. Amyloid-β and α-synuclein cerebrospinal fluid biomarkers and cognition in early Parkinson's disease. Parkinsonism Relat. Disord. 21, 758–764 (2015).

    Article  PubMed  Google Scholar 

  92. Backstrom, D. C. et al. Cerebrospinal fluid patterns and the risk of future dementia in early, incident Parkinson disease. JAMA Neurol. 72, 1175–1182 (2015).

    Article  PubMed  Google Scholar 

  93. Hall, S. et al. CSF biomarkers and clinical progression of Parkinson disease. Neurology 84, 57–63 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Alves, G. et al. CSF Aβ42 predicts early-onset dementia in Parkinson disease. Neurology 82, 1784–1790 (2014).

    Article  CAS  PubMed  Google Scholar 

  95. Terrelonge, M., Marder, K. S., Weintraub, D. & Alcalay, R. N. CSF β-amyloid 1–42 predicts progression to cognitive impairment in newly diagnosed Parkinson disease. J. Mol. Neurosci. 58, 88–92 (2016).

    Article  CAS  PubMed  Google Scholar 

  96. Siderowf, A. et al. CSF amyloid β 1–42 predicts cognitive decline in Parkinson disease. Neurology 75, 1055–1061 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Compta, Y. et al. Combined dementia-risk biomarkers in Parkinson's disease: a prospective longitudinal study. Parkinsonism Relat. Disord. 19, 717–724 (2013).

    Article  PubMed  Google Scholar 

  98. Parnetti, L. et al. Differential role of CSF alpha-synuclein species, tau, and Aβ42 in Parkinson's disease. Front. Aging Neurosci. 6, 53 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Mollenhauer, B. et al. Monitoring of 30 marker candidates in early Parkinson disease as progression markers. Neurology 87, 168–177 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  100. Zhou, B., Wen, M., Yu, W.-F., Zhang, C.-L. & Jiao, L. The diagnostic and differential diagnosis utility of cerebrospinal fluid α-synuclein levels in Parkinson's disease: a meta-analysis. Parkinsons Dis. 2015, 567386 (2015).

    PubMed  PubMed Central  Google Scholar 

  101. Stewart, T. et al. Cerebrospinal fluid α-synuclein predicts cognitive decline in Parkinson disease progression in the DATATOP cohort. Am. J. Pathol. 184, 966–975 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Hall, S. et al. Longitudinal measurements of cerebrospinal fluid biomarkers in Parkinson's disease. Mov. Disord. 31, 898–905 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Ohrfelt, A. et al. Identification of novel α-synuclein isoforms in human brain tissue by using an online nanoLC-ESI-FTICR-MS method. Neurochem. Res. 36, 2029–2042 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Hansson, O. et al. Levels of cerebrospinal fluid α-synuclein oligomers are increased in Parkinson's disease with dementia and dementia with Lewy bodies compared to Alzheimer's disease. Alzheimers Res. Ther. 6, 25 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Simonsen, A. H. et al. The utility of α-synuclein as biofluid marker in neurodegenerative diseases: a systematic review of the literature. Biomark. Med. 10, 19–34 (2016).

    Article  CAS  PubMed  Google Scholar 

  106. Rocchi, L., Niccolini, F. & Politis, M. Recent imaging advances in neurology. J. Neurol. 262, 2182–2194 (2015).

    Article  CAS  PubMed  Google Scholar 

  107. Niccolini, F., Su, P. & Politis, M. Dopamine receptor mapping with PET imaging in Parkinson's disease. J. Neurol. 261, 2251–2263 (2014).

    Article  CAS  PubMed  Google Scholar 

  108. Loane, C. & Politis, M. Positron emission tomography neuroimaging in Parkinson's disease. Am. J. Transl Res. 3, 323–341 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Politis, M. Neuroimaging in Parkinson disease: from research setting to clinical practice. Nat. Rev. Neurol. 10, 708–722 (2014).

    Article  PubMed  Google Scholar 

  110. Santos-Garcia, D. et al. COPPADIS-2015 (COhort of Patients with PArkinson's DIsease in Spain, 2015), a global — clinical evaluations, serum biomarkers, genetic studies and neuroimaging prospective, multicenter, non-interventional, long-term study on Parkinson's disease progression. BMC Neurol. 16, 26 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Politis, M., Su, P. & Piccini, P. Imaging of microglia in patients with neurodegenerative disorders. Front. Pharmacol. 3, 96 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Wu, K. et al. The catechol-O-methyltransferase Val158Met polymorphism modulates fronto-cortical dopamine turnover in early Parkinson's disease: a PET study. Brain 135, 2449–2457 (2012).

    Article  PubMed  Google Scholar 

  113. Ibarretxe-Bilbao, N. et al. Neuroanatomical correlates of impaired decision-making and facial emotion recognition in early Parkinson's disease. Eur. J. Neurosci. 30, 1162–1171 (2009).

    Article  PubMed  Google Scholar 

  114. Ellfolk, U. et al. Brain volumetric correlates of memory in early Parkinson's disease. J. Parkinsons Dis. 3, 593–601 (2013).

    PubMed  Google Scholar 

  115. Duncan, G. W. et al. Gray and white matter imaging: a biomarker for cognitive impairment in early Parkinson's disease? Mov. Disord. 31, 103–110 (2016).

    Article  PubMed  Google Scholar 

  116. Yildiz, D. et al. Impaired cognitive performance and hippocampal atrophy in Parkinson disease. Turk. J. Med. Sci. 45, 1173–1177 (2015).

    Article  CAS  PubMed  Google Scholar 

  117. Mak, E. et al. Baseline and longitudinal grey matter changes in newly diagnosed Parkinson's disease: ICICLE-PD study. Brain 138, 2974–2986 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  118. Pereira, J. B. et al. Aberrant cerebral network topology and mild cognitive impairment in early Parkinson's disease. Hum. Brain Mapp. 36, 2980–2995 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  119. Hanganu, A. et al. Mild cognitive impairment is linked with faster rate of cortical thinning in patients with Parkinson's disease longitudinally. Brain 137, 1120–1129 (2014).

    Article  PubMed  Google Scholar 

  120. Kandiah, N. et al. Hippocampal volume and white matter disease in the prediction of dementia in Parkinson's disease. Parkinsonism Relat. Disord. 20, 1203–1208 (2014).

    Article  PubMed  Google Scholar 

  121. Lee, J. E. et al. Exploratory analysis of neuropsychological and neuroanatomical correlates of progressive mild cognitive impairment in Parkinson's disease. J. Neurol. Neurosurg. Psychiatry 85, 7–16 (2014).

    Article  PubMed  Google Scholar 

  122. Rektorova, I. et al. Grey matter changes in cognitively impaired Parkinson's disease patients. PLoS ONE 9, e85595 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Hwang, K. S. et al. Mapping cortical atrophy in Parkinson's disease patients with dementia. J. Parkinsons Dis. 3, 69–76 (2013).

    PubMed  PubMed Central  Google Scholar 

  124. Zarei, M. et al. Cortical thinning is associated with disease stages and dementia in Parkinson's disease. J. Neurol. Neurosurg. Psychiatry 84, 875–881 (2013).

    Article  PubMed  Google Scholar 

  125. Pagonabarraga, J. et al. Pattern of regional cortical thinning associated with cognitive deterioration in Parkinson's disease. PLoS ONE 8, e54980 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Borroni, B. et al. Structural and functional imaging study in dementia with Lewy bodies and Parkinson's disease dementia. Parkinsonism Relat. Disord. 21, 1049–1055 (2015).

    Article  PubMed  Google Scholar 

  127. Carlesimo, G. A. et al. Hippocampal abnormalities and memory deficits in Parkinson disease: a multimodal imaging study. Neurology 78, 1939–1945 (2012).

    Article  CAS  PubMed  Google Scholar 

  128. Agosta, F. et al. Mild cognitive impairment in Parkinson's disease is associated with a distributed pattern of brain white matter damage. Hum. Brain Mapp. 35, 1921–1929 (2014).

    Article  PubMed  Google Scholar 

  129. Chen, B., Fan, G. G., Liu, H. & Wang, S. Changes in anatomical and functional connectivity of Parkinson's disease patients according to cognitive status. Eur. J. Radiol. 84, 1318–1324 (2015).

    Article  PubMed  Google Scholar 

  130. Olde Dubbelink, K. T. et al. Functional connectivity and cognitive decline over 3 years in Parkinson disease. Neurology 83, 2046–2053 (2014).

    Article  CAS  PubMed  Google Scholar 

  131. Seibert, T. M., Murphy, E. A., Kaestner, E. J. & Brewer, J. B. Interregional correlations in Parkinson disease and Parkinson-related dementia with resting functional MR imaging. Radiology 263, 226–234 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  132. Rektorova, I., Krajcovicova, L., Marecek, R. & Mikl, M. Default mode network and extrastriate visual resting state network in patients with Parkinson's disease dementia. Neurodegener. Dis. 10, 232–237 (2012).

    Article  CAS  PubMed  Google Scholar 

  133. Lin, W. C. et al. Dopaminergic therapy modulates cortical perfusion in Parkinson disease with and without dementia according to arterial spin labeled perfusion magnetic resonance imaging. Medicine (Baltimore) 95, e2206 (2016).

    Article  CAS  PubMed Central  Google Scholar 

  134. Le Heron, C. J. et al. Comparing cerebral perfusion in Alzheimer's disease and Parkinson's disease dementia: an ASL-MRI study. J. Cereb. Blood Flow Metab. 34, 964–970 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  135. Ito, K. et al. Striatal and extrastriatal dysfunction in Parkinson's disease with dementia: a 6-[18F]fluoro-L-dopa PET study. Brain 125, 1358–1365 (2002).

    Article  PubMed  Google Scholar 

  136. Klein, J. C. et al. Neurotransmitter changes in dementia with Lewy bodies and Parkinson disease dementia in vivo. Neurology 74, 885–892 (2010).

    Article  CAS  PubMed  Google Scholar 

  137. Marquie, M. et al. Striatal and extrastriatal dopamine transporter levels relate to cognition in Lewy body diseases: an 11C altropane positron emission tomography study. Alzheimers Res. Ther. 6, 52 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Song, I. U., Kim, Y. D., Cho, H. J., Chung, S. W. & Chung, Y. A. An FP-CIT PET comparison of the differences in dopaminergic neuronal loss between idiopathic Parkinson disease with dementia and without dementia. Alzheimer Dis. Assoc. Disord. 27, 51–55 (2013).

    Article  PubMed  Google Scholar 

  139. Vander Borght, T. et al. Cerebral metabolic differences in Parkinson's and Alzheimer's diseases matched for dementia severity. J. Nucl. Med. 38, 797–802 (1997).

    CAS  PubMed  Google Scholar 

  140. Gonzalez-Redondo, R. et al. Grey matter hypometabolism and atrophy in Parkinson's disease with cognitive impairment: a two-step process. Brain 137, 2356–2367 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  141. Pappata, S. et al. Mild cognitive impairment in drug-naive patients with PD is associated with cerebral hypometabolism. Neurology 77, 1357–1362 (2011).

    Article  CAS  PubMed  Google Scholar 

  142. Minoshima, S. et al. Alzheimer's disease versus dementia with Lewy bodies: cerebral metabolic distinction with autopsy confirmation. Ann. Neurol. 50, 358–365 (2001).

    Article  CAS  PubMed  Google Scholar 

  143. Huang, C. et al. Changes in network activity with the progression of Parkinson's disease. Brain 130, 1834–1846 (2007).

    Article  PubMed  Google Scholar 

  144. Yong, S. W., Yoon, J. K., An, Y. S. & Lee, P. H. A comparison of cerebral glucose metabolism in Parkinson's disease, Parkinson's disease dementia and dementia with Lewy bodies. Eur. J. Neurol. 14, 1357–1362 (2007).

    Article  CAS  PubMed  Google Scholar 

  145. Roy, R., Niccolini, F., Pagano, G. & Politis, M. Cholinergic imaging in dementia spectrum disorders. Eur. J. Nucl. Med. Mol. Imaging 43, 1376–1386 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Shinotoh, H. et al. Positron emission tomographic measurement of acetylcholinesterase activity reveals differential loss of ascending cholinergic systems in Parkinson's disease and progressive supranuclear palsy. Ann. Neurol. 46, 62–69 (1999).

    Article  CAS  PubMed  Google Scholar 

  147. Hilker, R. et al. Dementia in Parkinson disease: functional imaging of cholinergic and dopaminergic pathways. Neurology 65, 1716–1722 (2005).

    Article  CAS  PubMed  Google Scholar 

  148. Bohnen, N. I. et al. Cortical cholinergic function is more severely affected in parkinsonian dementia than in Alzheimer disease: an in vivo positron emission tomographic study. Arch. Neurol. 60, 1745–1748 (2003).

    Article  PubMed  Google Scholar 

  149. Hiraoka, K. et al. Cholinergic deficit and response to donepezil therapy in Parkinson's disease with dementia. Eur. Neurol. 68, 137–143 (2012).

    Article  CAS  PubMed  Google Scholar 

  150. Kotagal, V., Muller, M. L., Kaufer, D. I., Koeppe, R. A. & Bohnen, N. I. Thalamic cholinergic innervation is spared in Alzheimer disease compared to parkinsonian disorders. Neurosci. Lett. 514, 169–172 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Bohnen, N. I. et al. Heterogeneity of cholinergic denervation in Parkinson's disease without dementia. J. Cereb. Blood Flow Metab. 32, 1609–1617 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Edison, P. et al. Amyloid load in Parkinson's disease dementia and Lewy body dementia measured with [11C]PIB positron emission tomography. J. Neurol. Neurosurg. Psychiatry 79, 1331–1338 (2008).

    Article  CAS  PubMed  Google Scholar 

  153. Petrou, M. et al. Aβ-amyloid deposition in patients with Parkinson disease at risk for development of dementia. Neurology 79, 1161–1167 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Maetzler, W. et al. [11C]PIB binding in Parkinson's disease dementia. Neuroimage 39, 1027–1033 (2008).

    Article  PubMed  Google Scholar 

  155. Petrou, M. et al. Amyloid deposition in Parkinson's disease and cognitive impairment: a systematic review. Mov. Disord. 30, 928–935 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Akhtar, R. S. et al. Amyloid-beta positron emission tomography imaging of Alzheimer's pathology in Parkinson's disease dementia. Mov. Disord. Clin. Pract. 3, 367–375 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  157. Shah, N. et al. Striatal and cortical β-amyloidopathy and cognition in Parkinson's disease. Mov. Disord. 31, 111–117 (2016).

    Article  CAS  PubMed  Google Scholar 

  158. Gomperts, S. N. et al. Amyloid is linked to cognitive decline in patients with Parkinson disease without dementia. Neurology 80, 85–91 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  159. Gomperts, S. N. et al. Tau positron emission tomographic imaging in the Lewy body diseases. JAMA Neurol. 73, 1334–1341 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  160. Kamei, S., Morita, A., Serizawa, K., Mizutani, T. & Hirayanagi, K. Quantitative EEG analysis of executive dysfunction in Parkinson disease. J. Clin. Neurophysiol. 27, 193–197 (2010).

    Article  PubMed  Google Scholar 

  161. Morita, A., Kamei, S. & Mizutani, T. Relationship between slowing of the EEG and cognitive impairment in Parkinson disease. J. Clin. Neurophysiol. 28, 384–387 (2011).

    PubMed  Google Scholar 

  162. Caviness, J. N. et al. Longitudinal EEG changes correlate with cognitive measure deterioration in Parkinson's disease. J. Parkinsons Dis. 5, 117–124 (2015).

    PubMed  Google Scholar 

  163. Zimmermann, R. et al. Correlation of EEG slowing with cognitive domains in nondemented patients with Parkinson's disease. Dement. Geriatr. Cogn. Disord. 39, 207–214 (2015).

    Article  PubMed  Google Scholar 

  164. Schlede, N. et al. Clinical EEG in cognitively impaired patients with Parkinson's disease. J. Neurol. Sci. 310, 75–78 (2011).

    Article  PubMed  Google Scholar 

  165. Fonseca, L. C., Tedrus, G. M., Carvas, P. N. & Machado, E. C. Comparison of quantitative EEG between patients with Alzheimer's disease and those with Parkinson's disease dementia. Clin. Neurophysiol. 124, 1970–1974 (2013).

    Article  PubMed  Google Scholar 

  166. Klassen, B. T. et al. Quantitative EEG as a predictive biomarker for Parkinson disease dementia. Neurology 77, 118–124 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Seer, C., Lange, F., Georgiev, D., Jahanshahi, M. & Kopp, B. Event-related potentials and cognition in Parkinson's disease: an integrative review. Neurosci. Biobehav. Rev. 71, 691–714 (2016).

    Article  PubMed  Google Scholar 

  168. Zhang, D. et al. Multimodal classification of Alzheimer's disease and mild cognitive impairment. Neuroimage 55, 856–867 (2011).

    Article  PubMed  Google Scholar 

  169. Compta, Y. et al. Grey matter volume correlates of cerebrospinal markers of Alzheimer-pathology in Parkinson's disease and related dementia. Parkinsonism Relat. Disord. 18, 941–947 (2012).

    Article  PubMed  Google Scholar 

  170. Beyer, M. K. et al. Cerebrospinal fluid Aβ levels correlate with structural brain changes in Parkinson's disease. Mov. Disord. 28, 302–310 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Chiaravalloti, A. et al. Do CSF levels of t-Tau, p-Tau and β1–42 amyloid correlate with dopaminergic system impairment in patients with a clinical diagnosis of Parkinson disease? A 123I-FP-CIT study in the early stages of the disease. Eur. J. Nucl. Med. Mol. Imaging 41, 2137–2143 (2014).

    Article  CAS  PubMed  Google Scholar 

  172. van Dijk, K. D. et al. Reduced α-synuclein levels in cerebrospinal fluid in Parkinson's disease are unrelated to clinical and imaging measures of disease severity. Eur. J. Neurol. 21, 388–394 (2014).

    Article  CAS  PubMed  Google Scholar 

  173. Campbell, M. C. et al. CSF proteins and resting-state functional connectivity in Parkinson disease. Neurology 84, 2413–2421 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Wang, H. F. et al. Efficacy and safety of cholinesterase inhibitors and memantine in cognitive impairment in Parkinson's disease, Parkinson's disease dementia, and dementia with Lewy bodies: systematic review with meta-analysis and trial sequential analysis. J. Neurol. Neurosurg. Psychiatry 86, 135–143 (2015).

    Article  PubMed  Google Scholar 

  175. Emre, M. et al. Rivastigmine for dementia associated with Parkinson's disease. N. Engl. J. Med. 351, 2509–2518 (2004).

    Article  CAS  PubMed  Google Scholar 

  176. Dubois, B. et al. Donepezil in Parkinson's disease dementia: a randomized, double-blind efficacy and safety study. Mov. Disord. 27, 1230–1238 (2012).

    Article  CAS  PubMed  Google Scholar 

  177. Aarsland, D. et al. Memantine in patients with Parkinson's disease dementia or dementia with Lewy bodies: a double-blind, placebo-controlled, multicentre trial. Lancet Neurol. 8, 613–618 (2009).

    Article  CAS  PubMed  Google Scholar 

  178. Emre, M. et al. Memantine for patients with Parkinson's disease dementia or dementia with Lewy bodies: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 9, 969–977 (2010).

    Article  CAS  PubMed  Google Scholar 

  179. Colloby, S. J. et al. Cholinergic and perfusion brain networks in Parkinson disease dementia. Neurology 87, 178–185 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Jurado-Coronel, J. C. et al. Implication of green tea as a possible therapeutic approach for Parkinson disease. CNS Neurol. Disord. Drug Targets 15, 292–300 (2016).

    Article  CAS  PubMed  Google Scholar 

  181. Postuma, R. B. et al. Caffeine for treatment of Parkinson disease: a randomized controlled trial. Neurology 79, 651–658 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Mamikonyan, E., Xie, S. X., Melvin, E. & Weintraub, D. Rivastigmine for mild cognitive impairment in Parkinson disease: a placebo-controlled study. Mov. Disord. 30, 912–918 (2015).

    Article  CAS  PubMed  Google Scholar 

  183. Weintraub, D. et al. Rasagiline for mild cognitive impairment in Parkinson's disease: a placebo-controlled trial. Mov. Disord. 31, 709–714 (2016).

    Article  CAS  PubMed  Google Scholar 

  184. Weintraub, D. et al. Atomoxetine for depression and other neuropsychiatric symptoms in Parkinson disease. Neurology 75, 448–455 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Kehagia, A. A. et al. Targeting impulsivity in Parkinson's disease using atomoxetine. Brain 137, 1986–1997 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  186. Katona, C., Hansen, T. & Olsen, C. K. A randomized, double-blind, placebo-controlled, duloxetine-referenced, fixed-dose study comparing the efficacy and safety of Lu AA21004 in elderly patients with major depressive disorder. Int. Clin. Psychopharmacol. 27, 215–223 (2012).

    Article  PubMed  Google Scholar 

  187. Valera, E., Spencer, B. & Masliah, E. Immunotherapeutic approaches targeting amyloid-β, α-synuclein, and tau for the treatment of neurodegenerative disorders. Neurotherapeutics 13, 179–189 (2016).

    Article  CAS  PubMed  Google Scholar 

  188. Killick, R. et al. Clusterin regulates β-amyloid toxicity via Dickkopf-1-driven induction of the wnt–PCP–JNK pathway. Mol. Psychiatry 19, 88–98 (2014).

    Article  CAS  PubMed  Google Scholar 

  189. Himeno, E. et al. Apomorphine treatment in Alzheimer mice promoting amyloid-β degradation. Ann. Neurol. 69, 248–256 (2011).

    Article  CAS  PubMed  Google Scholar 

  190. Yarnall, A. J. et al. Apomorphine: a potential modifier of amyloid deposition in Parkinson's disease? Mov. Disord. 31, 668–675 (2016).

    Article  CAS  PubMed  Google Scholar 

  191. Martinez-Martin, P. et al. EuroInf: a multicenter comparative observational study of apomorphine and levodopa infusion in Parkinson's disease. Mov. Disord. 30, 510–516 (2015).

    Article  CAS  PubMed  Google Scholar 

  192. Leung, I. H. et al. Cognitive training in Parkinson disease: a systematic review and meta-analysis. Neurology 85, 1843–1851 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  193. Reynolds, G. O., Otto, M. W., Ellis, T. D. & Cronin-Golomb, A. The therapeutic potential of exercise to improve mood, cognition, and sleep in Parkinson's disease. Mov. Disord. 31, 23–38 (2016).

    Article  PubMed  Google Scholar 

  194. David, F. J. et al. Exercise improves cognition in Parkinson's disease: the PRET-PD randomized, clinical trial. Mov. Disord. 30, 1657–1663 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  195. Klingelhoefer, L., Samuel, M., Chaudhuri, K. R. & Ashkan, K. An update of the impact of deep brain stimulation on non motor symptoms in Parkinson's disease. J. Parkinsons Dis. 4, 289–300 (2014).

    PubMed  Google Scholar 

  196. Kuhn, J. et al. Deep brain stimulation of the nucleus basalis of Meynert in Alzheimer's dementia. Mol. Psychiatry 20, 353–360 (2015).

    Article  CAS  PubMed  Google Scholar 

  197. Gratwicke, J. et al. The nucleus basalis of Meynert: a new target for deep brain stimulation in dementia? Neurosci. Biobehav. Rev. 37, 2676–2688 (2013).

    Article  PubMed  Google Scholar 

  198. Seto-Salvia, N. et al. Dementia risk in Parkinson disease: disentangling the role of MAPT haplotypes. Arch. Neurol. 68, 359–364 (2011).

    Article  PubMed  Google Scholar 

  199. Goris, A. et al. Tau and α-synuclein in susceptibility to, and dementia in, Parkinson's disease. Ann. Neurol. 62, 145–153 (2007).

    Article  CAS  PubMed  Google Scholar 

  200. Kurz, M. W. et al. APOE alleles in Parkinson disease and their relationship to cognitive decline: a population-based, longitudinal study. J. Geriatr. Psychiatry Neurol. 22, 166–170 (2009).

    Article  PubMed  Google Scholar 

  201. Marras, C. et al. Motor and nonmotor heterogeneity of LRRK2-related and idiopathic Parkinson's disease. Mov. Disord. 31, 1192–1202 (2016).

    Article  CAS  PubMed  Google Scholar 

  202. Thaler, A. et al. Lower cognitive performance in healthy G2019S LRRK2 mutation carriers. Neurology 79, 1027–1032 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Farrer, M. et al. Comparison of kindreds with parkinsonism and α-synuclein genomic multiplications. Ann. Neurol. 55, 174–179 (2004).

    Article  CAS  PubMed  Google Scholar 

  204. Foltynie, T. et al. Planning ability in Parkinson's disease is influenced by the COMT val158met polymorphism. Mov. Disord. 19, 885–891 (2004).

    Article  PubMed  Google Scholar 

  205. Williams-Gray, C. H., Hampshire, A., Barker, R. A. & Owen, A. M. Attentional control in Parkinson's disease is dependent on COMT val158met genotype. Brain 131, 397–408 (2008).

    Article  PubMed  Google Scholar 

  206. Svetel, M. et al. No association between brain-derived neurotrophic factor G196A polymorphism and clinical features of Parkinson's disease. Eur. Neurol. 70, 257–262 (2013).

    Article  CAS  PubMed  Google Scholar 

  207. Gao, L. et al. Brain-derived neurotrophic factor G196A polymorphism and clinical features in Parkinson's disease. Acta Neurol. Scand. 122, 41–45 (2010).

    Article  CAS  PubMed  Google Scholar 

  208. Białecka, M. et al. BDNF G196A (Val66Met) polymorphism associated with cognitive impairment in Parkinson's disease. Neurosci. Lett. 561, 86–90 (2014).

    Article  CAS  PubMed  Google Scholar 

  209. Arias-Vasquez, A. et al. Relationship of the Ubiquilin 1 gene with Alzheimer's and Parkinson's disease and cognitive function. Neurosci. Lett. 424, 1–5 (2007).

    Article  CAS  PubMed  Google Scholar 

  210. Kurz, M. W. et al. FMR1 alleles in Parkinson's disease: relation to cognitive decline and hallucinations, a longitudinal study. J. Geriatr. Psychiatry Neurol. 20, 89–92 (2007).

    Article  PubMed  Google Scholar 

  211. Nie, K. et al. Polymorphisms in immune/inflammatory cytokine genes are related to Parkinson's disease with cognitive impairment in the Han Chinese population. Neurosci. Lett. 541, 111–115 (2013).

    Article  CAS  PubMed  Google Scholar 

  212. Liu, Z. et al. Lack of association between IL-10 and IL-18 gene promoter polymorphisms and Parkinson's disease with cognitive impairment in a Chinese population. Sci. Rep. 6, 19021 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Broeders, M. et al. Evolution of mild cognitive impairment in Parkinson disease. Neurology 81, 346–352 (2013).

    Article  CAS  PubMed  Google Scholar 

  214. Domellof, M. E., Ekman, U., Forsgren, L. & Elgh, E. Cognitive function in the early phase of Parkinson's disease, a five-year follow-up. Acta Neurol. Scand. 132, 79–88 (2015).

    Article  CAS  PubMed  Google Scholar 

  215. Hely, M. A., Reid, W. G., Adena, M. A., Halliday, G. M. & Morris, J. G. The Sydney multicenter study of Parkinson's disease: the inevitability of dementia at 20 years. Mov. Disord. 23, 837–844 (2008).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank Dr Michael Haworth for help in preparing the final manuscript. The authors would like to thank the National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre and Dementia Unit at South London and Maudsley NHS Foundation Trust and Institute of Psychiatry, Psychology and Neuroscience, King's College London, UK. D.A. is a Royal Society Wolfson Research Merit Award Holder and would like to thank the Wolfson Foundation and the Royal Society for their support. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.

Author information

Authors and Affiliations

Authors

Contributions

All authors contributed equally to all aspects of manuscript preparation.

Corresponding author

Correspondence to Dag Aarsland.

Ethics declarations

Competing interests

D.A. has received research support and/or honoraria from Astra-Zeneca, H. Lundbeck, Novartis Pharmaceuticals and GE Health, and serves as a paid consultant for H. Lundbeck and Axovant. K.R.C. has consulted and served on advisory boards for Britannia, AbbVie, Neuronova, Mundipharma and UCB, and has also served on advisory boards for Synapsus and Medtronic. He has received honoraria from Boehringer Ingelheim, GlaxoSmithKline, AbbVie, Britannia, UCB, Mundipharma, Otsuka and Zambon, and grants from Boehringer Ingelheim, GlaxoSmithKline, Britannia, AbbVie, UCB and Neuronova. He holds intellectual property rights for the KPP scale and the PDSS, and receives royalties for the books Non-Motor Symptoms of Parkinson's Disease and Fastfacts: Parkinson's Disease. C.B. declares grants and personal fees from Lundbeck and Acadia, and personal fees from Roche, Orion, GlaxoSmithKline, Otusaka, Heptares and Lilly. The other authors declare no competing interests.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Aarsland, D., Creese, B., Politis, M. et al. Cognitive decline in Parkinson disease. Nat Rev Neurol 13, 217–231 (2017). https://doi.org/10.1038/nrneurol.2017.27

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrneurol.2017.27

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing