Key Points
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The full spectrum of cognitive impairment, from subjective cognitive decline to dementia, has been observed in Parkinson disease (PD)
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Mild cognitive impairment in PD usually progresses to dementia, but can be stable and even revert in some patients
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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
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Amyloid plaque pathology also contributes to cognitive decline in PD, and amyloid pathology detected by cerebrospinal fluid analysis and imaging can predict subsequent dementia
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Other probable mechanisms include genetics, synaptic pathology, neurotransmitter changes and inflammation
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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.
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References
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).
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).
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).
Emre, M. et al. Clinical diagnostic criteria for dementia associated with Parkinson's disease. Mov. Disord. 22, 1689–1707 (2007).
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).
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).
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).
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).
Santangelo, G. et al. Mild cognitive impairment in newly diagnosed Parkinson's disease: a longitudinal prospective study. Parkinsonism Relat. Disord. 21, 1219–1226 (2015).
Pigott, K. et al. Longitudinal study of normal cognition in Parkinson disease. Neurology 85, 1276–1282 (2015).
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).
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).
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).
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).
Postuma, R. B. et al. MDS clinical diagnostic criteria for Parkinson's disease. Mov. Disord. 30, 1591–1601 (2015).
Marras, C. & Chaudhuri, K. R. Nonmotor features of Parkinson's disease subtypes. Mov. Disord. 31, 1095–1102 (2016).
Chaudhuri, K. R. & Sauerbier, A. Parkinson disease: unravelling the nonmotor mysteries of Parkinson disease. Nat. Rev. Neurol. 12, 10–11 (2016).
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).
Anang, J. B. et al. Predictors of dementia in Parkinson disease: a prospective cohort study. Neurology 83, 1253–1260 (2014).
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).
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).
Braak, H. et al. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol. Aging 24, 197–211 (2003).
Compta, Y. et al. Lewy- and Alzheimer-type pathologies in Parkinson's disease dementia: which is more important? Brain 134, 1493–1505 (2011).
Howlett, D. R. et al. Regional multiple pathology scores are associated with cognitive decline in Lewy body dementias. Brain Pathol. 25, 401–408 (2015).
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).
Ballard, C. et al. Differences in neuropathologic characteristics across the Lewy body dementia spectrum. Neurology 67, 1931–1934 (2006).
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).
Pienaar, I. S., Burn, D., Morris, C. & Dexter, D. Synaptic protein alterations in Parkinson's disease. Mol. Neurobiol. 45, 126–143 (2012).
Bellucci, A. et al. Review: Parkinson's disease: from synaptic loss to connectome dysfunction. Neuropathol. Appl. Neurobiol. 42, 77–94 (2016).
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).
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).
Bereczki, E. et al. Synaptic proteins predict cognitive decline in Alzheimer's disease and Lewy body dementia. Alzheimers Dement. 12, 1149–1158 (2016).
Wellington, H. et al. Increased CSF neurogranin concentration is specific to Alzheimer disease. Neurology 86, 829–835 (2016).
Bereczki, E. et al. Synaptic proteins in CSF relate to Parkinson`s disease stage markers. NPJ Parkinsons Dis. 3, 7 (2017).
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).
Shimada, H. et al. Mapping of brain acetylcholinesterase alterations in Lewy body disease by PET. Neurology 73, 273–278 (2009).
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).
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).
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).
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).
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).
Gatt, A. P. et al. Dementia in Parkinson's disease is associated with enhanced mitochondrial complex I deficiency. Mov. Disord. 31, 352–359 (2016).
Cagin, U. et al. Mitochondrial retrograde signaling regulates neuronal function. Proc. Natl Acad. Sci. USA 112, E6000–E6009 (2015).
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).
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).
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).
Aviles-Olmos, I., Limousin, P., Lees, A. & Foltynie, T. Parkinson's disease, insulin resistance and novel agents of neuroprotection. Brain 136, 374–384 (2013).
Petrou, M. et al. Diabetes, gray matter loss, and cognition in the setting of Parkinson disease. Acad. Radiol. 23, 577–581 (2016).
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).
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).
Baek, J. H. et al. Unfolded protein response is activated in Lewy body dementias. Neuropathol. Appl. Neurobiol. 42, 352–365 (2015).
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).
Paul, G. et al. Safety and tolerability of intracerebroventricular PDGF-BB in Parkinson's disease patients. J. Clin. Invest. 125, 1339–1346 (2015).
Collins, L. M. & Williams-Gray, C. H. The genetic basis of cognitive impairment and dementia in Parkinson's disease. Front. Psychiatry 7, 89 (2016).
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).
Srivatsal, S. et al. Cognitive profile of LRRK2-related Parkinson's disease. Mov. Disord. 30, 728–733 (2015).
Shanker, V. et al. Mood and cognition in leucine-rich repeat kinase 2 G2019S Parkinson's disease. Mov. Disord. 26, 1875–1880 (2011).
Ben Sassi, S. et al. Cognitive dysfunction in Tunisian LRRK2 associated Parkinson's disease. Parkinsonism Relat. Disord. 18, 243–246 (2012).
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).
Nichols, W. C. et al. Genetic screening for a single common LRRK2 mutation in familial Parkinson's disease. Lancet 365, 410–412 (2005).
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).
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).
Aasly, J. O. et al. Clinical features of LRRK2-associated Parkinson's disease in central Norway. Ann. Neurol. 57, 762–765 (2005).
Chartier-Harlin, M. C. et al. α-Synuclein locus duplication as a cause of familial Parkinson's disease. Lancet 364, 1167–1169 (2004).
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).
Seidel, K. et al. First appraisal of brain pathology owing to A30P mutant alpha-synuclein. Ann. Neurol. 67, 684–689 (2010).
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).
Mata, I. F. et al. APOE. MAPT, and SNCA genes and cognitive performance in Parkinson disease. JAMA Neurol. 71, 1405–1412 (2014).
Guella, I. et al. α-Synuclein genetic variability: a biomarker for dementia in Parkinson disease. Ann. Neurol. 79, 991–999 (2016).
Alcalay, R. N. et al. Cognitive performance of GBA mutation carriers with early-onset PD: the CORE-PD study. Neurology 78, 1434–1440 (2012).
Setó- Salvia, N. et al. Glucocerebrosidase mutations confer a greater risk of dementia during Parkinson's disease course. Mov. Disord. 27, 393–399 (2012).
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).
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).
Oeda, T. et al. Impact of glucocerebrosidase mutations on motor and nonmotor complications in Parkinson's disease. Neurobiol. Aging 36, 3306–3313 (2015).
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).
Liu, G. et al. Specifically neuropathic Gaucher's mutations accelerate cognitive decline in Parkinson's. Ann. Neurol. 80, 674–685 (2016).
Cilia, R. et al. Survival and dementia in GBA-associated Parkinson's disease: the mutation matters. Ann. Neurol. 80, 662–673 (2016).
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).
Morley, J. F. et al. Genetic influences on cognitive decline in Parkinson's disease. Mov. Disord. 27, 512–518 (2012).
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).
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).
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).
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).
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).
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).
Chung, S. J. et al. Genomic determinants of motor and cognitive outcomes in Parkinson's disease. Parkinsonism Relat. Disord. 18, 881–886 (2012).
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).
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).
Lin, C. H. & Wu, R. M. Biomarkers of cognitive decline in Parkinson's disease. Parkinsonism Relat. Disord. 21, 431–443 (2015).
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).
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).
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).
Hall, S. et al. CSF biomarkers and clinical progression of Parkinson disease. Neurology 84, 57–63 (2015).
Alves, G. et al. CSF Aβ42 predicts early-onset dementia in Parkinson disease. Neurology 82, 1784–1790 (2014).
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).
Siderowf, A. et al. CSF amyloid β 1–42 predicts cognitive decline in Parkinson disease. Neurology 75, 1055–1061 (2010).
Compta, Y. et al. Combined dementia-risk biomarkers in Parkinson's disease: a prospective longitudinal study. Parkinsonism Relat. Disord. 19, 717–724 (2013).
Parnetti, L. et al. Differential role of CSF alpha-synuclein species, tau, and Aβ42 in Parkinson's disease. Front. Aging Neurosci. 6, 53 (2014).
Mollenhauer, B. et al. Monitoring of 30 marker candidates in early Parkinson disease as progression markers. Neurology 87, 168–177 (2016).
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).
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).
Hall, S. et al. Longitudinal measurements of cerebrospinal fluid biomarkers in Parkinson's disease. Mov. Disord. 31, 898–905 (2016).
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).
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).
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).
Rocchi, L., Niccolini, F. & Politis, M. Recent imaging advances in neurology. J. Neurol. 262, 2182–2194 (2015).
Niccolini, F., Su, P. & Politis, M. Dopamine receptor mapping with PET imaging in Parkinson's disease. J. Neurol. 261, 2251–2263 (2014).
Loane, C. & Politis, M. Positron emission tomography neuroimaging in Parkinson's disease. Am. J. Transl Res. 3, 323–341 (2011).
Politis, M. Neuroimaging in Parkinson disease: from research setting to clinical practice. Nat. Rev. Neurol. 10, 708–722 (2014).
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).
Politis, M., Su, P. & Piccini, P. Imaging of microglia in patients with neurodegenerative disorders. Front. Pharmacol. 3, 96 (2012).
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).
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).
Ellfolk, U. et al. Brain volumetric correlates of memory in early Parkinson's disease. J. Parkinsons Dis. 3, 593–601 (2013).
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).
Yildiz, D. et al. Impaired cognitive performance and hippocampal atrophy in Parkinson disease. Turk. J. Med. Sci. 45, 1173–1177 (2015).
Mak, E. et al. Baseline and longitudinal grey matter changes in newly diagnosed Parkinson's disease: ICICLE-PD study. Brain 138, 2974–2986 (2015).
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).
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).
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).
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).
Rektorova, I. et al. Grey matter changes in cognitively impaired Parkinson's disease patients. PLoS ONE 9, e85595 (2014).
Hwang, K. S. et al. Mapping cortical atrophy in Parkinson's disease patients with dementia. J. Parkinsons Dis. 3, 69–76 (2013).
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).
Pagonabarraga, J. et al. Pattern of regional cortical thinning associated with cognitive deterioration in Parkinson's disease. PLoS ONE 8, e54980 (2013).
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).
Carlesimo, G. A. et al. Hippocampal abnormalities and memory deficits in Parkinson disease: a multimodal imaging study. Neurology 78, 1939–1945 (2012).
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).
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).
Olde Dubbelink, K. T. et al. Functional connectivity and cognitive decline over 3 years in Parkinson disease. Neurology 83, 2046–2053 (2014).
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).
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).
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).
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).
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).
Klein, J. C. et al. Neurotransmitter changes in dementia with Lewy bodies and Parkinson disease dementia in vivo. Neurology 74, 885–892 (2010).
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).
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).
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).
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).
Pappata, S. et al. Mild cognitive impairment in drug-naive patients with PD is associated with cerebral hypometabolism. Neurology 77, 1357–1362 (2011).
Minoshima, S. et al. Alzheimer's disease versus dementia with Lewy bodies: cerebral metabolic distinction with autopsy confirmation. Ann. Neurol. 50, 358–365 (2001).
Huang, C. et al. Changes in network activity with the progression of Parkinson's disease. Brain 130, 1834–1846 (2007).
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).
Roy, R., Niccolini, F., Pagano, G. & Politis, M. Cholinergic imaging in dementia spectrum disorders. Eur. J. Nucl. Med. Mol. Imaging 43, 1376–1386 (2016).
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).
Hilker, R. et al. Dementia in Parkinson disease: functional imaging of cholinergic and dopaminergic pathways. Neurology 65, 1716–1722 (2005).
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).
Hiraoka, K. et al. Cholinergic deficit and response to donepezil therapy in Parkinson's disease with dementia. Eur. Neurol. 68, 137–143 (2012).
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).
Bohnen, N. I. et al. Heterogeneity of cholinergic denervation in Parkinson's disease without dementia. J. Cereb. Blood Flow Metab. 32, 1609–1617 (2012).
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).
Petrou, M. et al. Aβ-amyloid deposition in patients with Parkinson disease at risk for development of dementia. Neurology 79, 1161–1167 (2012).
Maetzler, W. et al. [11C]PIB binding in Parkinson's disease dementia. Neuroimage 39, 1027–1033 (2008).
Petrou, M. et al. Amyloid deposition in Parkinson's disease and cognitive impairment: a systematic review. Mov. Disord. 30, 928–935 (2015).
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).
Shah, N. et al. Striatal and cortical β-amyloidopathy and cognition in Parkinson's disease. Mov. Disord. 31, 111–117 (2016).
Gomperts, S. N. et al. Amyloid is linked to cognitive decline in patients with Parkinson disease without dementia. Neurology 80, 85–91 (2013).
Gomperts, S. N. et al. Tau positron emission tomographic imaging in the Lewy body diseases. JAMA Neurol. 73, 1334–1341 (2016).
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).
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).
Caviness, J. N. et al. Longitudinal EEG changes correlate with cognitive measure deterioration in Parkinson's disease. J. Parkinsons Dis. 5, 117–124 (2015).
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).
Schlede, N. et al. Clinical EEG in cognitively impaired patients with Parkinson's disease. J. Neurol. Sci. 310, 75–78 (2011).
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).
Klassen, B. T. et al. Quantitative EEG as a predictive biomarker for Parkinson disease dementia. Neurology 77, 118–124 (2011).
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).
Zhang, D. et al. Multimodal classification of Alzheimer's disease and mild cognitive impairment. Neuroimage 55, 856–867 (2011).
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).
Beyer, M. K. et al. Cerebrospinal fluid Aβ levels correlate with structural brain changes in Parkinson's disease. Mov. Disord. 28, 302–310 (2013).
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).
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).
Campbell, M. C. et al. CSF proteins and resting-state functional connectivity in Parkinson disease. Neurology 84, 2413–2421 (2015).
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).
Emre, M. et al. Rivastigmine for dementia associated with Parkinson's disease. N. Engl. J. Med. 351, 2509–2518 (2004).
Dubois, B. et al. Donepezil in Parkinson's disease dementia: a randomized, double-blind efficacy and safety study. Mov. Disord. 27, 1230–1238 (2012).
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).
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).
Colloby, S. J. et al. Cholinergic and perfusion brain networks in Parkinson disease dementia. Neurology 87, 178–185 (2016).
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).
Postuma, R. B. et al. Caffeine for treatment of Parkinson disease: a randomized controlled trial. Neurology 79, 651–658 (2012).
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).
Weintraub, D. et al. Rasagiline for mild cognitive impairment in Parkinson's disease: a placebo-controlled trial. Mov. Disord. 31, 709–714 (2016).
Weintraub, D. et al. Atomoxetine for depression and other neuropsychiatric symptoms in Parkinson disease. Neurology 75, 448–455 (2010).
Kehagia, A. A. et al. Targeting impulsivity in Parkinson's disease using atomoxetine. Brain 137, 1986–1997 (2014).
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).
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).
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).
Himeno, E. et al. Apomorphine treatment in Alzheimer mice promoting amyloid-β degradation. Ann. Neurol. 69, 248–256 (2011).
Yarnall, A. J. et al. Apomorphine: a potential modifier of amyloid deposition in Parkinson's disease? Mov. Disord. 31, 668–675 (2016).
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).
Leung, I. H. et al. Cognitive training in Parkinson disease: a systematic review and meta-analysis. Neurology 85, 1843–1851 (2015).
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).
David, F. J. et al. Exercise improves cognition in Parkinson's disease: the PRET-PD randomized, clinical trial. Mov. Disord. 30, 1657–1663 (2015).
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).
Kuhn, J. et al. Deep brain stimulation of the nucleus basalis of Meynert in Alzheimer's dementia. Mol. Psychiatry 20, 353–360 (2015).
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).
Seto-Salvia, N. et al. Dementia risk in Parkinson disease: disentangling the role of MAPT haplotypes. Arch. Neurol. 68, 359–364 (2011).
Goris, A. et al. Tau and α-synuclein in susceptibility to, and dementia in, Parkinson's disease. Ann. Neurol. 62, 145–153 (2007).
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).
Marras, C. et al. Motor and nonmotor heterogeneity of LRRK2-related and idiopathic Parkinson's disease. Mov. Disord. 31, 1192–1202 (2016).
Thaler, A. et al. Lower cognitive performance in healthy G2019S LRRK2 mutation carriers. Neurology 79, 1027–1032 (2012).
Farrer, M. et al. Comparison of kindreds with parkinsonism and α-synuclein genomic multiplications. Ann. Neurol. 55, 174–179 (2004).
Foltynie, T. et al. Planning ability in Parkinson's disease is influenced by the COMT val158met polymorphism. Mov. Disord. 19, 885–891 (2004).
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).
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).
Gao, L. et al. Brain-derived neurotrophic factor G196A polymorphism and clinical features in Parkinson's disease. Acta Neurol. Scand. 122, 41–45 (2010).
Białecka, M. et al. BDNF G196A (Val66Met) polymorphism associated with cognitive impairment in Parkinson's disease. Neurosci. Lett. 561, 86–90 (2014).
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).
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).
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).
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).
Broeders, M. et al. Evolution of mild cognitive impairment in Parkinson disease. Neurology 81, 346–352 (2013).
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).
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).
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.
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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.
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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
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DOI: https://doi.org/10.1038/nrneurol.2017.27
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