Journal of Neurology

, Volume 256, Supplement 3, pp 280–285 | Cite as

Biochemical and pathological correlates of cognitive and behavioural change in DLB/PDD

Article

Abstract

Dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD) are second only to Alzheimer’s disease (AD) in frequency. In particular it is evident that up to 80% of people with PD will develop dementia towards the end of their life. While the neurobiology of movement disorder has been well studied in PD, much less attention has been given to mechanisms underlying the cognitive and behavioural symptoms associated with DLB and PDD. To date, the best correlate of cognitive impairment appears to be cortical Lewy bodies; however, new emphasis has been placed on small aggregates of synuclein. Furthermore, very few studies have attempted to investigate the neurochemical correlates of behavioural disorders in DLB/PDD and whether these are similar or distinct from AD. Aggregated α-synuclein forms the core component of Lewy bodies, a major pathological feature of Parkinson’s-related conditions. The 26S proteasome is an ATP-dependent protease that catalyses the breakdown of α-synuclein. Previous studies have implicated alterations in the proteasome in PD. Furthermore, proteasome inhibitors have been reported to induce α-synuclein aggregation and Lewy body-like inclusions, resulting in neuronal loss both in vitro and in vivo. Our preliminary results indicate that selective alterations in the expression of proteosome sub-units are a feature of both DLB and PDD, while changes in activity are restricted to PDD. Depression is a common symptom in DLB/PDD, yet the evidence base for standard treatment with SSRIs is limited. In contrast to previous studies of AD, our results indicate that there is no association between depression and the 5-HT transporter, while there was a significant increase in the number of 5-HT1A receptors in those DLB/PDD patients with depression. These data may provide an insight into the lack of success of current treatments and suggest alternative approaches.

Keywords

Dementia with Lewy bodies Parkinson’s disease dementia Glutamate Acetylcholine Serotonin Proteasome 

Reference list

  1. 1.
    Albasanz JL, Dalfo E, Ferrer I, Martin M (2005) Impaired metabotropic glutamate receptor/phospholipase C signaling pathway in the cerebral cortex in Alzheimer’s disease and dementia with Lewy bodies correlates with stage of Alzheimer’s-disease-related changes. Neurobiol Dis 20:685–693PubMedCrossRefGoogle Scholar
  2. 2.
    Ballard C, Holmes C, McKeith I, Neill D, O’Brien J, Cairns N, Lantos P, Perry E, Ince P, Perry et al (1999) Psychiatric morbidity in dementia with Lewy bodies: a prospective clinical and neuropathological comparative study with Alzheimer’s disease. Am J Psychiatry 156:1039–1045Google Scholar
  3. 3.
    Ballard C, Johnson M, Piggott M, Perry R, O’Brien J, Rowan E, Perry E, Lantos P, Cairns N, Holmes C (2002) A positive association between 5HT re-uptake binding sites and depression in dementia with Lewy bodies. J Affect Disord 69:219–223PubMedCrossRefGoogle Scholar
  4. 4.
    Ballard C, Piggott M, Johnson M, Cairns N, Perry R, McKeith I, Jaros E, O’Brien J, Holmes C, Perry E (2000) Delusions associated with elevated muscarinic binding in dementia with Lewy bodies. Ann Neurol 48:868–876PubMedCrossRefGoogle Scholar
  5. 5.
    Bedford L, Hay D, Devoy A, Paine S, Powe DG, Seth R, Gray T, Topham I, Fone K, Rezvani N, Mee M, Soane T, Layfield R, Sheppard PW, Ebendal T, Usoskin D, Lowe J, Mayer RJ (2008) Depletion of 26S proteasomes in mouse brain neurons causes neurodegeneration and Lewy-like inclusions resembling human pale bodies. J Neurosci 28:8189–8198PubMedCrossRefGoogle Scholar
  6. 6.
    Bhasin M, Rowan E, Edwards K, McKeith I (2007) Cholinesterase inhibitors in dementia with Lewy bodies: a comparative analysis. Int J Geriatr Psychiatry 22:890–895PubMedCrossRefGoogle Scholar
  7. 7.
    Bronnick K, Aarsland D, Larsen JP (2005) Neuropsychiatric disturbances in Parkinson’s disease clusters in five groups with different prevalence of dementia. Acta Psychiatr Scand 112:201–207PubMedCrossRefGoogle Scholar
  8. 8.
    Burton EJ, McKeith IG, Burn DJ, O’Brien JT (2005) Brain atrophy rates in Parkinson’s disease with and without dementia using serial magnetic resonance imaging. Mov Disord 20:1571–1576Google Scholar
  9. 9.
    Burton EJ, McKeith IG, Burn DJ, Williams ED, OBrien JT (2004) Cerebral atrophy in Parkinson’s disease with and without dementia: a comparison with Alzheimer’s disease, dementia with Lewy bodies and controls. Brain 127:791–800PubMedCrossRefGoogle Scholar
  10. 10.
    Camicioli R, Moore MM, Kinney A, Corbridge E, Glassberg K, Kaye JA (2003) Parkinson’s disease is associated with hippocampal atrophy. Mov Disord 18:784–790PubMedCrossRefGoogle Scholar
  11. 11.
    Chen CPLH, Alder JT, Bray L, Kingsbury AE, Francis PT, Foster OJF (1998) Post-synaptic 5-HT1A and 5-HT2A receptors are increased in Parkinson’s disease neocortex. Adv Serotonin Recept Res Mol Biol Signal Transduct Ther 861:288–289Google Scholar
  12. 12.
    Court J, Martin-Ruiz C, Piggott M, Spurden D, Griffiths M, Perry E (2001) Nicotinic receptor abnormalities in Alzheimer’s disease. Biol Psychiatry 49:175–184PubMedCrossRefGoogle Scholar
  13. 13.
    Crosby N, Deane KH, Clarke CE (2003) Amantadine in Parkinson’s disease. Cochrane Database Syst Rev CD003468Google Scholar
  14. 14.
    Crosby NJ, Deane KH, Clarke CE (2003) Amantadine for dyskinesia in Parkinson’s disease. Cochrane Database Syst Rev CD003467Google Scholar
  15. 15.
    D’Amato RJ, Zweig RM, Whitehouse PJ, Wenk GL, Singer HS, Mayeux R, Price DL, Snyder SH (1987) Aminergic systems in Alzheimer’s disease and Parkinson’s disease. Ann Neurol 22:229–236PubMedCrossRefGoogle Scholar
  16. 16.
    Danysz W, Parsons CG, Kornhuber J, Schmidt WJ, Quack G (1997) Aminoadamantanes as NMDA receptor antagonists and antiparkinsonian agents–preclinical studies. Neurosci Biobehav Rev 21:455–468PubMedCrossRefGoogle Scholar
  17. 17.
    Double KL, Halliday GM, McRitchie DA, Reid WG, Hely MA, Morris JG (1996) Regional brain atrophy in idiopathic Parkinson’s disease and diffuse Lewy body disease. Dementia 7:304–313PubMedGoogle Scholar
  18. 18.
    Emmanouilidou E, Stefanis L, Vekrellis K (2008) Cell-produced alpha-synuclein oligomers are targeted to, and impair, the 26S proteasome. Neurobiol Aging. doi:10.1016/j.neurobiolaging.2008.07.008
  19. 19.
    Emre M, Aarsland D, Albanese A, Byrne EJ, Deuschl G, De Deyn PP, Durif F, Kulisevsky J, van Laar T, Lees A, Poewe W, Robillard A, Rosa MM, Wolters E, Quarg P, Tekin S, Lane R (2004) Rivastigmine for dementia associated with Parkinson’s disease. N Engl J Med 351:2509–2518PubMedCrossRefGoogle Scholar
  20. 20.
    Francis PT (2003) Glutamatergic systems in Alzheimer’s disease. Int J Geriat Psychiatry 18:S15–S21CrossRefGoogle Scholar
  21. 21.
    Francis PT, Palmer AM, Snape M, Wilcock GK (1999) The cholinergic hypothesis of Alzheimer’s disease: a review of progress. J Neurol Neurosurg Psychiatry 66:137–147PubMedCrossRefGoogle Scholar
  22. 22.
    Goetz CG, Poewe W, Rascol O, Sampaio C (2005) Evidence-based medical review update: pharmacological and surgical treatments of Parkinson’s disease: 2001–2004. Mov Disord 20:523–539PubMedCrossRefGoogle Scholar
  23. 23.
    Halliday GM, Li YW, Blumbergs PC, Joh TH, Cotton RG, Howe PR, Blessing WW, Geffen LB (1990) Neuropathology of immunohistochemically identified brainstem neurons in Parkinson’s disease. Ann Neurol 27:373–385PubMedCrossRefGoogle Scholar
  24. 24.
    Hanagasi HA, Emre M (2005) Treatment of behavioural symptoms and dementia in Parkinson’s disease. Fundam Clin Pharmacol 19:133–146PubMedCrossRefGoogle Scholar
  25. 25.
    Hansen LA, Daniel SE, Wilcock GK, Love S (1998) Frontal cortical synaptophysin in Lewy body diseases: relation to Alzheimer’s disease and dementia. J Neurol Neurosurg Psychiatry 64:653–656PubMedCrossRefGoogle Scholar
  26. 26.
    Hantz P, Caradoc-Davies G, Caradoc-Davies T, Weatherall M, Dixon G (1994) Depression in Parkinson’s disease. Am J Psychiatry 151:1010–1014PubMedGoogle Scholar
  27. 27.
    Kashani A, Betancur C, Giros B, Hirsch E, Mestikawy SE (2006) Altered expression of vesicular glutamate transporters VGLUT1 and VGLUT2 in Parkinson disease. Neurobiol Aging 28:568–578PubMedCrossRefGoogle Scholar
  28. 28.
    Kramer ML, Schulz-Schaeffer WJ (2007) Presynaptic alpha-synuclein aggregates, not Lewy bodies, cause neurodegeneration in dementia with Lewy bodies. J Neurosci 27:1405–1410PubMedCrossRefGoogle Scholar
  29. 29.
    Kuhn W, Muller T, Gerlach M, Sofic E, Fuchs G, Heye N, Prautsch R, Przuntek H (1996) Depression in Parkinson’s disease: biogenic amines in CSF of “de novo” patients. J Neural Transm 103:1441–1445PubMedCrossRefGoogle Scholar
  30. 30.
    Laakso MP, Partanen K, Riekkinen P, Lehtovirta M, Helkala EL, Hallikainen M, Hanninen T, Vainio P, Soininen H (1996) Hippocampal volumes in Alzheimer’s disease, Parkinson’s disease with and without dementia, and in vascular dementia: an MRI study. Neurology 46:678–681PubMedGoogle Scholar
  31. 31.
    Litvan I, Mohr E, Williams J, Gomez C, Chase TN (1991) Differential memory and executive functions in demented patients with Parkinson’s and Alzheimer’s disease. J Neurol Neurosurg Psychiatry 54:25–29PubMedCrossRefGoogle Scholar
  32. 32.
    Liu CW, Giasson BI, Lewis KA, Lee VM, Demartino GN, Thomas PJ (2005) A precipitating role for truncated alpha-synuclein and the proteasome in alpha-synuclein aggregation: implications for pathogenesis of Parkinson disease. J Biol Chem 280:22670–22678PubMedCrossRefGoogle Scholar
  33. 33.
    Martin-Ruiz C, Court J, Lee M, Piggott M, Johnson M, Ballard C, Kalaria R, Perry R, Perry E (2000) Nicotinic receptors in dementia of Alzheimer, Lewy body and vascular types. Acta Neurol Scand Suppl 176:34–41PubMedCrossRefGoogle Scholar
  34. 34.
    Mayeux R, Stern Y, Sano M, Williams JB, Cote LJ (1988) The relationship of serotonin to depression in Parkinson’s disease. Mov Disord 3:237–244PubMedCrossRefGoogle Scholar
  35. 35.
    McKeith IG, Grace JB, Walker Z, Byrne EJ, Wilkinson D, Stevens T, Perry EK (2000) Rivastigmine in the treatment of dementia with lewy bodies: preliminary findings from an open trial. Int J Geriat Psychiatry 15:387–392CrossRefGoogle Scholar
  36. 36.
    McNaught KS, Belizaire R, Isacson O, Jenner P, Olanow CW (2003) Altered proteasomal function in sporadic Parkinson’s disease. Exp Neurol 179:38–46PubMedCrossRefGoogle Scholar
  37. 37.
    McNaught KS, Olanow CW, Halliwell B, Isacson O, Jenner P (2001) Failure of the ubiquitin-proteasome system in Parkinson’s disease. Nat Rev Neurosci 2:589–594PubMedCrossRefGoogle Scholar
  38. 38.
    Merello M, Nouzeilles MI, Cammarota A, Leiguarda R (1999) Effect of memantine (NMDA antagonist) on Parkinson’s disease: a double-blind crossover randomized study. Clin Neuropharmacol 22:273–276PubMedGoogle Scholar
  39. 39.
    Perry EK, Kerwin JM, Perry RH, Irving D, Blessed G, Fairbairn AF (1990) Cerebral cholinergic activity is related to the incidence of visual hallucinations in senile dementia of Lewy body type. Dementia 1:2–4Google Scholar
  40. 40.
    Perry EK, Marshall E, Kerwin J, Smith CJ, Jabeen S, Cheng AV, Perry RH (1990) Evidence of a monoaminergic cholinergic imbalance related to visual hallucinations in Lewy body dementia. J Neurochem 55:1454–1456PubMedCrossRefGoogle Scholar
  41. 41.
    Perry EK, Morris CM, Court JA, Cheng A, Fairbairn AF, McKeith IG, Irving D, Brown A, Perry RH (1995) Alteration in nicotine binding sites in Parkinson’s disease, Lewy body dementia and Alzheimer’s: possible index of early neuropathology. Neuroscience 64:385–395PubMedCrossRefGoogle Scholar
  42. 42.
    Rechsteiner M, Hill CP (2005) Mobilizing the proteolytic machine: cell biological roles of proteasome activators and inhibitors. Trends Cell Biol 15:27–33PubMedCrossRefGoogle Scholar
  43. 43.
    Reid RT, Sabbagh MN, Corey-Bloom J, Tiraboschi P, Thal LJ (2000) Nicotinic receptor losses in dementia with Lewy bodies: comparisons with Alzheimer’s disease. Neurobiol Aging 21:741–746CrossRefGoogle Scholar
  44. 44.
    Reisberg B, Doody R, Stoffler A, Schmitt F, Ferris S, Mobius HJ (2003) Memantine in moderate-to-severe Alzheimer’s disease. N Engl J Med 348:1333–1341PubMedCrossRefGoogle Scholar
  45. 45.
    Ridha BH, Josephs KA, Rossor MN (2005) Delusions and hallucinations in dementia with Lewy bodies: worsening with memantine. Neurology 65:481–482PubMedCrossRefGoogle Scholar
  46. 46.
    Sabbagh MN, Hake AM, Ahmed S, Farlow MR (2005) The use of memantine in dementia with Lewy bodies. J Alzheimers Dis 7:285–289PubMedGoogle Scholar
  47. 47.
    Scatton B, Javoy-Agid F, Rouquier L, Dubois B, Agid Y (1983) Reduction of cortical dopamine, noradrenaline, serotonin and their metabolites in Parkinson’s disease. Brain Res 275:321–328PubMedCrossRefGoogle Scholar
  48. 48.
    Scott HL, Pow DV, Tannenberg AE, Dodd PR (2002) Aberrant expression of the glutamate transporter excitatory amino acid transporter 1 (EAAT1) in Alzheimer’s disease. J Neurosci 22:(RC206):1–5Google Scholar
  49. 49.
    Sharp SI, Ballard CG, Ziabreva I, Perry EK, Aarsland D, Larsen JP, Francis PT (2005) Sertonin-1A receptor binding to frontal cortex in dementia with Lewy bodies and Parkinson’s disease dementia. pA2 (Ejournal of the British Pharmacological Society) v2 p65 (abstract)Google Scholar
  50. 50.
    Sharp SI, Ballard CG, Ziabreva I, Piggott MA, Perry RH, Perry EK, Aarsland D, Ehrt U, Larsen JP, Francis PT (2008) Cortical serotonin 1A receptor levels are associated with depression in patients with dementia with Lewy bodies and Parkinson’s disease dementia. Dement Geriatr Cogn Disord 26:330–338PubMedCrossRefGoogle Scholar
  51. 51.
    Shiozaki K, Iseki E, Hino H, Kosaka K (2001) Distribution of m1 muscarinic acetylcholine receptors in the hippocampus of patients with Alzheimer’s disease and dementia with Lewy bodies—an immunohistochemical study. J Neurol Sci 193:23–28PubMedCrossRefGoogle Scholar
  52. 52.
    Shiozaki K, Iseki E, Uchiyama H, Watanabe Y, Haga T, Kameyama K, Ikeda T, Yamamoto T, Kosaka K (1999) Alterations of muscarinic acetylcholine receptor subtypes in diffuse lewy body disease: relation to Alzheimer’s disease. J Neurol Neurosurg Psychiatry 67:209–213PubMedCrossRefGoogle Scholar
  53. 53.
    Thorns V, Mallory M, Hansen L, Masliah E (1997) Alterations in glutamate receptor 2/3 subunits and amyloid precursor protein expression during the course of Alzheimer’s disease and Lewy body variant. Acta Neuropathol (Berl) 94:539–548CrossRefGoogle Scholar
  54. 54.
    Tiraboschi P, Hansen LA, Alford M, Merdes A, Masliah E, Thal LJ, Corey-Bloom J (2002) Early and widespread cholinergic losses differentiate dementia with Lewy bodies from Alzheimer disease. Arch Gen Psychiatry 59:946–951PubMedCrossRefGoogle Scholar
  55. 55.
    Tsuboi Y, Dickson DW (2005) Dementia with Lewy bodies and Parkinson’s disease with dementia: are they different? Parkinsonism Relat Disord 11(Suppl 1):S47–S51PubMedCrossRefGoogle Scholar
  56. 56.
    Wonnacott S (1997) Presynaptic nicotinic ACh receptors. Trends Neurosci 20:92–98PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  1. 1.King’s College LondonWolfson Centre for Age-Related DiseasesLondonUK

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