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Abstract

For more than a decade, researchers have refined criteria for the diagnosis of dementia with Lewy bodies (DLB) and at the same time have recognized that cognitive impairment and dementia occur commonly in patients with Parkinson disease (PD). This article addresses the relationship between DLB, PD, and PD with dementia (PDD). The authors agreed to endorse “Lewy body disorders” as the umbrella term for PD, PDD, and DLB, to promote the continued practical use of these three clinical terms, and to encourage efforts at drug discovery that target the mechanisms of neurodegeneration shared by these disorders of α-synuclein metabolism. We concluded that the differing temporal sequence of symptoms and clinical features of PDD and DLB justify distinguishing these disorders. However, a single Lewy body disorder model was deemed more useful for studying disease pathogenesis because abnormal neuronal α-synuclein inclusions are the defining pathologic process common to both PDD and DLB. There was consensus that improved understanding of the pathobiology of α-synuclein should be a major focus of efforts to develop new disease-modifying therapies for these disorders. The group agreed on four important priorities: 1) continued communication between experts who specialize in PDD or DLB; 2) initiation of prospective validation studies with autopsy confirmation of DLB and PDD; 3) development of practical biomarkers for α-synuclein pathologies; 4) accelerated efforts to find more effective treatments for these diseases.

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References

1.
McKeith IG, Galasko D, Kosaka K, et al. Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop. Neurology 1996;47:1113–1124.
2.
Hansen L, Salmon D, Galasko D, et al. The Lewy body variant of Alzheimer's disease: a clinical and pathologic entity. Neurology 1990;40:1–8.
3.
Parkkinen L, Soininen H, Alafuzoff I. Regional distribution of alpha-synuclein pathology in unimpaired aging and Alzheimer disease. J Neuropathol Exp Neurol 2003;62:363–367.
4.
Hamilton RL. Lewy bodies in Alzheimer's disease: a neuropathological review of 145 cases using alpha-synuclein immunohistochemistry. Brain Pathol 2000;10:378–384.
5.
Emre M. Dementia associated with Parkinson's disease. Lancet Neurol 2003;2:229–237.
6.
Polymeropoulos MH, Lavedan C, Leroy E, et al. Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science 1997;276:2045–2047.
7.
McKeith IG, Dickson DW, Lowe J, et al. Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology 2005;65:1863–1872.
8.
Litvan I, MacIntyre A, Goetz CG, et al. Accuracy of the clinical diagnoses of Lewy body disease, Parkinson disease, and dementia with Lewy bodies: a clinicopathologic study. Arch Neurol 1998;55:969–978.
9.
Lopez OL, Litvan I, Catt KE, et al. Accuracy of four clinical diagnostic criteria for the diagnosis of neurodegenerative dementias. Neurology 1999;53:1292–1299.
10.
McKeith IG, Ballard CG, Perry RH, et al. Prospective validation of consensus criteria for the diagnosis of dementia with Lewy bodies. Neurology 2000;54:1050–1058.
11.
Merdes AR, Hansen LA, Jeste DV, et al. Influence of Alzheimer pathology on clinical diagnostic accuracy in dementia with Lewy bodies. Neurology 2003;60:1586–1590.
12.
Boeve BF, Silber MH, Ferman TJ, et al. REM sleep behavior disorder and degenerative dementia: an association likely reflecting Lewy body disease. Neurology 1998;51:363–370.
13.
Aarsland D, Perry R, Larsen JP, et al. Neuroleptic sensitivity in Parkinson's disease and parkinsonian dementias. J Clin Psychiatry 2005;66:633–637.
14.
Aarsland D, Litvan I, Salmon D, Galasko D, Wentzel-Larsen T, Larsen JP. Performance on the dementia rating scale in Parkinson's disease with dementia and dementia with Lewy bodies: comparison with progressive supranuclear palsy and Alzheimer's disease. J Neurol Neurosurg Psychiatry 2003;74:1215–1220.
15.
Collerton D, Burn D, McKeith I, O'Brien J. Systematic review and meta-analysis show that dementia with Lewy bodies is a visual-perceptual and attentional-executive dementia. Dement Geriatr Cogn Disord 2003;16:229–237.
16.
Mosimann UP, Mather G, Wesnes KA, O'Brien JT, Burn DJ, McKeith IG. Visual perception in Parkinson disease dementia and dementia with Lewy bodies. Neurology 2004;63:2091–2096.
17.
Mosimann UP, Rowan EN, Partington CE, et al. Characteristics of visual hallucinations in Parkinson disease dementia and dementia with Lewy bodies. Am J Geriatr Psychiatry 2006;14:153–160.
18.
Noe E, Marder K, Bell KL, Jacobs DM, Manly JJ, Stern Y. Comparison of dementia with Lewy bodies to Alzheimer's disease and Parkinson's disease with dementia. Mov Disord 2004;19:60–67.
19.
Pillon B, Deweer B, Michon A, Malapani C, Agid Y, Dubois B. Are explicit memory disorders of progressive supranuclear palsy related to damage to striatofrontal circuits? Comparison with Alzheimer's, Parkinson's, and Huntington's diseases. Neurology 1994;44:1264–1270.
20.
Downes JJ, Priestley NM, Doran M, Ferran J, Ghadiali E, Cooper P. Intellectual, mnemonic, and frontal functions in dementia with Lewy bodies: a comparison with early and advanced Parkinson's disease. Behav Neurol 1998;11:173–183.
21.
Aarsland D, Ballard C, Larsen JP, McKeith I. A comparative study of psychiatric symptoms in dementia with Lewy bodies and Parkinson's disease with and without dementia. Int J Geriatr Psychiatry 2001;16:528–536.
22.
Mosimann UP, Muri RM, Burn DJ, Felblinger J, O'Brien JT, McKeith IG. Saccadic eye movement changes in Parkinson's disease dementia and dementia with Lewy bodies. Brain 2005;128:1267–1276.
23.
Burn DJ, McKeith IG. Current treatment of dementia with Lewy bodies and dementia associated with Parkinson's disease. Mov Disord 2003;18(suppl 6):S72–S79.
24.
Hurtig HI, Trojanowski JQ, Galvin J, et al. Alpha-synuclein cortical Lewy bodies correlate with dementia in Parkinson's disease. Neurology 2000;54:1916–1921.
25.
Aarsland D, Perry R, Brown A, Larsen JP, Ballard C. Neuropathology of dementia in Parkinson's disease: a prospective, community-based study. Ann Neurol 2005;58:773–776.
26.
Duda JE, Giasson BI, Mabon ME, Lee VM, Trojanowski JQ. Novel antibodies to synuclein show abundant striatal pathology in Lewy body diseases. Ann Neurol 2002;52:205–210.
27.
McKeel DW, Jr., Price JL, Miller JP, et al. Neuropathologic criteria for diagnosing Alzheimer disease in persons with pure dementia of Alzheimer type. J Neuropathol Exp Neurol 2004;63:1028–1037.
28.
Del Ser T, Hachinski V, Merskey H, Munoz DG. Clinical and pathologic features of two groups of patients with dementia with Lewy bodies: effect of coexisting Alzheimer-type lesion load. Alzheimer Dis Assoc Disord 2001;15:31–44.
29.
Baba M, Nakajo S, Tu PH, et al. Aggregation of alpha-synuclein in Lewy bodies of sporadic Parkinson's disease and dementia with Lewy bodies. Am J Pathol 1998;152:879–884.
30.
Forman MS, Lee VM, Trojanowski JQ. Nosology of Parkinson's disease: looking for the way out of a quagmire. Neuron 2005;47:479–482.
31.
Giasson BI, Lee V.M.-Y, and Trojanowski JQ. Parkinson's disease, dementia With Lewy bodies, multiple system atrophy and the spectrum of diseases with alpha-synuclein inclusions. In: The neuropathology of dementia, Esiri M, Lee VM-Y, Trojanowski JQ, eds. Cambridge, England: Cambridge University Press, 2004:353–375.
32.
Harding AJ, Broe GA, Halliday GM. Visual hallucinations in Lewy body disease relate to Lewy bodies in the temporal lobe. Brain 2002;125:391–403.
33.
Aarsland D, Perry E, Perry R, Larsen JP, Ballard CG. Duration of Parkinsonism prior to dementia is associated with a different pattern of neuropathological and neurochemical substrates in DLB and PDD [abstract]. Mov Disord 2006;21:S96.
34.
Fujiwara H, Hasegawa M, Dohmae N, et al. Alpha-synuclein is phosphorylated in synucleinopathy lesions. Nat Cell Biol 2002;4:160–164.
35.
Li J, Zhu M, Manning-Bog AB, Di Monte DA, Fink AL. Dopamine and L-dopa disaggregate amyloid fibrils: implications for Parkinson's and Alzheimer's disease. FASEB J 2004;18:962–964.
36.
Cappai R, Leck SL, Tew DJ, et al. Dopamine promotes alpha-synuclein aggregation into SDS-resistant soluble oligomers via a distinct folding pathway. FASEB J 2005;19:1377–1379.
37.
Li W, West N, Colla E, et al. Aggregation promoting C-terminal truncation of alpha-synuclein is a normal cellular process and is enhanced by the familial Parkinson's disease-linked mutations. Proc Natl Acad Sci USA 2005;102:2162–2167.
38.
Klucken J, Ingelsson M, Shin Y, et al. Clinical and biochemical correlates of insoluble alpha-synuclein in dementia with Lewy bodies. Acta Neuropathol (Berl) 2006;111:101–108.
39.
McNaught KS, Shashidharan P, Perl DP, Jenner P, Olanow CW. Aggresome-related biogenesis of Lewy bodies. Eur J Neurosci 2002;16:2136–2148.
40.
Olanow CW, Perl DP, Demartino GN, McNaught KS. Lewy-body formation is an aggresome-related process: a hypothesis. Lancet Neurol 2004;3:496–503.
41.
Deramecourt V, Bombois S, Maurage CA, et al. Biochemical staging of synucleinopathy and amyloidopathy in dementia with Lewy bodies. J Neuropathol Exp Neurol 2006;65:278–288.
42.
Langston JW, Sastry S, Chan P, Forno LS, Bolin LM, Di Monte DA. Novel alpha-synuclein-immunoreactive proteins in brain samples from the Contursi kindred, Parkinson's, and Alzheimer's disease. Exp Neurol 1998;154:684–690.
43.
Zarranz JJ, Alegre J, Gomez-Esteban JC, et al. The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Ann Neurol 2004;55:164–173.
44.
Chartier-Harlin MC, Kachergus J, Roumier C, et al. Alpha-synuclein locus duplication as a cause of familial Parkinson's disease. Lancet 2004;364:1167–1169.
45.
Nishioka K, Hayashi S, Farrer MJ, et al. Clinical heterogeneity of alpha-synuclein gene duplication in Parkinson's disease. Ann Neurol 2006;59:298–309.
46.
Singleton AB, Farrer M, Johnson J, et al. Alpha-synuclein locus triplication causes Parkinson's disease. Science 2003;302:841.
47.
Singleton A, Gwinn-Hardy K. Parkinson's disease and dementia with Lewy bodies: a difference in dose? Lancet 2004;364:1105–1107.
48.
Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M. Alpha-synuclein in Lewy bodies. Nature 1997;388:839–840.
49.
Kruger R, Kuhn W, Muller T, et al. Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson's disease. Nat Genet 1998;18:106–108.
50.
Zarranz JJ, Alegre J, Gomez-Esteban JC, et al. The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Ann Neurol 2004;55:164–173.
51.
Lippa CF, Fujiwara H, Mann DM, et al. Lewy bodies contain altered alpha-synuclein in brains of many familial Alzheimer's disease patients with mutations in presenilin and amyloid precursor protein genes. Am J Pathol 1998;153:1365–1370.
52.
Lippa CF, Schmidt ML, Lee VM, Trojanowski JQ. Antibodies to alpha-synuclein detect Lewy bodies in many Down's syndrome brains with Alzheimer's disease. Ann Neurol 1999;45:353–357.
53.
Zimprich A, Biskup S, Leitner P, et al. Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 2004;44:601–607.
54.
Farrer MJ. Genetics of Parkinson disease: paradigm shifts and future prospects. Nat Rev Genet 2006;7:306–318.
55.
Ghetti B, Hutton M, Wszolek ZK. Frontotemporal dementia and parkinsonism linked to chromosome 17 associated with tau gene mutations (FTDP-17T). In: Dickson DW, ed. Neurodegeneration: the molecular pathology of dementia and movement disorders. Basel: International Society of Neuropathology Press, 2003:86–102.
56.
Barber R, Ballard C, McKeith IG, Gholkar A, O'Brien JT. MRI volumetric study of dementia with Lewy bodies: a comparison with AD and vascular dementia. Neurology 2000;54:1304–1309.
57.
O'Brien JT, Metcalfe S, Swann A, et al. Medial temporal lobe width on CT scanning in Alzheimer's disease: comparison with vascular dementia, depression and dementia with Lewy bodies. Dement Geriatr Cogn Disord 2000;11:114–118.
58.
Cousins DA, Burton EJ, Burn D, Gholkar A, McKeith IG, O'Brien JT. Atrophy of the putamen in dementia with Lewy bodies but not Alzheimer's disease: an MRI study. Neurology 2003;61:1191–1195.
59.
Cordery RJ, Tyrrell PJ, Lantos PL, Rossor MN. Dementia with Lewy bodies studied with positron emission tomography. Arch Neurol 2001;58:505–508.
60.
Klunk WE, Engler H, Nordberg A, et al. Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound-B. Ann Neurol 2004;55:306–319.
61.
Brooks DJ, Piccini P. Imaging in Parkinson's disease: the role of monoamines in behavior. Biol Psychiatry 2006;59:908–918.
62.
Lippa CF, Smith TW, Perry E. Dementia with Lewy bodies: choline acetyltransferase parallels nucleus basalis pathology. J Neural Transm 1999;106:525–535.
63.
Perry EK, Haroutunian V, Davis KL, et al. Neocortical cholinergic activities differentiate Lewy body dementia from classical Alzheimer's disease. Neuroreport 1994;5:747–749.
64.
Perry EK, Morris CM, Court JA, et al. Alteration in nicotine binding sites in Parkinson's disease, Lewy body dementia and Alzheimer's disease: possible index of early neuropathology. Neuroscience 1995;64:385–395.
65.
Bohnen NI, Kaufer DI, Ivanco LS, 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 2003;60:1745–1748.
66.
Shinotoh H, Namba H, Yamaguchi M, et al. In vivo mapping of brain cholinergic function in Parkinson's disease and progressive supranuclear palsy. Adv Neurol 2001;86:249–255.
67.
El Agnaf OM, Salem SA, Paleologou KE, et al. Detection of oligomeric forms of alpha-synuclein protein in human plasma as a potential biomarker for Parkinson's disease. FASEB J 2006;20:419–425.
68.
Aarsland D, Laake K, Larsen JP, Janvin C. Donepezil for cognitive impairment in Parkinson's disease: a randomised controlled study. J Neurol Neurosurg Psychiatry 2002;72:708–712.
69.
Emre M, Aarsland D, Albanese A, et al. Rivastigmine for dementia associated with Parkinson's disease. N Engl J Med 2004;351:2509–2518.
70.
McKeith I, Del Ser T, Spano P, et al. Efficacy of rivastigmine in dementia with Lewy bodies: a randomised, double-blind, placebo-controlled international study. Lancet 2000;356:2031–2036.
71.
Ravina B, Putt M, Siderowf A, et al. Donepezil for dementia in Parkinson's disease: a randomised, double blind, placebo controlled, crossover study. J Neurol Neurosurg Psychiatry 2005;76:934–939.
72.
Wesnes KA, McKeith IG, Ferrara R, et al. Effects of rivastigmine on cognitive function in dementia with Lewy bodies: a randomised placebo-controlled international study using the cognitive drug research computerised assessment system. Dement Geriatr Cogn Disord 2002;13:183–192.
73.
Thomas AJ, Burn DJ, Rowan EN, et al. A comparison of the efficacy of donepezil in Parkinson's disease with dementia and dementia with Lewy bodies. Int J Geriatr Psychiatry 2005;20:938–944.
74.
Bohnen NI, Kaufer DI, Hendrickson R, et al. Degree of inhibition of cortical acetylcholinesterase activity and cognitive effects by donepezil treatment in Alzheimer's disease. J Neurol Neurosurg Psychiatry 2005;76:315–319.
75.
Ritchie CW, Ames D, Clayton T, Lai R. Metaanalysis of randomized trials of the efficacy and safety of donepezil, galantamine, and rivastigmine for the treatment of Alzheimer disease. Am J Geriatr Psychiatry 2004;12:358–369.
76.
Minett TS, Thomas A, Wilkinson LM, et al. What happens when donepezil is suddenly withdrawn? An open label trial in dementia with Lewy bodies and Parkinson's disease with dementia. Int J Geriatr Psychiatry 2003;18:988–993.
77.
Menendez-Gonzalez M, Calatayud MT, Blazquez-Menes B. Exacerbation of Lewy bodies dementia due to memantine. J Alzheimers Dis 2005;8:289–291.
78.
Ridha BH, Josephs KA, Rossor MN. Delusions and hallucinations in dementia with Lewy bodies: worsening with memantine. Neurology 2005;65:481–482.
79.
Sabbagh MN, Hake AM, Ahmed S, Farlow MR. The use of memantine in dementia with Lewy bodies. J Alzheimers Dis 2005;7:285–289.
80.
Molloy S, McKeith IG, O'Brien JT, Burn DJ. The role of levodopa in the management of dementia with Lewy bodies. J Neurol Neurosurg Psychiatry 2005;76:1200–1203.
81.
Skovronsky DM, Lee VM, Trojanowski JQ. Neurodegenerative diseases: new concepts of pathogenesis and their therapeutic implications. Annu Rev Pathol 2006;1:151–170.
82.
Bilen J, Bonini NM. Drosophila as a model for human neurodegenerative disease. Annu Rev Genet 2005;39:153–171.
83.
Cookson MR. Neurons inflict self-harm. Nat Med 2005;11:1159–1161.
84.
Savitt JM, Dawson VL, Dawson TM. Diagnosis and treatment of Parkinson disease: molecules to medicine. J Clin Invest 2006;116:1744–1754.
85.
Giasson BI. Mitochondrial injury: a hot spot for parkinsonism and Parkinson's disease? Sci Aging Knowl Environ 2004:pe42.
86.
Greenamyre JT, Hastings TG. Biomedicine. Parkinson's—divergent causes, convergent mechanisms. Science 2004;304:1120–1122.
87.
Petersen RC, Stevens JC, Ganguli M, Tangalos EG, Cummings JL, DeKosky ST. Practice parameter: early detection of dementia: mild cognitive impairment (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2001;56:1133–1142.

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Published In

Neurology®
Volume 68Number 11March 13, 2007
Pages: 812-819
PubMed: 17353469

Publication History

Published online: March 12, 2007
Published in print: March 13, 2007

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Affiliations & Disclosures

A. B. Singleton, MD, PhD
J. Q. Trojanowski, MD, PhD
for the DLB/PDD Working Group

Notes

Address correspondence and reprint requests to Dr. Carol F. Lippa, Department of Neurology, Drexel University College of Medicine, Mail Stop 423, 245 N. 15th Street, Philadelphia, PA 19102; e-mail: [email protected]

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