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Dementia with Lewy Bodies: Molecular Pathogenesis and Implications for Classification

Reed Neurological Research Center, UCLA, 710 Westwood Plaza, Box 951769, Los Angeles, CA 90095-1769jcummings{at}mednet.ucla.edu

Dementia with Lewy bodies results from the accumulation from Lewy-type pathology (Lewy bodies, Lewy neurites), secondary cellular injury, and apoptotic neurodegeneration. The severity of dementia correlates with the abundance of Lewy bodies in the cortex. Dementia with Lewy bodies co-occurs with 2 specific syndromes, one beginning with dementia complicated by visual hallucinations and parkinsonism; the other beginning with Parkinson’s disease and progressing to a parkinsonian-dementia syndrome. Clinical syndromes associated with these 2 pathways to dementia share many clinical features including the type of cognitive impairment, fluctuating attentional disturbances, prominent visual hallucinations and psychosis, depression, and rapid eye movement sleep behavior disorder. Lewy pathology results from protein misfolding and the accumulation of alpha-synuclein in the cell cytoplasm. Dementia with Lewy bodies is one of many neurodegenerative disorders linked to protein misfolding. Identification of clinical symptoms indicative of the presence of a specific protein disturbance will assist in choosing therapies when protein-specific disease-modifying treatments are available. Classification systems based on symptom complexes related to the presence of protein misfolding will assist therapeutic decisions. (J Geriatr Psychiatry Neurol 2004; 17:112-119)

Key Words: dementia with Lewy bodies • molecular pathogenesis

References

• 1. Dawson TM, Dawson VL. Molecular pathways of neurodegeneration in Parkinson’s disease. Science 2003; 302:819-822.[Abstract/Free Full Text]
• 2. Dickson D. A-synuclein and the Lewy body disorders. Curr Opin Neurol 2001; 14:423-432.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• 3. Bence NF, Sampat RM, Kopito RR. Impairment of the ubiquitinproteasome system by protein aggregation. Science 2001; 292:1552-1555.[Abstract/Free Full Text]
• 4. Lotharius J, Brundin P. Pathogenesis of Parkinson’s disease: dopamine, vesicles and alpha-synuclein. Nat Rev 2002; 3:1-11.
• 5. Cummings JL. Towards a molecular neuropsychiatry of neurodegenerative diseases. Ann Neurol 2003; 54:147-154.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• 6. Hardy J, Gwinn-Hardy K. Genetic classification of primary neurodegenerative disease. Science 1998; 282:1075-1079.[Abstract/Free Full Text]
• 7. Shoulson I. Experimental therapeutics of neurodegenerative disorders: unmet needs. Science 1998; 282:1072-1074.[Abstract/Free Full Text]
• 8. Martin JB, Longo FM. Molecular neurobiology. In: Jameson LJ, ed. Principles of molecular medicine. Totowa, NJ: Humana Press, 1998:871-890.
• 9. Taylor JP, Hardy J, Fischbeck KH. Toxic proteins in neurodegenerative disease. Science 2002; 296:1991-1995.[Abstract/Free Full Text]
• 10. Trojanowski JQ, Lee VM-Y."Fatal attractions" of proteins.A comprehensive hypothetical mechanism underlying Alzheimer’s disease and other neurodegenerative disorders. Ann N Y Acad Sci 2000; 924:62-67.[Web of Science][Medline] [Order article via Infotrieve]
• 11. Lovestone S, McLoughlin DM. Protein aggregates and dementia: is there a common toxicity? J Neurol Neurosurg Psychiatry 2002; 72:152-161.[Abstract/Free Full Text]
• 12. Walker LC, LeVine H 3rd. The cerebral proteopathies. Neurobiol Aging 2000; 21:559-561.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• 13. Ganesh S, Delgado-Escueta AV, Suzuki T, et al. Genotype-phenotype correlations for EPM2A mutations in Lafora’s progressive myoclonus epilepsy: exon 1 mutations associate with an early-onset cognitive deficit subphenotype. Hum Mol Genet 2002; 11:1263-1271.[Abstract/Free Full Text]
• 14. Stumpf E, Masson H, Duquette A, et al. Adult Alexander disease with autosomal dominant transmission: a distinct entity caused by mutation in the glial fibrillary acid protein gene. Arch Neurol 2003; 60:1307-1312.[Abstract/Free Full Text]
• 15. Forman MS, Lee VM, Trojanowski JQ. ‘Unfolding’ pathways in neurodegenerative disease. Trends Neurosci 2003; 26:407-410.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• 16. Trivedi JR, Wolfe GI, Nations SP, et al. Adult polyglucosan body disease associated with Lewy bodies and tremor. Arch Neurol 2003; 60:764-766.[Abstract/Free Full Text]
• 17. Bradshaw CB, Davis RL, Shrimpton AE, et al. Cognitive deficits associated with a recently reported familial neurodegenerative disease. Arch Neurol 2001; 58:1429-1434.[Abstract/Free Full Text]
• 18. Davis RL, Shrimpton AE, Holohan PD, et al. Familial dementia caused by polymerization of mutant neuroserpin. Nature 1999; 401:376-379.[Medline] [Order article via Infotrieve]
• 19. Lomas DA, Carrell RW. Serpinopathies and the conformational dementias. Nat Rev Genet 2002; 3:759-768.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• 20. Saito Y, Suzuki K, Nanba E, et al. Niemann-Pick type C disease: accelerated neurofibrillary tangle formation and amyloid beta deposition associated with apolipoprotein E epsilon 4 homozygosity. Ann Neurol 2002; 52:351-355.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• 21. Dobson CM. Protein folding and disease: a view from the first Horizon Symposium. Nat Rev Drug Discov 2003; 2:154-160.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• 22. Wolozin B, Behl C. Mechanisms of neurodegenerative disorders part 1: protein aggregates. Arch Neurol 2000; 57:793-796.[Free Full Text]
• 23. Wolozin B, Behl C. Mechanisms of neurodegenerative disorders part 2: control of cell death. Arch Neurol 2000; 57:801-804.[Free Full Text]
• 24. Bucciantini M, Giannoni E, Chiti F, et al. Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases. Nature 2002; 416:507-511.[CrossRef][Medline] [Order article via Infotrieve]
• 25. Golbe LI. Neurodegeneration in the age of molecular biology. Br Med J 2002; 324:1467-1468.[Free Full Text]
• 26. Brookes AJ, St Clair D. Synuclein proteins and Alzheimer’s disease. Trends Neurosci 1994; 17:404-405.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• 27. Lippa CF, Schmidt ML, Lee VM, et al. Alpha-synuclein in familial Alzheimer disease: epitope mapping parallels dementia with Lewy bodies and Parkinson disease. Arch Neurol 2001; 58:1817-1820.[Abstract/Free Full Text]
• 28. Lippa CF, Schmidt ML, Lee VM, et al. Antibodies to alpha-synuclein detect Lewy bodies in many Down’s syndrome brains with Alzheimer’s disease. Ann Neurol 1999; 45:353-357.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• 29. 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.[Abstract/Free Full Text]
• 30. Masliah E, Rockenstein E, Veinbergs I, et al. Beta-amyloid peptides enhance alpha-synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer’s disease and Parkinson’s disease. Proc Natl Acad Sci U S A 2001; 98:12245-12250.[Abstract/Free Full Text]
• 31. Giasson BI, Forman MS, Higuchi M, et al. Initiation and synergistic fibrillization of tau and alpha-synuclein. Science 2003; 300:636-640.[Abstract/Free Full Text]
• 32. Oddo S, Caccamo A, Kitazawa M, et al. Amyloid deposition precedes tangle formation in a triple transgenic model of Alzheimer’s disease. Neurobiol Aging 2003; 24:1063-1070.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• 33. Braak H, De Tredici K, Rub U, et al. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 2003; 24:197-211.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• 34. Cummings JL, Cole G. Alzheimer’s disease. JAMA 2002; 287:2335-2338.[Free Full Text]
• 35. McKeith IG, Perry EK, Perry RH. Report of the second dementia with Lewy body international workshop: Diagnosis and treatment. Neurology 1999; 53:902-905.[Abstract/Free Full Text]
• 36. Cummings JL. Conference summary: Third International Workshop on Dementia with Lewy Bodies and Parkinson’s Disease Dementia. Reviews in Neurological Disease, in press.
• 37. Duda JE, Giasson BI, Mabon ME, et al. Novel antibodies to synuclein show abundant striatal pathology in Lewy body diseases. Ann Neurol 2002; 52:205-210.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• 38. Rub U, Del Tredici K, Schultz C, et al. Parkinson’s disease: the thalamic components of the limbic loop are severely impaired by alpha-synuclein immunopositive inclusion body pathology. Neurobiol Aging 2002; 23:245-254.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• 39. Spillantini MG, Schimdt ML, Lee VM-Y, et al. A-synuclein in Lewy bodies. Nature 1997; 388:839-840.[CrossRef][Medline] [Order article via Infotrieve]
• 40. Trojanowski JQ, Lee VM. Aggregation of neurofilament and alpha-synuclein proteins in Lewy bodies: implications for the pathogenesis of Parkinson disease and Lewy body dementia. Arch Neurol 1998; 55:151-152.[Free Full Text]
• 41. Boeve BF, Silber MH, Parisi JE, et al. Synucleinopathy pathology and REM sleep behavior disorder plus dementia or parkinsonism. Neurology 2003; 61:40-45.[Abstract/Free Full Text]
• 42. Turner RS. Idiopathic rapid eye movement sleep behavior disorder is a harbinger of dementia with Lewy bodies. J Geriatr Psychiatry Neurol 2002; 15:195-199.
• 43. Churchyard A, Lees AJ. The relationship between dementia and direct involvement of the hippocampus and amygdala in Parkinson’s disease. Neurology 1997; 49:1570-1576.[Abstract/Free Full Text]
• 44. Mattila PM, Rinne JO, Helenius H, et al. Alpha-synucleinimmunoreactive cortical Lewy bodies are associated with cognitive impairment in Parkinson’s disease. Acta Neuropathol 2000; 100:285-290.[CrossRef][Medline] [Order article via Infotrieve]
• 45. Hurtig H, Trojanowski JQ, Galvin J, et al. Alpha-synuclein cortical Lewy bodies correlate with dementia in Parkinson’s disease. Neurology 2000; 54:1916-1921.[Abstract/Free Full Text]
• 46. Ballard CG, Aarsland D, McKeith I, et al. Fluctuations in attention: PD dementia vs DLB with parkinsonism. Neurology 2002; 59:1714-1720.[Abstract/Free Full Text]
• 47. Golbe LI, Di Iorio G, Sanges G, et al. Clinical genetic analysis of Parkinson’s disease in the Contursi kindred. Ann Neurol 1996; 40:767-775.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• 48. 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.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• 49. 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.[Abstract/Free Full Text]
• 50. Payami H, Lee N, Zareparsi S, et al. Parkinson’s disease, CYP2D6 polymorphism, and age. Neurology 2001; 56:1363-1370.[Abstract/Free Full Text]
• 51. Tan EK, Chai A, Teo YY, et al. Alpha-synuclein haplotypes implicated in risk of Parkinson’s disease. Neurology 2004; 62:128-131.[Abstract/Free Full Text]
• 52. Mizuno Y, Hattori N, Mori H, et al. Parkin and Parkinson’s disease. Curr Opin Neurol 2001; 14:477-482.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• 53. Lucking CB, Durr A, Bonifati V, et al. Association between early-onset Parkinson’s disease and mutations in Parkin gene. N Engl J Med 2000; 342:1560-1567.[Abstract/Free Full Text]
• 54. Hardy J, Cookson MR, Singleton A. Genes and parkinsonism. Lancet Neurol 2003; 2:221-228.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• 55. Lansbury PT Jr, Brice A. Genetics of Parkinson’s disease and biochemical studies of implicated gene products. Curr Opin Cell Biol 2002; 14:653-660.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

Journal of Geriatric Psychiatry and Neurology, Vol. 17, No. 3, 112-119 (2004)
DOI: 10.1177/0891988704267473


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