Dementia Lewy bodies with

Dementia with Lewy bodies (DLB) is considered the second most common cause of dementia after AD. The disorder is characterized by progressive fluctuating cognitive impairment, visual hallucinations and motor features of Parkinsonism. Neocoitical cholinergic activity is more severely depleted in DLB than in AD, and DLB also affects the caudate nucleus, the thalamus and the brain stem. Tolerability of ChEI in DLB appears similar to AD, with some gastrointestinal effects and muscle cramps. 

Baba M, Nakajo S, Tu PH, Tomita T, Nakaya K, Lee VM, Trojanowski JQ, Iwatsubo T. Aggregation of alpha-synuclein in Lewy bodies of sporadic Parkinson s disease and dementia with Lewy bodies. Am J Pathol 1998 152 879-884. 

Spillantini MG, Crowther RA, Jakes R, Cairns NJ, Lantos PT, Goedert M. Filamentous a-synuclein inclusions link multiple system atrophy with Parkinson s disease and dementia with Lewy bodies. Neurosci Lett 1998 251 205-208. 

Baumann C., Dauvilliers Y., Mignot E., Bassetti C. (2004). Normal CSF hypocretin-1 (orexin A) levels in dementia with Lewy bodies associated with excessive daytime sleepiness. Eur. Neurol. 52, 73-6. 

McKeith, I. G., Galasko, D., Kosaka, K. etal. Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB) report of the consortium on DLB international workshop. Neurology 47 1113— 1124,1996. 

Tsuang, D. W., DiGiacomo, L. and Bird, T. D. Familial occurrence of dementia with Lewy bodies. Am. J. Geriatr. Psychiatr. 12 179-188,2004. 

Singleton, A. B., Gibson, A. M., McKeith, I. G. et al. Alpha2-macroglobulin polymorphisms in Alzheimer s disease and dementia with Lewy bodies. Neuroreport 10 1507-1510, 1999. 

Lewy bodies, neurofibrillary lesions and Pick bodies are intracellular filamentous inclusions. It is now well established that Lewy bodies are made of the protein a-synuclein and both neurofibrillary lesions and Pick bodies of the microtubule-associated protein tau. Mutations in the a-synuclein gene or an increase in its copy number cause autosomal-dominantly inherited forms of Parkinson s disease and dementia with Lewy bodies. Mutations in the tau gene cause a familial form of frontotemporal dementia. Here we review the evidence implicating a-synuclein and tau in these inherited and a number of sporadic neurodegenerative diseases. Collectively, a-synucleinopathies and tauopathies account for the vast majority of cases of late-onset neurodegenerative disease (Tables 45-1 and 45-2). 

TABLE 45-1 a-Synuclein diseases Idiopathic Parkinson s disease Dementia with Lewy bodies Pure autonomic failure REM sleep behavior disorder Lewy body dysphagia Incidental Lewy body disease Inherited Lewy body diseases Multiple system atrophy... 

E46K) was described in a Spanish family with Parkinson s disease and dementia with Lewy bodies. All three missense mutations are located in the repeat region of a-synuclein (Fig. 45-1 and Fig. 45-2). 

FIGURE 45-2 Missense mutations in the a-synuclein gene and multiplication of the chromosomal region containing the a-synuclein gene cause autosomal-dominantly inherited forms of Parkinson s disease and dementia with Lewy bodies. The a-synuclein gene is shown schematically in green. 

Filaments associated with Parkinson s disease and dementia with Lewy bodies are unbranched, with a length of 200-600 nm and a width of 5-10 nm. Full-length a-synuclein is present, with its amino- and carboxy-termini being exposed on the filament surface. The core of the filament extends over a stretch of about 70 amino acids that overlaps almost entirely with the lipid-binding region of a-synuclein. Of the three human synucleins, only a-synuclein is associated with the filamentous inclusions of Lewy body diseases. 

Glial cytoplasmic inclusions are strongly immunoreac-tive for a-synuclein and filaments isolated from the brains of patients with multiple system atrophy are labeled by a-synuclein antibodies [10]. As in dementia with Lewy bodies, assembled a-synuclein is nitrated and phosphory-lated at S129, and the number of a-synuclein-positive structures exceeds that stained by anti-ubiquitin antibodies, confirming that the accumulation of a-synuclein precedes ubiquitination. Filament morphologies and their staining characteristics were found to be similar to those of filaments extracted from the brains of patients with Parkinson s disease and dementia with Lewy bodies. 

FIGURE 45-5 Filaments extracted from the brains of patients with dementia with Lewy bodies (DLB) and multiple system atrophy (MSA) or assembled from bacterially expressed human a-synuclein (SYN) were decorated by an anti-a-synuclein antibody. The gold particles conjugated to the second antibody appear as black dots. Scale bar lOOnm. 

Atkinson, A., Singleton, A.B., Steward, A., et al. (1999) CYP2D6 is associated with Parkinson s disease but not with dementia with Lewy bodies or Alzheimer s disease. Pharmacogenetics, 9,31-35. 

Furuno, T., Kawanishi, C., Iseki, E., et al. (2001) No evidence of an association between CYP2D6 polymorphisms among Japanese and dementia with Lewy bodies. Psychiatry Clin. Neurosci., 55, 89-92. 

Junn, E., Ronchetti, R. D., Quezado, M. M., Kim, S. Y., and Mouradian, M. M. (2003). Tissue transglutaminase-induced aggregation of alpha-synuclein Implications for Lewy body formation in Parkinson s disease and dementia with Lewy bodies. Proc. Natl. Acad. Sci. USA 100, 2047-2052. 

Dementia with Lewy bodies, Parkinson s disease and neuroleptic sensitivity... 

Dementia with Lewy bodies (DLB) is a common neurodegenerative dementia, which mainly occurs in late life (McKeith et al., 1996). The main clinical symptoms include visual hallucinations, parkinsonism and disturbances of consciousness, in the context of a global cognitive dysfunction with prominent... 

Table 1. Dopaminergic activities in orbitofrontal cortex in dementia with Lewy bodies...

Figure 1. Dopamine D2 receptor binding in human temporal cortex from a patient with dementia with Lewy bodies and matched control. Numbers refer to cortical Brod-mann areas and Ent cx = entorhinal cortex.

Dementia with Lewy bodies A disorder of consciousness 265... 

The increasingly well-defined pathophysiology of the degenerative dementias adds a new domain to our understanding of the neural substrates of consciousness. The syndrome of dementia with Lewy bodies is distinguished by severe disturbances in consciousness. Patients with DLB suffer not only fluctuations... 

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