Lewy body diseases

Wakabayashi K, Hansen LA, Vincent I, Mallory M, Masliah E. Neurofibrillary tangles in the dentate granule cells of patients with Alzheimer s disease, Lewy body disease and progressive supranuclear palsy. Acta Neuropathol Berl 1997 93 7-12. 

PARKINSON S DISEASE AND OTHER LEWY BODY DISEASES 747... 

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... 

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. 

This work revealed an unexpected molecular link between multiple system atrophy and Lewy body diseases. The main difference is that in multiple system atrophy most of the a-synuclein pathology is found in glial cells, whereas in Lewy body diseases most of the pathology is present in nerve cells. 

They have many of the morphological and ultrastructural characteristics of disease filaments [11, 12] (Fig. 45-5). Assembly is a nucleation-dependent process that occurs through its amino-terminal repeats. The carboxy-terminal region, in contrast, is inhibitory. Assembly is accompanied by the transition from random coil to a [3-pleated sheet. By electron diffraction, a-synuclein filaments show a conformation characteristic of amyloid fibers. Under the conditions of these experiments, P- and y-synucleins failed to assemble, consistent with their absence from the filamentous lesions of the human diseases. When incubated with a-synuclein, P- and y-synucleins inhibit the fibrillation of a-synuclein, suggesting that they may indirectly influence the pathogenesis of Lewy body diseases and multiple system atrophy. 

The new work has established that a neurodegenerative pathway leading from soluble to insoluble, filamentous a-synuclein is central to Lewy body diseases and multiple system atrophy. The development of experimental models of a-synucleinopathies has opened the way to the identification of the detailed mechanisms by which the formation of inclusions causes disease. These model systems have also made it possible to identify disease modifiers that may well lead to the development of the first mechanism-based therapies for these diseases. At a conceptual level, it will be important to understand whether a-synuclein has a role to play in disorders, such as autosomal-recessive juvenile forms of parkinsonism caused by mutations in the Parkin, DJ-1 and PINK-1 genes, or whether there are entirely separate mechanisms by which the dopaminergic nerve cells of the substantia nigra degenerate in Parkinson s disease and in inherited disorders with parkinsonism. 

Dalfo, E. and Ferrer, I. (2008). Early a-synuclein lipoxidation in neocortex in Lewy body diseases. Neurobiol. Aging 29,408—417. 

Gortical Lewy body disease produces a clinically distinct dementia syndrome. Two of the three core features of this syndrome involve abnormalities of consciousness, firstly marked fluctuations in consciousness (usually most apparent in applied cognitive performance) and secondly psychosis, in... 

Although some of the earliest case presentations of cortical Lewy body disease were characterised by disorientation (Mitsuyama et al., 1984 Okazaki et al., 1961 Yagishita etal., 1980), the first study to specifically characterise fluctuations was that of By meet al. (1989) on 15 DLB cases. For one patient (case 11),... 

Atypical neuroleptics have a better side-effect profile, and several studies have confirmed their efficacy. Risperidone has been found effective in the treatment of dementia in patients with agitation (N. Hermann et al. 1998 Jeanblanc and Davis 1995 Jeste et al. 1996 I. R. Katz et al. 1999 Lavretsky and Sultzer 1998), in patients with Lewy body disease (Geizer and Ancill 1998), or in patients with L-dopa-induced hallucinations (Meco et al. 1994). Risperidone has better tolerability than classic neuroleptics such as thioridazine and haloperidol (Frenchman and Prince 1997). No studies of the efficacy of olanzapine in the treatment of agitation in patients with dementia have been done, but its use is widely advocated. 

Lee H, Cooney JM, Lawlor BA. The use of risperidone, an atypical neuroleptic, in Lewy body disease. Int J Geriatr Psychiatry 1994 9 415-417. 

Patients with ALS/PDC also show a moderate loss of choline acetyl transferase activity in the midfrontal and inferior parietal cortex and a severe loss in the superior temporal cortex (Masliah et al., 2001). This deficit is similar to that seen in Alzheimer disease and less severe than in Lewy body disease. Thus, cholinergic deficits in the neocortex may contribute to some of the cognitive alterations in ALS/PDC. 

A reduction in GSH has been detected in the substantia nigra pars compacta of patients with Parkinson s disease. Furthermore, a similar reduction in GSH has been found in substantia nigra pars compacta of cases with incidental Lewy body diseases, who are thought to have a preclinical form of Parkinson s disease. These findings suggest that a reduction in GSH, with the ensuing oxidative stress, may be a critical factor in the pathogenesis of Parkinson s disease. 

Ohara K, Kondo N (1998) Changes of monoamines in post-mortem brains from patients with diffuse Lewy body disease. Prog. Neuropsychopharmacol. Biol. Psychiatry 22 311-317. 

Anderson JP, Walker DE, Goldstein JM, de Laat R, Banducci K, et al. 2006. Phosphorylation of Ser-129 is the dominant pathological modification of a-synuclein in familial and sporadic Lewy body disease. J Biol Chem 281 29739-29752. 

The efficacy and safety of risperidone have been evaluated in 44 patients (25 women and 19 men) with Parkinson s disease (80). There was either complete or near-complete resolution of hallucinations in 23, but an unsatisfactory response (n = 6) or worsening of parkinsonism (n = 6) in 12. Excluding patients with diffuse Lewy body disease, there was no significant worsening of scores on the Unified Parkinson s Disease Rating Scale after either 3 or 6 months of treatment, and the presence of dementia did not predict the response to treatment. 

Lewy body disease Difficult to clinically distinguish from Alzheimer s disease at times and may coexist with Alzheimer s disease frequent fluctuations in cognition and behavior (can look like delirium but persists) tremor and rigidity similar to Parkinson s disease repeated unexplained falls unusual sensitivity to neuroleptic medications (more side effects). Lewy bodies are found in neurons at autopsy. 

Avoid high-potency drugs (e.g., haloperidol) in Lewy body disease. 

It should be noted that the abnormalities on brain imaging described above are not exclusive to or diagnostic of vascular cognitive impairment deep white matter lesions and periventricular lesions have been shown in 50% and 90%, respectively, of patients with Alzheimer s disease and are also often present in patients with Lewy body disease (Barber et al. 1999). 

Ross OA, Toft M, Whittle AJ, Johnson JL, Papapetropoulos S, Mash DC, Litvan I, Gordon MF, Wszolek ZK, Farrer MJ, Dickson DW (2006) Lrrk2 and Lewy body disease. Ann Neurol 59 388-393... 

Bohr IJ, Ray MA, McIntosh JM, Chalon S, GuiUoteau D, McKeith IG, Perry RH, Clement F, Perry EK, Court JA, Piggott MA (2005) Cholinergic nicotinic receptor involvement in movement disorders associated with Lewy body diseases. An autoradiography study using [(125)l]alpha-conotoxinMII in the striatum and thalamus. Exp Neurol 191 292-300... 

Dementia syndromes Alzheimer disease, diffuse Lewy body disease, frontotemporal dementia... 

---