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Dopamine and lewy bodies

(52 References)

Yoo, M. S., H. S. Chun, et al. (2003). "Oxidative stress regulated genes in nigral dopaminergic neuronal cells: correlation with the known pathology in Parkinson's disease." Brain Res Mol Brain Res 110(1): 76-84.

            Oxidative stress (OS) is a primary pathogenic mechanism of nigral dopaminergic (DA) cell death in Parkinson's disease (PD). Oxidative damage, Lewy body formation and decreased mitochondrial complex I activity are the consistent pathological findings in PD. In nigral DA neurons, however, it is unknown whether any gene expressional changes induced by OS contribute to the typical PD pathology. Here, using microarray analysis, we identified several groups of genes in the nigral DA cell line, SN4741 [J. Neurosci. 19 (1999) 10; J. Neurochem. 76 (2001) 1010], that were regulated by OS. Approximately 36 significantly regulated genes that encode functional molecules of nuclear subunits of mitochondrial complex I, exocytosis and membrane trafficking proteins, markers for OS and oxidoreductases, regulatory molecules of apoptosis and unidentified EST clones were further analysed. OS modulated the expression of specific genes, of which physiological dysfunctions have been implicated in PD. For instance, the expression of the nuclear-encoded subunits of mitochondrial complex I, B8 and B17, were significantly down-regulated by OS, possibly contributing to selective defect in mitochondrial complex I activity in PD. Furthermore, syntaxin 8 and heme oxygenase-1 (HO-1) are most dramatically up-regulated by OS in DA cells. Syntaxin 8 is a SNARE protein, regulating lipid vesicle docking and fusion as well as early endosome membrane recycling. Lipid membranes are significantly oxidative-damaged in PD. HO-1 is an important cytoplasmic constituent of Lewy bodies, a pathological hallmark of idiopathic PD. Thus, our findings provide novel molecular probes that may be useful in unraveling the molecular mechanism(s) of OS-induced pathogenesis in PD. Further functional characterization of the affected genes including ESTs can help elucidate the underlying molecular pathology as well as develop biomarkers for monitoring degenerating DA neurons in PD.


Wersinger, C. and A. Sidhu (2003). "Attenuation of dopamine transporter activity by alpha-synuclein." Neurosci Lett 340(3): 189-92.

            Alpha-synuclein accumulates in Lewy bodies in idiopathic Parkinson's disease. Neither the normal function nor contribution of alpha-synuclein to the pathophysiology of neurodegeneration is known. Here we show that a normal function of alpha-synuclein is the negative modulation of human dopamine transporter (hDAT) activity. In cotransfected Ltk(-) cells, alpha-synuclein attenuated the reuptake of dopamine by hDAT, in a manner dependent on expression levels of alpha-synuclein. Alpha-synuclein-mediated inhibition of hDAT activity was independent of expression vectors, cell types and methods of transfection. The alpha-synuclein-mediated decrease in DAT activity occurred through diminished uptake velocity of dopamine, without changes in the affinity of hDAT for dopamine. Co-immunoprecipitation studies confirmed the formation of a stable complex between alpha-synuclein and DAT, through direct protein:protein interactions. Thus, under normal (non-toxic) expression conditions, alpha-synuclein negatively modulates dopamine uptake by DAT.


Wersinger, C. and A. Sidhu (2003). "Differential cytotoxicity of dopamine and H2O2 in a human neuroblastoma divided cell line transfected with alpha-synuclein and its familial Parkinson's disease-linked mutants." Neurosci Lett 342(1-2): 124-8.

            alpha-Synuclein accumulates in Lewy bodies and two missense mutations, A30P and A53T, have been linked to familial Parkinson's disease. Neither the normal function of alpha-synuclein nor the pathomechanism of alpha-synuclein-induced neuropathy are known. SK-N-MC neuroblastoma cells were transiently transfected with either wt alpha-synuclein, or its mutants, and their abilities to protect against oxidative stress were assessed. At low expression levels (1 microg cDNA/10(5) cells), all three synuclein variants were devoid of any effect on dopamine-induced cytotoxicity and nitrite production, whereas at higher expression (5 microg cDNA/10(5) cells), the variants enhanced dopamine-mediated effects. Low levels of wt alpha-synuclein blocked H(2)O(2)-induced cytotoxicity and nitrite production, a protective effect that was partly decreased upon higher expression. Both A30P and A53T increased in a dose-dependent manner H(2)O(2)-induced nitrite production and cell death. These results show an absence of protective effects for the A30P/A53T mutants, and a differential cytoprotective role of alpha-synuclein against oxidants, which varies according to expression levels.


Tabet, N., Z. Walker, et al. (2003). "In vivo Dopamine Pre-Synaptic Receptors and Antioxidant Activities in Patients with Alzheimer's Disease, Dementia with Lewy Bodies and in Controls. A Preliminary Report." Dement Geriatr Cogn Disord 16(1): 46-51.

            The degeneration of dopaminergic cells in dementia with Lewy bodies (DLB) may provide an important source of additional free radical generation. As a result, the oxidative stress status in DLB could be significantly enhanced. Subsequently, the levels of endogenous antioxidants, which are an indirect measure of free radical activities, may be different in DLB patients when compared with Alzheimer's disease (AD) patients and controls. In this preliminary study, we measured the activities of superoxide dismutase (SOD), catalase (CAT), glutathione (GLU) and total antioxidant capacity in the blood of DLB, AD and control subjects. The state of nigrostriatal dopaminergic system was also assessed in vivo by using a radioactive ligand with an affinity for the dopamine pre-synaptic receptors and by imaging with single-photon emission tomography. Data obtained showed a decrease in dopamine pre-synaptic receptors in all the brain regions of DLB patients. The levels of SOD did not differ significantly between DLB, AD and control subjects. However, GLU levels were significantly higher in the DLB patients when compared with AD patients (p < 0.05) and controls (p < 0.01). CAT blood levels were also higher in DLB when compared with AD, but this did not reach statistical significance. The results suggest that a different oxidative stress state may exist in DLB. This may occur due to increased free radical production from the degeneration of dopaminergic cells and auto-oxidation of dopamine, the availability of which may be maintained in early-stage DLB disease as a result of the compensatory increase in its turnover from the remaining dopaminergic cells. Copyright 2003 S. Karger AG, Basel


Sulkava, R. (2003). "Differential diagnosis between early Parkinson's disease and dementia with Lewy bodies." Adv Neurol 91: 411-3.


Scheepmaker, A. J., M. W. Horstink, et al. (2003). "[Dementia with Lewy bodies; 2 patients with exacerbation due to an atypical antipsychotic, but with a favorable response to the cholinesterase inhibitor rivastigmine]." Ned Tijdschr Geneeskd 147(1): 32-5.

            In two patients, men aged 80 and 75 years with cognitive deterioration, hallucinations and parkinsonism, the clinical diagnosis 'dementia with Lewy bodies' was established. Treatment with an atypical antipsychotic, risperidone and olanzapine respectively, resulted in an exacerbation of the parkinsonism. Rivastigmine evidently improved the psychosis, the anxiety and the cognitive, mood and behaviour disorders. Titrated treatment with levodopa improved the mobility without an increase of the psychosis. The treatment of dementia with Lewy bodies is complex. Levodopa can lead to an increase in visual hallucinations. Antipsychotics often cause serious side effects, such as increasing parkinsonism, sedation and cognitive deterioration. Cholinesterase inhibitors such as rivastigmine could possibly provide an alternative treatment for the neuropsychiatric symptoms.


Reyes, M. G., F. Faraldi, et al. (2003). "Decreased nigral neuromelanin in Alzheimer's disease." Neurol Res 25(2): 179-82.

            Using manual morphometric techniques, we estimated the amount of neuromelanin in hematoxylin and eosin-stained sections of the pars compacta of the substantia nigra of 19 Alzheimer's patients without nigral Lewy bodies and 12 age-matched controls. Our estimates showed that the mean area and areal fraction of neuromelanin were lower in Alzheimer's disease than controls but the number and size of the neuronal cell bodies, nuclei and nucleoli did not differ between the two groups. We speculated that the decreased amount of neuromelanin in nigral neuronal cell bodies could have resulted from neurofibrillary degeneration, retrograde degeneration from damage of nigral dopaminergic terminals in the striatum by the beta amyloid protein of the diffuse plaques and possibly transneuronal degeneration from damage of cell bodies or dendrites of nigral neurons by their plaque- and tangle-ravaged striatal, neocortical and other subcortical nigral connections. We hypothesized that any or all of the above types of degeneration could have lowered the rate of dopamine metabolism and the formation of one of its by-products, neuromelanin. Our study shows that a decrease in the amount of histopathologically-observable nigral neuromelanin commonly occurs in Alzheimer's disease without nigral Lewy bodies.


Piggott, M. A., J. Owens, et al. (2003). "Muscarinic receptors in basal ganglia in dementia with Lewy bodies, Parkinson's disease and Alzheimer's disease." J Chem Neuroanat 25(3): 161-73.

            Derivatives of the muscarinic antagonist 3-quinuclidinyl-4-iodobenzilate (QNB), particularly [123I]-(R,R)-I-QNB, are currently being assessed as in vivo ligands to monitor muscarinic receptors in Alzheimer's disease (AD) and dementia with Lewy bodies (DLB), relating changes to disease symptoms and to treatment response with cholinergic medication. To assist in the evaluation of in vivo binding, muscarinic receptor density in post-mortem human brain was measured by autoradiography with [125I]-(R,R)-I-QNB and [125I]-(R,S)-I-QNB and compared to M1 ([3H]pirenzepine) and M2 and M4 ([3H]AF-DX 384) receptor binding. Binding was calculated in tissue containing striatum, globus pallidus (GPe), claustrum, and cingulate and insula cortex, in cases of AD, DLB, Parkinson's disease (PD) and normal elderly controls. Pirenzepine, AF-DX 384 and (R,S)-I-QNB binding in the striatum correlated positively with increased Alzheimer-type pathology, and AF-DX 384 and (R,R)-I-QNB cortical binding correlated positively with increased Lewy body (LB) pathology; however, striatal pirenzepine binding correlated negatively with cortical LB pathology. M1 receptors were significantly reduced in striatum in DLB compared to AD, PD, and controls and there was a significant correlation between M1 and dopamine D2 receptor densities. [3H]AF-DX 384 binding was higher in the striatum and GPe in AD. Binding of [125I]-(R,R)-I-QNB, which may reflect increased muscarinic M4 receptors, was higher in cortex and claustrum in DLB and AD. [125I]-(R,S)-I-QNB binding was higher in the GPe in AD. Low M1 and D2 receptors in DLB imply altered regulation of the striatal projection neurons which express these receptors. Low density of striatal M1 receptors may relate to the extent of movement disorder in DLB, and to a reduced risk of parkinsonism with acetylcholinesterase inhibition.


McNaught, K. S., R. Belizaire, et al. (2003). "Altered proteasomal function in sporadic Parkinson's disease." Exp Neurol 179(1): 38-46.

            Parkinson's disease (PD) is characterized pathologically by preferential degeneration of the dopaminergic neurons in the substantia nigra pars compacta (SNc). Nigral cell death is accompanied by the accumulation of a wide range of poorly degraded proteins and the formation of proteinaceous inclusions (Lewy bodies) in dopaminergic neurons. Mutations in the genes encoding alpha-synuclein and two enzymes of the ubiquitin-proteasome system, parkin and ubiquitin C-terminal hydrolase L1, are associated with neurodegeneration in some familial forms of PD. We now show that, in comparison to age-matched controls, alpha-subunits (but not beta-subunits) of 26/20S proteasomes are lost within dopaminergic neurons and 20S proteasomal enzymatic activities are impaired in the SNc in sporadic PD. In addition, while the levels of the PA700 proteasome activator are reduced in the SNc in PD, PA700 expression is increased in other brain regions such as the frontal cortex and striatum. We also found that levels of the PA28 proteasome activator are very low to almost undetectable in the SNc compared to other brain areas in both normal and PD subjects. These findings suggest that failure of the ubiquitin-proteasome system to adequately clear unwanted proteins may underlie vulnerability and degeneration of the SNc in both sporadic and familial PD.


McKeith, I. G., D. J. Burn, et al. (2003). "Dementia with Lewy bodies." Semin Clin Neuropsychiatry 8(1): 46-57.

            The objective was to summarize recent findings about the clinical features, diagnosis and investigation of dementia with Lewy (DLB) bodies, together with its neuropathology, neurochemistry and genetics. Dementia with Lewy bodies (DLB) is a primary, neurodegenerative dementia sharing clinical and pathological characteristics with both Parkinson's disease (PD) and Alzheimer's disease (AD). Antiubiquitin immunocytochemical staining, developed in the early 1990s, allowed the frequency and distribution of cortical LBs to be defined. More recently, alpha-synuclein antibodies have revealed extensive neuritic pathology in DLB demonstrating a neurobiological link with other "synucleinopathies" including PD and multiple system atrophy (MSA). The most significant correlates of cognitive failure in DLB appear to be with cortical LB and Lewy neurites (LNs) rather than Alzheimer type pathology. Clinical diagnostic criteria for DLB, published in 1996, have been subjected to several validation studies against autopsy findings. These conclude that although diagnostic specificity is high (range 79- 100%, mean 92%), sensitivity is lower (range 0- 83 %, mean, 49%). Improved methods of case detection are therefore required. Fluctuating impairments in attention, visual recognition and construction are more indicative of DLB than AD. Relative preservation of medial temporal lobe volume on structural MRI and the use of SPECT tracers for regional blood flow and the dopamine transporter are the most reliable current biomarkers for DLB. There are no genetic or CSF tests recommended for the diagnosis of DLB at present. Between 15 and 20% of all elderly demented cases reaching autopsy have DLB, making it the most common cause of degenerative dementia after AD. Exquisite, not infrequently fatal, sensitivity to neuroleptic drugs and encouraging reports of the effects of cholinesterase inhibitors on cognitive, psychiatric and neurological features, mean that an accurate diagnosis of DLB is more than merely of academic interest. Dementia developing late in the course of PD shares many of the same clinical and pathological characteristics.


Mash, D. C., Q. Ouyang, et al. (2003). "Cocaine abusers have an overexpression of alpha-synuclein in dopamine neurons." J Neurosci 23(7): 2564-71.

            Alpha-synuclein is a presynaptic protein that has been implicated as a possible causative agent in the pathogenesis of Parkinson's disease. The native protein is a major component of nigral Lewy bodies in Parkinson's disease, and full-length alpha-synuclein accumulates in Lewy neurites. Here we present evidence that alpha-synuclein levels are elevated in midbrain dopamine (DA) neurons of chronic cocaine abusers. Western blot and immunoautoradiographic studies were conducted on postmortem neuropathological specimens from cocaine users and age-matched drug-free control subjects. The results demonstrated that alpha-synuclein levels in the DA cell groups of the substantia nigra/ventral tegmental complex were elevated threefold in chronic cocaine users compared with normal age-matched subjects. The increased protein levels in chronic cocaine users were accompanied by changes in the expression of alpha-synuclein mRNA in the substantia nigra and ventral tegmental area. Although alpha-synuclein expression is prominent in the hippocampus, there was no increase in protein expression in this brain region. The levels of beta-synuclein, a possible negative regulator of alpha-synuclein, also were not affected by cocaine exposure. Alpha-synuclein protein levels were increased in the ventral tegmental area, but not the substantia nigra, in victims of excited cocaine delirium who experienced paranoia, marked agitation, and hyperthermia before death. The overexpression of alpha-synuclein may occur as a protective response to changes in DA turnover and increased oxidative stress resulting from cocaine abuse. However, the accumulation of alpha-synuclein protein with long-term cocaine abuse may put addicts at increased risk for developing the motor abnormalities of Parkinson's disease.


Lim, K. L., V. L. Dawson, et al. (2003). "The cast of molecular characters in Parkinson's disease: felons, conspirators, and suspects." Ann N Y Acad Sci 991: 80-92.

            Parkinson's Disease (PD) is a common neurodegenerative disorder characterized by the progressive loss of dopamine neurons and the accumulation of Lewy bodies and neurites. Recent advances indicate that PD is due in some individuals to genetic mutations in alpha-synuclein, parkin, and ubiquitin C-terminal hydrolase L1 (UCHL1). All three PD-linked gene products are related directly or indirectly to the functioning of the cellular ubiquitin proteasomal system (UPS), suggesting that UPS dysfunction may be important in PD pathogenesis. Indeed, emerging evidence indicates that derangements of the UPS may be one of the underlying mechanisms of PD pathogenesis. The function of parkin as an ubiquitin protein ligase positions it as an important player in both familial and idiopathic PD. We recently demonstrated that parkin mediates a nondegradative form of ubiquitination on synphilin-1 that could contribute to synphilin-1's aggregation in PD. Our results implicate parkin involvement in the formation of Lewy bodies associated with sporadic PD. This review discusses the role of the UPS, as well as the modus operandi of the three PD candidate felons (alpha-synuclein, parkin, and UCHL1) along with their conspirators in bringing about dopaminergic cell death in PD.


Lee, E. N., S. Y. Lee, et al. (2003). "Lipid interaction of alpha-synuclein during the metal-catalyzed oxidation in the presence of Cu2+ and H2O2." J Neurochem 84(5): 1128-42.

            Alpha-synuclein co-exists with lipids in the Lewy bodies, a pathological hallmark of Parkinson's disease. Molecular interaction between alpha-synuclein and lipids has been examined by observing lipid-induced protein self-oligomerization in the presence of a chemical coupling reagent of N-(ethoxycarbonyl)-2-ethoxy-1,2-dihydroquinoline. Lipids such as phosphatidic acid, phosphatidylinositol, phosphatidylserine, phosphatidylethanolamine, and even arachidonic acid induced the self-oligomerization whereas phosphatidylcholine did not affect the protein. Because the oligomerizations occurred from critical micelle concentrations of the lipids, the self interaction of alpha-synuclein was shown to be a lipid-surface dependent phenomenon with head group specificity. By employing beta-synuclein and a C-terminally truncated alpha-synuclein (alpha-syn97), the head-group dependent self-oligomerization was demonstrated to occur preferentially at the N-terminal region while the fatty acid interaction leading to the protein self-association required the presence of the acidic C-terminus of alpha-synuclein. In the presence of Cu2+ and H2O2, phosphatidylinositol (PI), along with other acidic lipids, actually enhanced the metal-catalyzed oxidative self-oligomerization of alpha-synuclein. The dityrosine crosslink formation responsible for the PI-enhanced covalent self-oligomerization was more sensitive to variation of copper concentrations than that of H2O2 during the metal-catalyzed oxidation. The enhancement by PI was shown to be due to facilitation of copper localization to the protein because actual binding affinity between copper and alpha-synuclein increased from Kd of 44.7 microm to 5.9 microm in the presence of the lipid. Taken together, PI not only affects alpha-synuclein to be more self-interactive by providing the lipid surface, but also enhances the metal-catalyzed oxidative protein self-oligomerization by facilitating copper localization to the protein when the metal and H2O2 are provided. This observation therefore could be implicated in the formation of Lewy bodies as lipids and metal-catalyzed oxidative stress have been considered to be a part of pathological causes leading to the neurodegeneration.


Kaufmann, H. (2003). "[The most common dysautonomias]." Rev Neurol 36: 93-6.

            Aims. To review the classification and the clinical and pathological characteristics of the most common dysautonomias. Method. Primary dysautonomia includes neurodegenerative diseases of unknown causes that are characterised by the intracytoplasmic accumulations of alpha synuclein that manifest with four different phenotypes: pure autonomic failure, Parkinson s disease, dementia with Lewy bodies and multiple system atrophy. Of the secondary dysautonomias, diabetes mellitus is the most common cause of autonomic neuropathy in developed countries. Familiar dysautonomia is a recessive autosomic disease; the gene responsible for it has been located in the long arm of chromosome 9 (9q31). Paraneoplasic dysautonomia is associated with cancer of the lungs, the pancreas, Hodgkin s disease and testicular cancer. In Lambert Eaton myasthenic syndrome and in botulism the release of acetylcholine is deficient in both the somatic and the autonomic neurons. There are other diseases that affect autonomic cholinergic neurotransmission without bringing about any disorders in neuromuscular transmission. Chagas disease affects the neurons of the parasympathetic ganglion and produces megaesophagus, megacolon and myocardiopathy. Dopamine beta hydroxylase enzyme deficiency is a congenital disease characterised by the failure to convert dopamine into noradrenaline which results in orthostatic hypotension. Conclusions. Dysautonomias can be classified, according to their aetiology, as primary or secondary; according to the deficient neurotransmitter, as cholinergic, adrenergic and mixed (pan dysautonomia) or, according to the anatomical distribution of the neurons that are affected, as central and peripheral.


Jordan-Sciutto, K. L., R. Dorsey, et al. (2003). "Expression patterns of retinoblastoma protein in Parkinson disease." J Neuropathol Exp Neurol 62(1): 68-74.

            Cellular mechanisms implicated in Parkinson disease (PD) include oxidative stress, inflammatory response, excess dopamine, DNA damage, and loss of trophic support. These stimuli have been observed to induce changes in cell cycle proteins in several cell types. One of the key regulators of cell cycle progression is the retinoblastoma protein (pRb); therefore, we assessed the staining for pRb and its inactive hyperphosphorylated isoform, ppRb, in autopsy tissue from patients with PD. In PD we found abundant pRb staining in neuronal cytoplasm of the substantia nigra, mid-frontal cortex, and hippocampus by immunohistochemistry. In controls, pRb weakly stained nucleoli of neurons in the substantia nigra and exhibited no detectable staining in mid-frontal cortex and hippocampus. Staining for ppRb resulted in a shift from weak cytoplasmic staining in neurons from control cases to strong nuclear staining in PD cases, especially within the substantia nigra, mid-frontal cortex, and hippocampus. In the substantia nigra, ppRb also co-localized to Lewy bodies, which are a pathologic feature of PD. Lewy bodies are also found in diffuse Lewy body disease (DLBD) that do not consistently exhibit changes in pRb or ppRb. These results indicate that there are changes in pRb and its inactive phospho-isoform in neurons responding to neurodegenerative stimuli associated with PD.


Jakobsen, L. D. and P. H. Jensen (2003). "Parkinson's Disease: alpha -Synuclein and Parkin in Protein Aggregation and the Reversal of Unfolded Protein Stress." Methods Mol Biol 232: 57-66.

            Parkinson's disease (PD) is the second most common neurodegenerative disorder. The prevalence of PD increases dramatically with age, affecting 1-2% of the population above 65 years (1,2). PD is characterized by a progressive loss of dopaminergic neurons in the substantia nigra, pars compacta in the brain stem. The classical symptoms are tremor, rigidity, and slowness of movements. The symptoms appear when about 70% of the dopaminergic neurons are lost, demonstrating that the degenerative process is active long before the patients become aware of the disease. In the degenerating neurons, proteinaceous inclusions named Lewy bodies are found in the cell body and Lewy neurites in the neuronal processes (3). The inclusions exhibit filamentous protein aggregates with alpha- synuclein being a prominent component (4-7). The definitive diagnosis of PD requires both the clinical symptoms and post mortem examination. No preventive or neuroprotective therapies exist for PD, of which treatment primarily relies on substitution therapy with dopamine precursors or agonists. Genetic predispositions as well as environmental factors increase the risk of PD, but the etiology of PD is largely unknown. In rare familial cases, PD is linked to mutations in single genes encoding alpha-synuclein and parkin proteins. These cases have shed light on mechanisms leading to the selective dopaminergic cell loss.


Herholz, K. (2003). "PET studies in dementia." Ann Nucl Med 17(2): 79-89.

            Measurement of local cerebral glucose metabolism (lCMRGlc) by positron emission tomography (PET) and 18F-2-fluoro-2-deoxy-D-glucose (FDG) has become a standard technique during the past 20 years and is now available at many university hospitals in all highly developed countries. Many studies have documented a close relation between lCMRGlc and localized cognitive functions, such as language and visuoconstructive abilities. Alzheimer's disease (AD) is characterized by regional impairment of cerebral glucose metabolism in neocortical association areas (posterior cingulate, temporoparietal and frontal multimodal association cortex), whereas primary visual and sensorimotor cortex, basal ganglia, and cerebellum are relatively well preserved. In a multicenter study comprising 10 PET centers (Network for Efficiency and Standardisation of Dementia Diagnosis, NEST-DD) that employed an automated voxel-based analysis of FDG PET images, the distinction between controls and AD patients was 93% sensitive and 93% specific, and even in very mild dementia (at MMSE 24 or higher) sensitivity was still 84% at 93% specificity. Significantly abnormal metabolism in mild cognitive deficit (MCI) indicates a high risk to develop dementia within the next two years. Reduced neocortical glucose metabolism can probably be detected with FDG PET in AD on average one year before onset of subjective cognitive impairment. In addition to glucose metabolism, specific tracers for dopamine synthesis (18F-F-DOPA) and for (11C-MP4A) are of interest for differentiation among dementia subtypes. Cortical acetylcholine esterase activity (AChE) activity is significantly lower in patients with AD or with dementia with Lewy bodies (DLB) than in age-matched normal controls. In LBD there is also impairment of dopamine synthesis, similar to Parkinson disease.


Gomez-Santos, C., I. Ferrer, et al. (2003). "Dopamine induces autophagic cell death and alpha-synuclein increase in human neuroblastoma SH-SY5Y cells." J Neurosci Res 73(3): 341-350.

            Free cytoplasmic dopamine may be involved in the genesis of neuronal degeneration in Parkinson's disease and other such diseases. We used SH-SY5Y human neuroblastoma cells to study the effect of dopamine on cell death, activation of stress-induced pathways, and expression of alpha-synuclein, the characteristic protein accumulated in Lewy bodies. We show that 100 and 500 microM dopamine causes a 40% and 60% decrease of viability, respectively, and triggers autophagy after 24 hr of exposure, characterized by the presence of numerous cytoplasmic vacuoles with inclusions. Dopamine causes mitochondrial aggregation in adherent cells prior to the loss of functionality. Plasma membrane and nucleus also maintain their integrity. Cell viability is protected by the dopamine transporter blocker nomifensine and the antioxidants N-acetylcysteine and ascorbic acid. Dopamine activates the stress-response kinases, SAPK/JNK and p38, but not ERK/MAPK or MEK, and increases alpha-synuclein expression. Both cell viability and the increase in alpha-synuclein expression are prevented by antioxidants; by the specific inhibitors of p38 and SAPK/JNK, SB203580 and SP600125, respectively; and by the inhibitor of autophagy 3-methyladenine. This indicates that oxidative stress, stress-activated kinases, and factors involved in autophagy up-regulate alpha-synuclein content. The results show that nonapoptotic death pathways are triggered by dopamine, leading to autophagy. These findings should be taken into account in the search for strategies to protect dopaminergic neurons from degeneration. Copyright 2003 Wiley-Liss, Inc.


Gomez-Isla, T., M. C. Irizarry, et al. (2003). "Motor dysfunction and gliosis with preserved dopaminergic markers in human alpha-synuclein A30P transgenic mice." Neurobiol Aging 24(2): 245-58.

            Alpha-synuclein is a major component of Lewy bodies (LBs) in the substantia nigra and cortex in Parkinson's disease (PD) and dementia with Lewy bodies (DLB), and in glial inclusions in multiple systems atrophy (MSA). Mutations in alpha-synuclein have been associated with autosomal dominant forms of PD. We investigated the clinical and neuropathological effects of overexpression of human alpha-synuclein, alpha-synuclein A30P, and alpha-synuclein A53T under the control of the hamster prion protein (PrP) promoter; 5-15x endogenous levels of protein expression were achieved with widespread neuronal, including nigral, transgene expression. High expression of alpha-synuclein A30P in the Tg5093 line was associated with a progressive motor disorder with rigidity, dystonia, gait impairment, and tremor. Histological analysis of this line showed aberrant expression of the protein in cell soma and progressive CNS gliosis, but no discrete Lewy body-like alpha-synuclein inclusions could be identified. Biochemical analysis demonstrated alpha-synuclein fragmentation. Despite strong expression of the transgene in the nigra, there was no specific deterioration of the nigrostriatal dopaminergic system as assessed by quantitation of nigral tyrosine hydroxylase (TH) containing neurons, striatal TH immunoreactivity, dopamine levels, or dopamine receptor number and function. Lower expressing lines had no specific behavioral or histopathological phenotype. Thus, high expression of mutant human alpha-synuclein resulted in a progressive motor and widespread CNS gliotic phenotype independent of dopaminergic dysfunction in the Tg5093 line.


Fahn, S. (2003). "Description of Parkinson's disease as a clinical syndrome." Ann N Y Acad Sci 991: 1-14.

            Parkinsonism is a clinical syndrome comprising combinations of motor problems-namely, bradykinesia, resting tremor, rigidity, flexed posture, "freezing," and loss of postural reflexes. Parkinson's disease (PD) is the major cause of parkinsonism. PD is a slowly progressive parkinsonian syndrome that begins insidiously and usually affects one side of the body before spreading to involve the other side. Pathology shows loss of neuromelanin-containing monoamine neurons, particularly dopamine (DA) neurons in the substantia nigra pars compacta. A pathologic hallmark is the presence of cytoplasmic eosinophilic inclusions (Lewy bodies) in monoamine neurons. The loss of DA content in the nigrostriatal neurons accounts for many of the motor symptoms, which can be ameliorated by DA replacement therapy-that is, levodopa. Most cases are sporadic, of unknown etiology; but rare cases of monogenic mutations (10 genes at present count) show that there are multiple causes for the neuronal degeneration. The pathogenesis of PD remains unknown. Clinical fluctuations and dyskinesias are frequent complications of levodopa therapy; these, as well as some motor features of PD, improve by resetting the abnormal brain physiology towards normal by surgical therapy. Nonmotor symptoms (depression, lack of motivation, passivity, and dementia) are common. As the disease progresses, even motor symptoms become intractable to therapy. No proven means of slowing progression have yet been found.


Baptista, M. J., C. O'Farrell, et al. (2003). "Co-ordinate transcriptional regulation of dopamine synthesis genes by alpha-synuclein in human neuroblastoma cell lines." J Neurochem 85(4): 957-68.

            Abnormal accumulation of alpha-synuclein in Lewy bodies is a neuropathological hallmark of both sporadic and familial Parkinson's disease (PD). Although mutations in alpha-synuclein have been identified in autosomal dominant PD, the mechanism by which dopaminergic cell death occurs remains unknown. We investigated transcriptional changes in neuroblastoma cell lines transfected with either normal or mutant (A30P or A53T) alpha-synuclein using microarrays, with confirmation of selected genes by quantitative RT-PCR. Gene products whose expression was found to be significantly altered included members of diverse functional groups such as stress response, transcription regulators, apoptosis-inducing molecules, transcription factors and membrane-bound proteins. We also found evidence of altered expression of dihydropteridine reductase, which indirectly regulates the synthesis of dopamine. Because of the importance of dopamine in PD, we investigated the expression of all the known genes in dopamine synthesis. We found co-ordinated downregulation of mRNA for GTP cyclohydrolase, sepiapterin reductase (SR), tyrosine hydroxylase (TH) and aromatic acid decarboxylase by wild-type but not mutant alpha-synuclein. These were confirmed at the protein level for SR and TH. Reduced expression of the orphan nuclear receptor Nurr1 was also noted, suggesting that the co-ordinate regulation of dopamine synthesis is regulated through this transcription factor.


Zhou, W., J. Schaack, et al. (2002). "Overexpression of human alpha-synuclein causes dopamine neuron death in primary human mesencephalic culture." Brain Res 926(1-2): 42-50.

            Mutations in the alpha-synuclein gene have been linked to rare cases of familial Parkinson's disease (PD). Alpha-synuclein is a major component of Lewy bodies (LB), a pathological hallmark of PD. Transgenic mice and Drosophila expressing either wild-type or mutant human alpha-synuclein develop motor deficits, LB-like inclusions in some neurons, and neuronal degeneration. However, the relationship between abnormal aggregates of alpha-synuclein and human dopamine (DA) neuron degeneration remains unclear. In this report, we have investigated the influence of alpha-synuclein expression on DA neurons in primary culture of embryonic human mesencephalon. Two days after culture, human DA cells were transduced with wild-type or mutant human (Ala(53)Thr) alpha-synuclein adenoviruses and maintained for 5 days. Overexpression of mutant and wild-type human alpha-synuclein resulted in 49% (P<0.01) and 27% (P<0.05) loss of DA neurons, respectively, while not affecting viability of other cells in the culture. Overexpression of rat alpha-synuclein or GFP (green fluorescent protein) had no effect on DA neuron survival. Cytoplasmic inclusions of alpha-synuclein were detected immunohistochemically in DA cells transduced with mutant human alpha-synuclein, but not wild-type alpha-synuclein. These results show that overexpression of human alpha-synuclein, particularly the mutant form, can cause human DA neuron death, suggesting that alpha-synuclein may have a primary role in the pathogenesis of PD.


Walker, Z., D. C. Costa, et al. (2002). "Differentiation of dementia with Lewy bodies from Alzheimer's disease using a dopaminergic presynaptic ligand." J Neurol Neurosurg Psychiatry 73(2): 134-40.

            BACKGROUND: Dementia with Lewy bodies (DLB) is one of the main differential diagnoses of Alzheimer's disease (AD). Key pathological features of patients with DLB are not only the presence of cerebral cortical neuronal loss, with Lewy bodies in surviving neurones, but also loss of nigrostriatal dopaminergic neurones, similar to that of Parkinson's disease (PD). In DLB there is 40-70% loss of striatal dopamine. OBJECTIVE: To determine if detection of this dopaminergic degeneration can help to distinguish DLB from AD during life. METHODS: The integrity of the nigrostriatal metabolism in 27 patients with DLB, 17 with AD, 19 drug naive patients with PD, and 16 controls was assessed using a dopaminergic presynaptic ligand, (123)I-labelled 2beta-carbomethoxy-3beta-(4-iodophenyl)-N-(3-fluoropropyl)nortropane (FP-CIT), and single photon emission tomography (SPET). A SPET scan was carried out with a single slice, brain dedicated tomograph (SME 810) 3.5 hours after intravenous injection of 185 MBq FP-CIT. With occipital cortex used as a radioactivity uptake reference, ratios for the caudate nucleus and the anterior and posterior putamen of both hemispheres were calculated. All scans were also rated by a simple visual method. RESULTS: Both DLB and PD patients had significantly lower uptake of radioactivity than patients with AD (p<0.001) and controls (p<0.001) in the caudate nucleus and the anterior and posterior putamen. CONCLUSION: FP-CIT SPET provides a means of distinguishing DLB from AD during life.


Tariot, P. N. and M. S. Ismail (2002). "Use of quetiapine in elderly patients." J Clin Psychiatry 63 Suppl 13: 21-6.

            Behavioral problems associated with psychosis in the elderly have a significant negative impact on patients' quality of life and can lead to placement in a nursing home. Because of their decreased propensity to produce extrapyramidal symptoms, atypical antipsychotics such as quetiapine hold promise in the treatment of these vulnerable patients. Quetiapine may, in theory, be particularly advantageous in this regard because of its lack of anticholinergic activity and its relatively loose binding to dopamine receptors. This article reviews the somewhat limited number of clinical studies of the use of quetiapine in treating older patients with schizophrenia and other psychotic disorders, patients with psychosis associated with Alzheimer's disease or dementia with Lewy bodies, and patients with Parkinson's disease and drug-induced psychosis.


Tabet, N. and S. Sivaloganathan (2002). "Meige's syndrome in dementia with Lewy bodies." J R Soc Med 95(4): 201-2.


Szirmai, I. and T. Kovacs (2002). "[Parkinson syndrome and cognitive disorders]." Ideggyogy Sz 55(7-8): 220-5.

            The cognitive (executive) ability of patients with Parkinson's-disease (PD) deteriorates gradually during the progression of the disease. Fluency of speech, word finding, working memory, ability to plan the future and flexibility decline. Cognitive disturbance was found to be proportional with the speech, posture, gait and balance problems and can not be influenced by L-dopa substitution. Apart the dorsal and ventral mesolimbic dopaminergic systems the coerulo-cortical noradrenergic, serotoninergic and cholinergic systems are also impaired in PD. Subcortical dementia in PD can also be explained by the functional disability of dorsolateral and anterior cingular circuits. Attention deficit can be explained by the dopamine depletion of cingular cortex. Cortical Lewy bodies, neurofibrillary tangles, neurit plaques and additional vascular pathology should also play a role in cognitive impairment of PD. In several systemic degenerative diseases associating with Parkinson's syndrome (PS) i.e. progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), multiple system atrophy (MSA) dementia can be detected with various severity, therefore the question arises concerning the correlation between cognitive disability and PS. Parkinson syndrome can also develop in frontotemporal dementias (FTD), Alzheimer's disease and cortical Lewy body disease (CLBD) but no correlation exists between motor disability and severity of dementia. In CLBD dementia can be the initial symptom in 18% of cases but PS can also preceeds the dementia. In PSP profound depletion of other monoaminergic neurotransmitter system was also reported. In FTDs associated with PS degeneration of substantia nigra, locus coeruleus and basal nucleus of Meynert has been reported with increased number of neurofibrillary tangles. In patients with vascular PS (VP) there is generally no tremor and rigidity, but pseudobulbar palsy, dementia, gate disturbance, incontinency appears; L-dopa treatment is generally ineffective. In VP no cellular loss can be found within the substantia nigra, but leukoaraiosis, lacunae in the white matter and basal ganglia are commonly demonstrated.


Richard, I. H., A. W. Justus, et al. (2002). "Worsening of motor function and mood in a patient with Parkinson's disease after pharmacologic challenge with oral rivastigmine." Clin Neuropharmacol 25(6): 296-9.

            Patients with Parkinson's disease (PD) can experience cognitive impairment. There are currently no medications indicated for the treatment of cognitive impairment in PD. Clinicians are faced with the dilemma as to whether or not to treat patients with PD with the acetylcholinesterase inhibitors that are currently approved for use in Alzheimer's disease (AD) and that have shown promise in clinical trials of Dementia with Lewy bodies (DLB). Although these medications may help cognition, there is a theoretical concern that by increasing acetylcholine relative to dopamine, they might worsen motor function. We report the case of a patient with PD and cognitive impairment who developed a marked worsening of motor function, mood, and anxiety in the setting of a pharmacologic challenge study using a 3-mg oral dose of the acetylcholinesterase inhibitor, rivastigmine. We believe that the mechanism of the motor and perhaps psychiatric worsening was increased central cholinergic tone. We conclude that further studies should be done to evaluate the efficacy and tolerability of these agents in this illness but that caution should be exercised when using acetylcholinesterase inhibitors in patients with PD.


Rajput, A. H., M. E. Fenton, et al. (2002). "Clinical-pathological study of levodopa complications." Mov Disord 17(2): 289-96.

            We sought to determine the continued benefit and the pattern of motor complications of long-term levodopa treatment in Parkinson's disease. Patients were evaluated between 1968 and 1996. Only those who had an adequate levodopa trial and in whom autopsy revealed Lewy body Parkinson's disease were included. Total levodopa and mean daily dose were calculated in each case. Dyskinesia, wearing-off and on-off were collectively classified as motor adverse effects and reported as cumulative incidence. Forty-two patients (male, 30; female, 12) with mean 15.9 years of illness and 9.1 years follow-up received on average 500-mg levodopa daily over 9.8 years. Seventeen of 21 patients assessed during the last 18 months of life reported some motor benefit. Adverse effects were seen in 71.4% of patients. The most common was dyskinesia, in 61.9%; wearing-off in 35.7%; and on-off in 16.7% of patients. The earliest adverse effect was dyskinesia and the last to emerge was on-off. Isolated dyskinesia was seen in 35.7% and wearing-off in 7.1% of patients; 15.5% of patients developed dyskinesia after 2.6 years and 31% after 6.4 years on levodopa. We concluded that levodopa benefit declined and adverse effects increased with time. Dyskinesia was the earliest and the most common isolated adverse effect.


Mouradian, M. M. (2002). "Recent advances in the genetics and pathogenesis of Parkinson disease." Neurology 58(2): 179-85.

            The identification of three genes and several additional loci associated with inherited forms of levodopa-responsive PD has confirmed that this is not a single disorder. Yet, analyses of the structure and function of these gene products point to the critical role of protein aggregation in dopaminergic neurons of the substantia nigra as the common mechanism leading to neurodegeneration in all known forms of this disease. The three specific genes identified to date--alpha-synuclein, Parkin, and ubiquitin C terminal hydrolase L1--are either closely involved in the proper functioning of the ubiquitin-proteasome pathway or are degraded by this protein-clearing machinery of cells. Knowledge gained from genetically transmitted PD also has clear implications for nonfamilial forms of the disease. Lewy bodies, even in sporadic PD, contain these three gene products, particularly abundant amounts of fibrillar alpha-synuclein. Increased aggregation of alpha-synuclein by oxidative stress, as well as oxidant-induced proteasomal dysfunction, link genetic and potential environmental factors in the onset and progression of the disease. The biochemical and molecular cascades elucidated from genetic studies in PD can provide novel targets for curative therapies.


Morikawa, M. and T. Kishimoto (2002). "Probable dementia with Lewy bodies and risperidone-induced delirium." Can J Psychiatry 47(10): 976.


McNaught, K. S., C. Mytilineou, et al. (2002). "Impairment of the ubiquitin-proteasome system causes dopaminergic cell death and inclusion body formation in ventral mesencephalic cultures." J Neurochem 81(2): 301-6.

            Mutations in alpha-synuclein, parkin and ubiquitin C-terminal hydrolase L1, and defects in 26/20S proteasomes, cause or are associated with the development of familial and sporadic Parkinson's disease (PD). This suggests that failure of the ubiquitin-proteasome system (UPS) to degrade abnormal proteins may underlie nigral degeneration and Lewy body formation that occur in PD. To explore this concept, we studied the effects of lactacystin-mediated inhibition of 26/20S proteasomal function and ubiquitin aldehyde (UbA)-induced impairment of ubiquitin C-terminal hydrolase (UCH) activity in fetal rat ventral mesencephalic cultures. We demonstrate that both lactacystin and UbA caused concentration-dependent and preferential degeneration of dopaminergic neurons. Inhibition of 26/20S proteasomal function was accompanied by the accumulation of alpha-synuclein and ubiquitin, and the formation of inclusions that were immunoreactive for these proteins, in the cytoplasm of VM neurons. Inhibition of UCH was associated with a loss of ubiquitin immunoreactivity in the cytoplasm of VM neurons, but there was a marked and localized increase in alpha-synuclein staining which may represent the formation of inclusions bodies in VM neurons. These findings provide direct evidence that impaired protein clearance can induce dopaminergic cell death and the formation of proteinaceous inclusion bodies in VM neurons. This study supports the concept that defects in the UPS may underlie nigral pathology in familial and sporadic forms of PD.


McNaught, K. S., R. Belizaire, et al. (2002). "Selective loss of 20S proteasome alpha-subunits in the substantia nigra pars compacta in Parkinson's disease." Neurosci Lett 326(3): 155-8.

            The proteolytic activities of 26/20S proteasomes are impaired in the substantia nigra pars compacta (SNc) in sporadic Parkinson's disease (PD). In the present study, we examined the structural integrity of the proteasome by determining the levels of the beta- and alpha-subunits which together normally constitute the catalytic core of 26/20S proteasomes. Western blot analyzes and immunohistochemical staining revealed a major and selective loss of alpha-subunits in dopaminergic neurons of the SNc but not in other brain regions in sporadic PD. This defect is known to cause the proteasome to become unstable and prevents its assembly with resultant impairment of enzymatic activity. Thus, structural and function defects in 26/20S proteasomes may underlie protein accumulation, formation of proteinaceous Lewy bodies and dopaminergic neuronal death in the SNc in sporadic PD.


McNaught, K. S., L. M. Bjorklund, et al. (2002). "Proteasome inhibition causes nigral degeneration with inclusion bodies in rats." Neuroreport 13(11): 1437-41.

            Structural and functional defects in 26/20S proteasomes occur in the substantia nigra pars compacta and may underlie protein accumulation, Lewy body formation and dopaminergic neuronal death in Parkinson's disease. We therefore determined the pathogenicity of proteasomal impairment following stereotaxic unilateral infusion of lactacystin, a selective proteasome inhibitor, into the substantia nigra pars compacta of rats. These animals became progressively bradykinetic, adopted a stooped posture and displayed contralateral head tilting. Administration of apomorphine to lactacystin-treated rats reversed behavioral abnormalities and induced contralateral rotations. Lactacystin caused dose-dependent degeneration of dopaminergic cell bodies and processes with the cytoplasmic accumulation and aggregation of alpha-synuclein to form inclusion bodies. These findings support the notion that failure of the ubiquitin-proteasome system to degrade and clear unwanted proteins is an important etiopathogenic factor in Parkinson's disease.


Lo Bianco, C., J. L. Ridet, et al. (2002). "alpha -Synucleinopathy and selective dopaminergic neuron loss in a rat lentiviral-based model of Parkinson's disease." Proc Natl Acad Sci U S A 99(16): 10813-8.

            Parkinson's disease (PD) is characterized by the progressive loss of substantia nigra dopaminergic neurons and the presence of cytoplasmic inclusions named Lewy bodies. Two missense mutations of the alpha-synuclein (alpha-syn; A30P and A53T) have been described in several families with an autosomal dominant form of PD. alpha-Syn also constitutes one of the main components of Lewy bodies in sporadic cases of PD. To develop an animal model of PD, lentiviral vectors expressing different human or rat forms of alpha-syn were injected into the substantia nigra of rats. In contrast to transgenic mice models, a selective loss of nigral dopaminergic neurons associated with a dopaminergic denervation of the striatum was observed in animals expressing either wild-type or mutant forms of human alpha-syn. This neuronal degeneration correlates with the appearance of abundant alpha-syn-positive inclusions and extensive neuritic pathology detected with both alpha-syn and silver staining. Lentiviral-mediated expression of wild-type or mutated forms of human alpha-syn recapitulates the essential neuropathological features of PD. Rat alpha-syn similarly leads to protein aggregation but without cell loss, suggesting that inclusions are not the primary cause of cell degeneration in PD. Viral-mediated genetic models may contribute to elucidate the mechanism of alpha-syn-induced cell death and allow the screening of candidate therapeutic molecules.


Klein, R. L., M. A. King, et al. (2002). "Dopaminergic cell loss induced by human A30P alpha-synuclein gene transfer to the rat substantia nigra." Hum Gene Ther 13(5): 605-12.

            Somatic cell gene transfer was used to express a mutant form of alpha-synuclein (alpha-syn) that is associated with Parkinson's disease (PD) in the rat substantia nigra (SN), a brain region that, in humans, degenerates during PD. DNA encoding the A30P mutant of human alpha-syn linked to familial PD was incorporated into an adeno-associated virus vector, which was injected into the adult rat midbrain. The cytomegalovirus/chicken beta-actin promoter was used to drive transgene expression. Over a 1-year time course, this treatment produced three significant features relevant to PD: (1) accumulation of alpha-syn in SN neuron perikarya, (2) Lewy-like dystrophic neurites in the SN and the striatum, and (3) a 53% loss of SN dopamine neurons. However, motor dysfunction was not found in either rotational or rotating rod testing. The lack of behavioral deficits, despite the significant cell loss, may reflect pathogenesis similar to that of PD, where greater than 50% losses occur before motor behavior is affected.


Kaufer, D. I. (2002). "Pharmacologic therapy of dementia with Lewy bodies." J Geriatr Psychiatry Neurol 15(4): 224-32.

            As a clinicopathologically defined entity, dementia with Lewy bodies (DLB) has overlapping features of Alzheimer's disease (AD) and Parkinson's disease (PD). Analogous characteristics of DLB offer a provisional rationale for pharmacologic therapy based on remediating cholinergic and dopaminergic deficits, respectively. However, the distinct clinical manifestations and pathophysiologic substrates of DLB pose unique therapeutic opportunities and challenges. More severe cholinergic deficits in DLB relative to AD support clinical evidence that cholinergic therapy may be particularly beneficial in DLB patients. In contrast, DLB patients are generally more sensitive to the adverse effects of antipsychotic agents, warranting caution in treating visual hallucinations and other psychotic symptoms. Similarly, parkinsonian motor signs in DLB, often manifest as rigidity and bradykinesia, may be less amenable to dopaminergic therapies than in PD. Increasing recognition of DLB as a common form of dementia in the elderly underscores the need for large-scale, placebo-controlled therapeutic trials.


Kato, K., T. Wada, et al. (2002). "Improvement of both psychotic symptoms and Parkinsonism in a case of dementia with Lewy bodies by the combination therapy of risperidone and L-DOPA." Prog Neuropsychopharmacol Biol Psychiatry 26(1): 201-3.

            A 69-year-old female of dementia with Lewy bodies (DLB) with fluctuating cognitive impairment, visual and auditory hallucinations, persecutory delusions and Parkinsonism was treated by the combination of 1 mg/day risperidone and 300-750 mg/day L-DOPA. By this combination therapy, both the psychotic symptoms and Parkinsonism improved, while cognitive function did not deteriorate. This report suggests that the combination therapy of risperidone and L-DOPA may be worth considering in the special cases of DLB.


Junn, E. and M. M. Mouradian (2002). "Human alpha-synuclein over-expression increases intracellular reactive oxygen species levels and susceptibility to dopamine." Neurosci Lett 320(3): 146-50.

            alpha-Synuclein is a major component of Lewy bodies found in the brains of patients with Parkinson's disease (PD). Two point mutations in alpha-synuclein (A53T and A30P) are identified in few families with dominantly inherited PD. Yet the mechanism by which this protein is involved in nigral cell death remains poorly understood. Mounting evidence suggests the importance of oxidative stress in the pathogenesis of PD. Here we investigated the effects of wild-type and two mutant forms of alpha-synuclein on intracellular reactive oxygen species (ROS) levels using clonal SH-SY5Y cells engineered to over-express these proteins. All three cell lines, and particularly mutant alpha-synuclein-expressing cells, had increased ROS levels relative to control LacZ-engineered cells. In addition, cell viability was significantly curtailed following the exposure of all three alpha-synuclein-engineered cells to dopamine, but more so with mutant alpha-synuclein. These results suggest that over-expression of alpha-synuclein, and especially its mutant forms, exaggerates the vulnerability of neurons to dopamine-induced cell death through excess intracellular ROS generation. Thus, these findings provide a link between mutations or over-expression of alpha-synuclein and apoptosis of dopaminergic neurons by lowering the threshold of these cells to oxidative damage.


Jha, N., M. J. Kumar, et al. (2002). "Glutathione decreases in dopaminergic PC12 cells interfere with the ubiquitin protein degradation pathway: relevance for Parkinson's disease?" J Neurochem 80(4): 555-61.

            Parkinson's disease (PD) is characterized by the presence of proteinaceous neuronal inclusions called Lewy bodies in susceptible dopaminergic midbrain neurons. Inhibition of the ubiquitin-proteasome protein degradation pathway may contribute to protein build-up and subsequent cell death. Ubiquitin is normally activated for transfer to substrate proteins by interaction with the E1 ubiquitin ligase enzyme via a thiol ester bond. Parkinson's disease is also characterized by decreases in midbrain levels of total glutathione which could impact on E1 enzyme activity via oxidation of the active site sulfhydryl. We have demonstrated that increasing reductions in total glutathione in dopaminergic PC12 cells results in corresponding decreases in ubiquitin-protein conjugate levels suggesting that ubiquitination of proteins is inhibited in a glutathione-dependent fashion. Decreased ubiquitinated protein levels appears to be due to inhibition of E1 activity as demonstrated by reductions in endogenous E1-ubiquitin conjugate levels as well as decreases in the production of de novo E1-ubiquitin conjugates when glutathione is depleted. This is a reversible process as E1 activity increases upon glutathione restoration. Our data suggests that decreases in cellular glutathione in dopaminergic cells results in decreased E1 activity and subsequent disruption of the ubiquitin pathway. This may have implications for neuronal degeneration in PD.


Jellinger, K. A. (2002). "Recent developments in the pathology of Parkinson's disease." J Neural Transm Suppl(62): 347-76.

            Parkinson's disease (PD) is morphologically characterized by progressive loss of neurons in the substantia nigra pars compacta (SNpc) and other subcortical nuclei associated with intracytoplasmic Lewy bodies and dystrophic (Lewy) neurites mainly in subcortical nuclei and hippocampus und, less frequently in cerebral cortex. SN cell loss is significantly related to striatal dopamine (DA) deficiency as well as to both the duration and clinical severity of disease, The two major clinical subtypes of PD show different morphologic lesion patterns: the akinetic-rigid form has more severe cell loss in the ventrolateral part of SN with negative correlation to DA loss in the posterior putamen, and motor symptoms related to overacitivty of the GABAergic "indirect" motor loop, which causes inhibition of the glutamatergic thalamocortical pathway and reduced cortical activation. The tremor-dominant type shows more severe cell loss in the medial SNpc and retrorubal field A 8, which project to the matrix of the dorsolateral striatum and ventromedial thalamus, thus causing hyperactivity of thalamomotor and cerebellar projections. These and experimental data suggesting different pathophysiological mechanisms for the major clinical subtypes of PD may have important therapeutic implications. Lewy bodies, the morphologic markers of PD, are composed of hyperphosphorylated neurofilament proteins, lipids, redox-active iron, ubiquitin, and alpha-synuclein, showing a continuous accumulation in the periphery and of ubiquitin in the central core. Alpha-synuclein, is usually unfolded in alpha-helical form. By gene mutation, environmental stress or other factors it can be transformed to beta-folding which is sensible to self-aggregation in filamentous fibrils and formation of insoluble intracellular inclusions that may lead to functional disturbances and, finally, to death of involved neurons. While experimental and tissue culture studies suggest that apoptosis, a genetically determined form of programmed cell death, represents the most common pathway in neurodegeneration, DNA fragmentation, overexpression of proapoptotic proteins and activated caspase-3, the effector enzyme of the terminal apopoptic cascade, have only extremely rarely been detected in SN of PD brains. This is in accordance with the rapid course of apoptotis and the extremely slow progression of the neurodegenerative process in PD. The biological role of Lewy bodies and other intracellular inclusions, the mechanisms of the intracellular aggregation of insoluble protein deposits, and their implication for cellular dysfunction resulting in neurodegeneration and cell demise are still unresolved. Further elucidation of the basic molecular mechanisms of cytoskeletal lesions will provide better insight into the pathogenesis of neurodegeneration in PD and related disorders.


Ishihara, K., A. Nonaka, et al. (2002). "Lewy body-free nigral degeneration--a case report." J Neurol Sci 198(1-2): 97-100.

            A 70-year-old Japanese woman developed progressive, dopa-responsive parkinsonism consisting of akinesia, resting tremor, rigidity, and postural instability. Neuropathological examination revealed a marked loss of nigral neurons, but no Lewy bodies (LBs) were observed. Lewy bodies were also absent from their usual site, with the exception of a small number seen in the dorsal motor nucleus of the vagus nerve (DVN) and sympathetic ganglion. We propose that our case and several similar reported cases represent Lewy body-free nigral degeneration.


Hu, M. T., K. R. Chaudhuri, et al. (2002). "An imaging study of parkinsonism among African-Caribbean and Indian London communities." Mov Disord 17(6): 1321-8.

            We previously reported on 131 parkinsonian patients of African-Caribbean and Indian origin attending movement disorders clinics in six London Hospitals, of whom approximately 20% manifested atypical parkinsonism with a late-onset, akinetic-rigid predominant syndrome, postural instability and minimal resting tremor refractory to levodopa therapy and dopamine agonists (see Hu et al., Neurology 2000;54[Suppl.3]: A188 and Hu et al., Mov Disord 2000;15[Suppl.3]:S212). To better elucidate the phenotype of these atypical patients (18)FDG/(18)F-dopa positron emission tomography (PET) were performed in a subgroup to look for cortical and striatal metabolic changes suggestive of multiple system atrophy (MSA), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), or dementia with Lewy bodies. Magnetic resonance imaging (MRI) rating of cerebral vascular lesion load, putaminal atrophy, and neuropsychological testing were also performed. Discriminant function analysis of (18)F-dopa/(18)FDG striatal metabolism in 43 patients failed to separate atypical ethnic minority from typical Caucasian Parkinson's disease (PD) patients. Additionally, atypical Indian and African-Caribbean patients did not show cortical reductions in glucose metabolism suggestive of PSP, CBD, or DLB. Cerebral vascular lesion load rated in these patients did not differ between atypical and typical PD groups, and none of the atypical patients had MRI changes suggestive of MSA or PSP. Our results suggest the atypical parkinsonian phenotype seen in African-Caribbean and Indian patients represents a levodopa-refractory form of PD separate from MSA or PSP in most patients.


Helfand, S. L. (2002). "Neurobiology. Chaperones take flight." Science 295(5556): 809-10.


Friedman, J. H. and H. H. Fernandez (2002). "Atypical antipsychotics in Parkinson-sensitive populations." J Geriatr Psychiatry Neurol 15(3): 156-70.

            Drug-induced iatrogenic hallucinations and psychosis occur in about 30% of Parkinson's disease (PD) patients and are the single most important precipitant for nursing home placement, which carries a grave prognosis. In addition, parkinsonism is a frequent accompaniment to the more common dementing syndromes, Alzheimer's disease (AD), vascular dementia, and dementia with Lewy bodies (DLB). The five most recent antipsychotic drugs approved by the Food and Drug Administration in the United States have been marketed as "atypical" antipsychotics (AA) due to their relative freedom from extrapyramidal symptoms when used in schizophrenia patients. The use of these newer antipsychotic drugs in PD and other parkinson-sensitive populations represents the most stringent test to their freedom from motor side effects. To date, clozapine, risperidone, olanzapine, and quetiapine have been studied in parkinson-vulnerable populations. This article reviews the data and highlights the differences that these four drugs have on motor function. It also emphasizes the challenges in evaluating the available data on the motor effects of AA, especially on the non-PD elderly and cognitively impaired population. Suggestions are made for future research to improve the interpretability of these studies.


Fernandez, H. H., M. E. Trieschmann, et al. (2002). "Quetiapine for psychosis in Parkinson's disease versus dementia with Lewy bodies." J Clin Psychiatry 63(6): 513-5.

            BACKGROUND: Most clinicians perceive psychosis in dementia with Lewy bodies (DLB) as more difficult to treat than Parkinson's disease, yet there are no reports comparing the antipsychotic response between the 2 disorders. METHOD: All charts of Parkinson's disease and DLB patients at our Movement Disorders Center, Memorial Hospital of Rhode Island, Pawtucket, given quetiapine for psychosis were reviewed. Demographic data, including type and severity of psychosis, before and after Unified Parkinson's Disease Rating Scale (UPDRS)-motor scores, motor worsening, and treatment response (recorded as poor/none, partial, or total), were obtained. The chi-square test was used to assess differences in efficacy and tolerability of quetiapine between Parkinson's disease and DLB patients. RESULTS: Eighty-seven Parkinson's disease and 11 DLB patients with psychosis were analyzed. No significant difference in mean age, levodopa dose, quetiapine dose, duration of quetiapine use, or baseline UPDRS-motor score was noted between Parkinson's disease and DLB patients. Eighty percent (70/87) of Parkinson's disease patients and 90% (10/11) of DLB patients had partial to complete resolution of psychosis using quetiapine (p = .40). Motor worsening was noted at one point in 32% (28/87) of Parkinson's disease and 27% (3/11) of DLB patients over the duration of quetiapine use (p = .74). CONCLUSION: Long-term quetiapine use was generally well tolerated in this geriatric Parkinson's disease and DLB population. Mild motor worsening occurred in some patients. No significant difference in long-term efficacy and motor worsening associated with quetiapine treatment was noted between the 2 disorders.


Elkon, H., J. Don, et al. (2002). "Mutant and wild-type alpha-synuclein interact with mitochondrial cytochrome C oxidase." J Mol Neurosci 18(3): 229-38.

            Alpha-synuclein, a presynaptic protein, was found to be the major component in the Lewy bodies (LB) in both inherited and sporadic Parkinson's disease (PD). Furthermore, rare mutations of alpha-synuclein cause autosomal-dominant PD. However, it is unknown how alpha-synuclein is involved in the pathogenesis of nigral degeneration in PD. In this study, we examine the protein-protein interactions of wild-type and mutant (A53T) a-synuclein with adult human brain cDNA expression library using the yeast two-hybrid technique. We found that both normal and mutant alpha-synuclein specifically interact with the mitochondrial complex IV enzyme, cytochrome C oxidase (COX). Wild-type and mutant alpha-synuclein genes were further fused with c-Myc tag and translated in rabbit reticulocyte lysate. Using anti-c-Myc antibody, we demonstrated that both wild-type and mutant alpha-synuclein, coimmunoprecipitated with COX. We also showed that potassium cyanide, a selective COX inhibitor, synergistically enhanced the sensitivity of SH-SY5Y neuroblastoma cells to dopamine-induced cell death. In conclusion, we found specific protein-protein interactions of alpha-synuclein, a major LB protein, to COX, a key enzyme of the mithochondrial respiratory system. This interaction suggests that alpha-synuclein aggregation may contribute to enhance the mitochondrial dysfunction, which might be a key factor in the pathogenesis of PD.


Dong, Z., B. Ferger, et al. (2002). "Overexpression of Parkinson's disease-associated alpha-synucleinA53T by recombinant adeno-associated virus in mice does not increase the vulnerability of dopaminergic neurons to MPTP." J Neurobiol 53(1): 1-10.

            Mutations in the alpha-synuclein gene are linked to a rare dominant form of familial Parkinson's disease, and alpha-synuclein is aggregated in Lewy bodies of both sporadic and dominant Parkinson's disease. It has been proposed that mutated alpha-synuclein causes dopaminergic neuron loss by enhancing the vulnerability of these neurons to a variety of insults, including oxidative stress, apoptotic stimuli, and selective dopaminergic neurotoxins, such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). To test this hypothesis in vivo, we overexpressed human alpha-synuclein(A53T) in the substantia nigra of normal and MPTP-treated mice by rAAV-mediated gene transfer. Determination of dopaminergic neuron survival, striatal tyrosine hydroxylase fiber density, and striatal content of dopamine and its metabolites in rAAV-injected and uninjected hemispheres demonstrated that alpha-synuclein(A53T) does not increase the susceptibility of dopaminergic neurons to MPTP. Our findings argue against a direct detrimental role for (mutant) alpha-synuclein in oxidative stress and/or apoptotic pathways triggered by MPTP, but do not rule out the possibility that alpha-synuclein aggregation in neurons exposed to oxidative stress for long periods of time may be neurotoxic.


Berciano, J., F. Valldeoriola, et al. (2002). "Presynaptic parkinsonism in multiple system atrophy mimicking Parkinson's disease: a clinicopathological case study." Mov Disord 17(4): 812-6.

            We describe the clinicopathological findings in a patient aged 63 years at death who, at age 55 years, developed levodopa-responsive parkinsonism with no atypical features. A diagnosis of idiopathic Parkinson's disease (PD) was made. During the clinical course, fluctuations and dyskinesias appeared. Eight years after onset, he was successfully treated with subthalamic nucleus stimulation but died 3 weeks postoperatively from pulmonary embolus. Brain autopsy showed marked neuronal loss and gliosis in the substantia nigra and locus coeruleus, and, to a much lesser extent, in the basis pontis, inferior olivary nuclei, and cerebellar cortex. Striatum was normal. There were numerous oligodendroglial and neuronal cytoplasmic inclusions and neuropil threads, the highest density being localized in the pons and cerebellar white matter. No Lewy bodies were observed. We conclude that nigral, presynaptic parkinsonism may occur in multiple system atrophy, which even in the long run can be indistinguishable from PD. Putaminal preservation accounts for good response to both levodopa therapy and subthalamic nucleus stimulation.


Auluck, P. K., H. Y. Chan, et al. (2002). "Chaperone suppression of alpha-synuclein toxicity in a Drosophila model for Parkinson's disease." Science 295(5556): 865-8.

            Parkinson's disease is a movement disorder characterized by degeneration of dopaminergic neurons in the substantia nigra pars compacta. Dopaminergic neuronal loss also occurs in Drosophila melanogaster upon directed expression of alpha-synuclein, a protein implicated in the pathogenesis of Parkinson's disease and a major component of proteinaceous Lewy bodies. We report that directed expression of the molecular chaperone Hsp70 prevented dopaminergic neuronal loss associated with alpha-synuclein in Drosophila and that interference with endogenous chaperone activity accelerated alpha-synuclein toxicity. Furthermore, Lewy bodies in human postmortem tissue immunostained for molecular chaperones, also suggesting that chaperones may play a role in Parkinson's disease progression.


Assal, F. and J. L. Cummings (2002). "Neuropsychiatric symptoms in the dementias." Curr Opin Neurol 15(4): 445-50.

            PURPOSE OF REVIEW: Neuropsychiatric, or non-cognitive symptoms are increasingly recognized as manifestations of dementias. RECENT FINDINGS: In Alzheimer's disease, recent advances have included the identification of behavioral profiles, differentiation of apathy and depression, characterization of risk factors for psychosis and its links to agitation and aggression, and an analysis of depressive symptoms in the absence of major depression. Functional neuroimaging data mainly supported the role of the anterior cingulate in apathy. The orbitofrontal and anterior cingulate tangle burden were associated with agitation, and increased orbitofrontal and mid-temporal muscarinic M2 receptors with psychosis and hallucinations. Selected genetic polymorphisms of dopamine and serotonin receptors or transporters were linked with aggression, hallucinations or psychosis. When compared with other dementias, individuals with frontotemporal dementia disclosed, as expected, different behaviors and particularly aberrant social behavior. The frequency of delusions and visual hallucinations was increased in Parkinson's disease, Parkinson's disease with dementia, and dementia with Lewy bodies, suggesting common mechanisms such as Lewy body pathology and cholinergic deficiency. The latter was supported by an improvement of these symptoms by cholinesterase inhibitors. SUMMARY: Future research directions include both clinical and basic neuroscience investigations. The detection of early neuropsychiatric symptoms might be a marker for dementia, and the possible existence of a mild neuropsychiatric impairment syndrome should be explored. More longitudinal studies with pathological confirmation will facilitate correlations with neuropsychiatric symptoms. Functional neuroimaging and behavioral neurogenetics will permit in-vivo correlations and consequently help patient management and care.


Arsland, D. (2002). "[Dementia with Lewy bodies]." Tidsskr Nor Laegeforen 122(5): 525-9.

            BACKGROUND: Some 10%-15% of patients with dementia are diagnosed as dementia with Lewy bodies (DLB), a disorder characterised by the presence of Lewy bodies in the brainstem and cortex. MATERIAL AND METHODS: Review of pathology, clinical symptoms, pharmacological and nonpharmacological treatment, based on the literature and on personal experience. RESULTS: Neurochemical findings are marked cortical reduction of acetylcholine and nigrostriatal dopamine deficiency. Key features of the clinical syndrome are dementia, fluctuating consciousness, visual hallucinations and parkinsonism. There are pathological and clinical overlaps between DLB and Alzheimer's disease on the one hand, and between DLB and Parkinson's disease on the other; the relationship between these diseases awaits further elucidation. Clinical consensus criteria for DLB have been published and shown to have high sensitivity and specificity. Fluctuating consciousness may be difficult to detect, but diagnostic instruments exist that may help in the evaluation. Drug treatment of DLB is difficult. Cholinesterase inhibitors have been shown to improve cognition and psychiatric symptoms. Atypical antipsychotics may improve psychosis, but some patients develop severe sensitivity reactions. The effect of antiparkinson agents is unknown.


Apaydin, H., J. E. Ahlskog, et al. (2002). "Parkinson disease neuropathology: later-developing dementia and loss of the levodopa response." Arch Neurol 59(1): 102-12.

            OBJECTIVE: To investigate the neuropathologic substrate for dementia occurring late in Parkinson disease (PD). DESIGN: We identified 13 patients with a clinical diagnosis of PD who experienced dementia at least 4 years after parkinsonism onset (mean, 10.5 years) and subsequently underwent postmortem examination. Despite levodopa therapy, 9 patients later became severely impaired and nonambulatory, requiring total or near-total care; this included 4 patients treated with 1200 mg/d or more of levodopa (with carbidopa), which was consistent with loss of the levodopa response. These 13 patients were compared with 9 patients clinically diagnosed as having PD, but without dementia, who had undergone autopsies. RESULTS: Twelve of 13 PD patients with dementia had findings of diffuse or transitional Lewy body disease as the primary pathologic substrate for dementia; 1 had progressive supranuclear palsy. This pathology also apparently accounted for the levodopa refractory state. Among the 12 PD patients with dementia, mean and median Lewy body counts were increased nearly 10-fold in neocortex and limbic areas compared with PD patients without dementia (P< or =.002). Alzheimer pathology was modest. Only one patient met the criteria defined by the National Institute on Aging and the Reagan Institute Working Group on the Diagnostic Criteria for the Neuropathologic Assessment of Alzheimer's Disease for "intermediate probability of Alzheimer's disease." There were, however, significant correlations between neocortical Lewy body counts and senile plaques as well as neurofibrillary tangles. Senile plaque counts did not significantly correlate with tangle counts in any of the analyzed nuclei. Arteriolar disease may have contributed to the clinical picture in 2 patients. CONCLUSIONS: Diffuse or transitional Lewy body disease is the primary pathologic substrate for dementia developing later in PD. This same pathologic substrate seemed to account for end-stage, levodopa refractory parkinsonism. The occurrence of Alzheimer pathology was modest, but was highly correlated with Lewy body pathology, suggesting common origins or one triggering the other.

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