Zatloukal, K., C. Stumptner, et al. (2002). "p62 Is a common component of cytoplasmic inclusions in protein aggregation diseases." Am J Pathol 160(1): 255-63. Exposure of cells to stress, particularly oxidative stress, leads to misfolding of proteins and, if they are not refolded or degraded, to cytoplasmic protein aggregates. Protein aggregates are characteristic features of a variety of chronic toxic and degenerative diseases, such as Mallory bodies (MBs) in hepatocytes in alcoholic and non-alcoholic steatohepatitis, neurofibrillary tangles in neurons in Alzheimer's, and Lewy bodies in Parkinson's disease. Using 2D gel electrophoresis and mass spectrometry, we identified p62 as a novel MB component. p62 and cytokeratins (CKs) are major MB constituents; HSP 70, HSP 25, and ubiquitinated CKs are also present. These proteins characterize MBs as a prototype of disease-associated cytoplasmic inclusions generated by stress-induced protein misfolding. As revealed by transfection of tissue culture cells overexpressed p62 did not induce aggregation of regular CK filaments but selectively bound to misfolded and ubiquitinated CKs. The general role of p62 in the cellular response to misfolded proteins was substantiated by detection of p62 in other cytoplasmic inclusions, such as neurofibrillary tangles, Lewy bodies, Rosenthal fibers, intracytoplasmic hyaline bodies in hepatocellular carcinoma, and alpha1-antitrypsin aggregates. The presence of p62 along with other stress proteins and ubiquitin in cytoplasmic inclusions indicates deposition as aggregates as a third line of defense against misfolded proteins in addition to refolding and degradation. Yokoyama, K., S. Ikebe, et al. (2002). "[A 68-year-old woman with dementia and parkinsonism]." No To Shinkei 54(2): 175-84. We report a 68-year-old woman who developed progressive dementia and parkinsonism. She was well until 1990 when she was 58 years of age. She started to show memory loss. Four years later, she developed difficulty in dressing and behavioral problems such as eating rice with her hands, going out of her house without purposes, and difficulty in finding the rest room in her house. She was admitted to the neurology service of Hatsuishi Hospital on January 19, 1996, when she was 64 years of the age. On admission, she was alert but markedly demented. The score of Hansegawa Dementia Scale was 0/30. She was unable to make any coherent conversation. She appeared to have dressing apraxia but did not appear to have aphasia. Cranial nerves were intact. She walked in small steps with stooped posture. She did not have motor weakness but she showed plastic rigidity in all four limbs. No tremor or ataxia was noted. Deep tendon reflexes were within normal limits but the plantar response was extensor bilaterally. She continued to deteriorate after admission. In May of 1998, she started to fall. In June of 1998, she had a generalized convulsion. In January of 1999, she became unable to take foods orally and a gastrostomy was placed. She expired on May 29, 1990. She was discussed in a neurological CPC and the chief discussant arrived at the conclusion that the patient had Alzheimer's disease. The question was whether her parkinsonism was a part of her Alzheimer's disease or she had an additional disease to explain her parkinsonism. Post-mortem examination revealed moderate to marked atrophy of the frontal and the temporal lobes as well as in the limbic areas with dilatation of the lateral ventricles. Marked neuronal loss was noted in the CA 1 to the subiculum region with gliosis. Neurofibrillary tangles were seen in the remaining neurons. Neuropil threads were seen by Gallyas-Braak staining. Similar changes were seen in the parahippocampal gyrus and in the entorhinal cortex. Senile plaques were seen in the insular cortex and in other cortical areas. Cortical type Lewy bodies were seen in the cingulate cortex. The Meynert nucleus showed marked neuronal loss and gliosis. The substantia nigra and the locus coeruleus showed moderate loss of pigmented neurons. Lewy bodies were seen in these regions. The dorsal motor nucleus of the vagal nerve was retained, however, one Lewy body was observed. Pathologic diagnosis was Alzheimer's disease plus Parkinson's disease. It is an interesting question whether or not her parkinsonism was due to nigral lesion or frontal lesions. It is known that parkinsonism may complicate in advanced Alzheimer's disease not necessarily due to nigral lesion. On the other hand, in incidental Lewy body disease, the substantia nigra shows mild Parkinson's disease-like change without clinical parkinsonism. This patient appeared to have been a true complication of Alzheimer's disease and Parkinson's disease. Yokota, O., S. Terada, et al. (2002). "NACP/alpha-synuclein immunoreactivity in diffuse neurofibrillary tangles with calcification (DNTC)." Acta Neuropathol (Berl) 104(4): 333-41. Diffuse neurofibrillary tangles with calcification (DNTC) is a rare tangle-predominant dementia, as well as one of the tauopathies lacking Abeta deposition. It is characterized by temporo-frontal lobar atrophy, Fahr-type calcification and, histopathologically, numerous neurofibrillary tangles in the limbic system and neocortex. Recently, accumulation of alpha-synuclein (alphaS), the precursor of the non-beta amyloid component (NAC) of Alzheimer's disease, has been shown in diverse neurodegenerative disorders, including Parkinson's disease, dementia with Lewy bodies, Alzheimer's disease, multiple system atrophy and parkinsonism-dementia complex of Guam. To clarify whether alphaS accumulates in other neurodegenerative disorders, we investigated eight DNTC brains using immunohistochemistry and demonstrated remarkable alphaS deposition in the neurons and astrocytes in many anatomical regions. Abundant Lewy bodies were observed in the amygdala (seven cases) and hippocampus (seven cases), and, to a lesser degree, in the substantia nigra (six cases) and dorsal vagal nucleus (five cases). In the hippocampus, many Lewy neurites were distributed in the stratum oriens and stratum pyramidale in the CA2-3 and the subiculum. Furthermore, numerous NAC-positive astrocytes were detected in the hippocampus and temporal cortex. This investigation reveals that neurons and astrocytes are extensively involved in remarkable alphaS pathology in the DNTC brain, and that the alphaS pathology compounds the cardinal pathological features of tau pathology. These findings suggest that (1) DNTC shares a common pathophysiological background with Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy in which abnormal alphaS aggregation is observed, and (2) there is an interaction between alphaS and tau pathology that does not involve amyloid in DNTC. Windisch, M., B. Hutter-Paier, et al. (2002). "Development of a new treatment for Alzheimer's disease and Parkinson's disease using anti-aggregatory beta-synuclein-derived peptides." J Mol Neurosci 19(1-2): 63-9. The synaptic protein alpha-synuclein is a major constituent of Lewy bodies (LB), pathological neuronal inclusion bodies found in Parkinson's disease (PD), Alzheimer's disease (AD), and other neurodegenerative disorders. Owing to data from patient brains, it was speculated that an imbalance between alpha-synuclein and beta-synuclein might be one of the reasons for formation of LBs and the consequent functional deficits. This was supported by the fact that beta-synuclein is able to prevent abnormal alpha-synuclein aggregation. Transgenic mice overexpressing alpha-synuclein display LB-like inclusions in different brain regions and motor deficits. To verify if re-establishing a normal relation between alpha-synuclein and beta-synuclein is able to prevent the pathology, bigenic mice have been created that overexpress both synucleins. Beta-synuclein decreased formation of LBs by 40% and prevented functional deficits. This is considered as preliminary in vivo proof of antiaggregatory function of beta-synuclein and its potential as therapeutic substance for treatment of neurodegenerative disorders linked with abnormal protein aggregation. Peptide libraries have been synthesized to explore the active structures of beta-synuclein. The first 15 N-terminal amino-acids turned out to be important for the antiaggregatory effect. Further smaller beta-synuclein-derived peptides have screened for antiaggregatory and neuroprotective potency in different tissue-culture systems. Preliminary data suggest some of them can be used as leads for further drug development. 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. Uversky, V. N. and A. L. Fink (2002). "Amino acid determinants of alpha-synuclein aggregation: putting together pieces of the puzzle." FEBS Lett 522(1-3): 9-13. Parkinson's disease is the second most common neurodegenerative disease, and results from loss of dopaminergic neurons in the substantia nigra. The aggregation and fibrillation of alpha-synuclein in the form of intracellular proteinaceous aggregates (Lewy bodies and Lewy neurites) have been implicated as a causative factor in this disease, as well as in several other neurodegenerative disorders, including dementia with Lewy bodies, Lewy body variant of Alzheimer's disease, multiple system atrophy and Hallervorden-Spatz disease. Thus, the aggregated forms of alpha-synuclein play a crucial role in the pathogenesis of the synucleinopathies. However, the molecular mechanisms underlying alpha-synuclein aggregation into specific filamentous inclusions remained unknown until recently. Data on the aggregation and fibrillation properties of human alpha-, beta- and gamma-synucleins, mouse alpha-synuclein and familial Parkinson's disease mutants of human alpha-synuclein (A30P and A53T) are analyzed in order to shed light on the amino acid determinants of synuclein aggregation. Tsuchiya, K., K. Ikeda, et al. (2002). "Parkinson's disease mimicking senile dementia of the Alzheimer type: a clinicopathological study of four autopsy cases." Neuropathology 22(2): 77-84. This report concerns four Japanese autopsy cases of Parkinson's disease (PD) mimicking senile dementia of the Alzheimer type. Three patients with a clinical diagnosis of senile dementia of the Alzheimer type developed memory disturbance as the initial sign, and a patient with a clinical diagnosis of atypical senile dementia presented with hallucination and delusion as the initial sign. Dementia was evident in all four patients, and slight parkinsonism appeared in the middle to late stages of the disease in two patients. Macroscopical examination of the brain disclosed slight depigmentation of the substantia nigra and prominent depigmentation of the locus ceruleus in all four cases. Histological examination of the four patients showed neuronal loss with astrocytosis and the appearance of Lewy bodies in the substantia nigra, locus ceruleus, and dorsal vagal nucleus. The nucleus basalis of Meynert was involved in three cases, in which this structure was examined. The total Lewy body scores of the four cases were 1 in three cases and 0 in the other, compatible with PD. Massive appearance of senile plaques, consistent with Braak stage C, was found in one case, and the slight appearance of senile plaques, consistent with Braak stage A, was evident in two cases. One case had no evidence of senile plaques. In all four cases, slight neurofibrillary changes were present in the limbic areas, compatible with Braak stages II to III. Based on these clinicopathological findings and a review of the literature, we concluded that PD simulating Alzheimer's disease without overt parkinsonism rarely exists. Furthermore, we postulate that the clinical features of PD are more widespread than previously believed. Tamo, W., T. Imaizumi, et al. (2002). "Expression of alpha-synuclein, the precursor of non-amyloid beta component of Alzheimer's disease amyloid, in human cerebral blood vessels." Neurosci Lett 326(1): 5-8. The non-amyloid beta component of Alzheimer's disease amyloid (NAC) is detected in cerebral amyloid angiopathy; and the precursor of NAC is now known to be identical to alpha-synuclein (alpha-S), a major component of Lewy bodies in Parkinson's disease. We studied if cerebral vascular cells express alpha-S. Immunohistochemical studies of human cerebral tissues from control and cerebral amyloid angiopathy patients revealed the expression of alpha-S in vascular endothelial and smooth muscle cells. Then we studied the expression of alpha-S in vitro using cultures of vascular cells. Cultures of human umbilical vein endothelial cells and umbilical artery smooth muscle cells were found to constitutively express alpha-S messenger RNA and protein. alpha-S is normally expressed in vascular cells and may play some physiological role in the vascular wall. Tabner, B. J., S. Turnbull, et al. (2002). "Formation of hydrogen peroxide and hydroxyl radicals from Abeta and alpha-synuclein as a possible mechanism of cell death in Alzheimer's disease and Parkinson's disease(1,2)." Free Radic Biol Med 32(11): 1076-83. The formation of extracellular or intracellular deposits of amyloid-like protein fibrils is a prominent pathological feature of many different neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). In AD, the beta-amyloid peptide (Abeta) accumulates mainly extracellularly at the center of senile plaques, whereas, in PD, the alpha-synuclein protein accumulates within neurons inside the Lewy bodies and Lewy neurites. We have shown recently that solutions of Abeta 1-40, Abeta 1-42, Abeta 25-35, alpha-synuclein and non-Abeta component (NAC; residues 61-95 of alpha-synuclein) all liberate hydroxyl radicals upon incubation in vitro followed by the addition of small amounts of Fe(II). These hydroxyl radicals were readily detected by means of electron spin resonance spectroscopy, employing 5,5-dimethyl-1-pyrroline N-oxide (DMPO) as a spin trapping agent. Hydroxyl radical formation was inhibited by the inclusion of catalase or metal-chelators during Abeta or alpha-synuclein incubation. Our results suggest that hydrogen peroxide accumulates during the incubation of Abeta or alpha-synuclein, by a metal-dependent mechanism, and that this is subsequently converted to hydroxyl radicals, on addition of Fe (II), by Fenton's reaction. Consequently, one of the fundamental molecular mechanisms underlying the pathogenesis of cell death in AD and PD, and possibly other neurodegenerative or amyloid diseases, could be the direct production of hydrogen peroxide during formation of the abnormal protein aggregates. Szirmai, I. and T. Kovacs (2002). "[In Process Citation]." 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. Rub, U., K. Del Tredici, et al. (2002). "Parkinson's disease: the thalamic components of the limbic loop are severely impaired by alpha-synuclein immunopositive inclusion body pathology." Neurobiol Aging 23(2): 245-54. The Parkinson's disease (PD)-related inclusion body pathology comprises Lewy bodies (LBs) as well as Lewy neurites (LNs). The distribution and severity of this pathology were investigated in the thalamus of 12 autopsy cases with clinically diagnosed and neuropathologically confirmed PD. The LBs and LNs were visualized by immunoreactions against the protein alpha-synuclein. In the human thalamus during PD, a specific and highly stereotypical distribution pattern of LBs and LNs evolves. As in cortical and other subcortical regions, the components of human thalamus assigned to the limbic loop bear the brunt of the PD-related pathology. In contrast, the thalamic components integrated into the striatal and cerebellar loops as well as the primary sensory nuclei of the thalamus show at best a mildly developed pathology. Damage to the thalamic components of the limbic loop nuclei may contribute not only to the cognitive, emotional, and autonomic symptoms of PD but to the somatomotor and oculomotor dysfunctions as well. Rosler, M. (2002). "The efficacy of cholinesterase inhibitors in treating the behavioural symptoms of dementia." Int J Clin Pract Suppl(127): 20-36. Multiple behavioural and psychological symptoms of dementia (BPSD) are commonly associated with all dementia subtypes, and worsen during disease progression. BPSD arise due to impairment of cholinergic function in the cortex, hippocampus and related limbic systems. Recent studies have investigated the effect of cholinesterase inhibitors on BPSD. The dual acetylcholinesterase/butyrylcholinesterase (AChE/BuChE) inhibitor rivastigmine was shown to have several potential advantages over the AChE-selective inhibitors donepezil and galantamine for the treatment of BPSD. Rivastigmine appears to be effective across the range of dementia severity from mild to severe, and across the spectrum of dementia (Alzheimer's disease [AD], the AD variant with Lewy bodies, Parkinson's disease dementia and vascular dementia subtypes). It also appears to have a disease-modifying potential. Rivastigmine improved a wider range of behavioural symptoms (apathy, anxiety/depression, hallucinations and delusions) than donepezil and galantamine (which improved apathy and depression/anxiety only). Unlike donepezil, rivastigmine reduced the need for psychotropic medications to treat BPSD. Dual inhibition of AChE and BuChE and brain-region selectivity through preferential inhibition of the G1 isoform of AChE may provide the underlying reasons for the apparently greater and broader efficacy of rivastigmine over AChE-selective inhibitors for the treatment of BPSD. However, randomised, controlled trials are required to compare dual inhibitors, such as rivastigmine, and AChE-selective agents, to confirm and quantify any differences in their effects on BPSD. Ransmayr, G. (2002). "[Dementia with Lewy bodies]." Wien Med Wochenschr 152(3-4): 81-4. Dementia with Lewy bodies (DLB) is the second most frequent neuropathologically diagnosed degenerative dementing illness. The clinical characteristics are progressive dementia, Parkinson syndrome, fluctuations of cognitive functions, vigilance and attention, visual hallucinations (usually detailed and well described), depression, REM-sleep behavior disorder, adverse responses to standard doses of neuroleptics, falls, syncopes, systematized delusions, and non-visual hallucinations. Mean age at disease onset ranges between 60 and 68 years. Male persons are more frequently affected than female. Disease duration is six to seven years. The differential diagnoses of DLB are dementia of the Alzheimer-type, Parkinson's disease, subcortical arteriosclerotic encephalopathy, progressive supranuclear palsy, multiple system atrophy, and, in rare cases, Creutzfeldt-Jakob disease. The genetic background of the disease is unclear. Magnetic resonance imaging and single photon emission tomography can contribute to the diagnosis. The disease is treated with L-dopa, atypical neuroleptics, acetylcholine esterase inhibitors, antihypotensive agents, and peripheral anticholinergic and alpha-receptor-blocking medicaments to improve neurogenic bladder dysfunction. McLean, P. J. and B. T. Hyman (2002). "An alternatively spliced form of rodent alpha-synuclein forms intracellular inclusions in vitro: role of the carboxy-terminus in alpha-synuclein aggregation." Neurosci Lett 323(3): 219-23. In the rat, the -synuclein gene is alternatively spliced and exists in three forms, rat synuclein 1 (rSYN1), synuclein 2 (rSYN2) and synuclein 3. rSYN2 cDNA encodes a 149 amino acid protein that is homologous to rSYN1 and human -synuclein for the first 100 amino acids, but is divergent for the 49 amino acid carboxy-terminal region. We demonstrate here that rSYN2 forms small aggregates throughout the cytoplasm when overexpressed in human H4 cells, whereas rSYN1 expression is diffuse. Inhibition of the proteasome promotes the formation of larger, cytoplasmic rSYN2 inclusions in transfected cells. Although a survey of the available databases suggests that there is no human splice form equivalent of rSYN2, thus arguing against a direct role in Lewy body formation and Parkinson's disease, these data nonetheless suggest that modifications of the carboxy-terminal region of -synuclein predispose it to inclusion formation. McKeith, I. G. (2002). "Dementia with Lewy bodies." Br J Psychiatry 180: 144-7. BACKGROUND: Dementia with Lewy bodies (DLB) is a common dementia subtype that has only been recognised in the past decade and that remains widely underdiagnosed. AIMS: To review the pathological and clinical features of DLB, to consider methods of investigation and diagnosis, and to recommend safe and effective management strategies. METHOD: A selective review was made of the key literature. RESULTS: Using operationalised criteria, DLB can be clinically diagnosed with an accuracy similar to that achieved for Alzheimer's disease or Parkinson's disease. Underdetection is largely due to poor definition of the criterion of cognitive fluctuation. Ancillary investigations, particularly neuroimaging, can aid in differential diagnosis. Extreme caution in the use of neuroleptic medication is advised. Cholinesterase inhibitors may be particularly effective in DLB. CONCLUSIONS: Clinicians should be aware of DLB as part of a spectrum of Lewy body disorders. Neuroleptic sensitivity reactions and good response to cholinergic therapies are important aspects of management. Madsen, A. M., R. K. Lomholt, et al. (2002). "[Diagnosis and treatment of Lewy body dementia]." Ugeskr Laeger 164(18): 2383-6. Dementia with Lewy bodies (DLB) has recently gained recognition as a separate disease. Lewy bodies are pathoanatomical inclusion bodies in the CNS. They are well known as part of Parkinson's disease where they are present mainly in the substantia nigra, and they are also found in large numbers in the neocortex. It is still an unanswered question why Lewy bodies are formed, but their appearance is connected with cellular degeneration of unknown aetiology. Neuropathological investigations of dementia populations show that DLB accounts for 12-36%, which places it as the second most frequent dementia disease after Alzheimer's disease (AD) with a frequency close to that of vascular dementia. This article reviews the development of the term DLB and describes the clinical characteristics, including the neuropsychological symptom profile, which can contribute to the diagnostic discrimination between DLB and AD. Furthermore, relevant treatment possibilities are discussed. Lopez, O. L., J. T. Becker, et al. (2002). "Research evaluation and prospective diagnosis of dementia with Lewy bodies." Arch Neurol 59(1): 43-6. OBJECTIVE: To evaluate the relative merits of recently developed criteria for dementia with Lewy bodies (DLBs) in a longitudinal study of dementia. DESIGN: The diagnosis of DLBs was used in combination with other clinical diagnosis. Patients were classified primarily based on the NINCDS-ADRDA (National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association) clinical criteria for probable or possible Alzheimer disease, or with other disease process that can cause dementia (eg, Parkinson disease), and secondarily according to the consensus guidelines for DLBs. This "double" clinical diagnosis was implemented to capture different pathological entities. The neuropathological diagnosis of Lewy bodies was made with monoclonal antibodies against alpha-synuclein. SETTING: Multidisciplinary research clinic. RESULTS: Prospective application of the consensus guidelines for DLBs from January 1, 1997, to September 29, 2000, identified 11 patients having the diagnosis of probable DLBs and 35 having possible DLBs. The diagnosis of probable or possible DLBs was associated with probable Alzheimer disease in 34 patients, with possible Alzheimer disease in 5 patients, with Parkinson disease in 2 patients, and with other disease processes in 2 patients. Three patients were diagnosed as having probable DLBs alone. An autopsy was performed in 26 of the cases who were clinically examined during the study period. Cortical Lewy bodies were identified in 13 cases; 4 had had premortem diagnosis of DLBs (sensitivity, 30.7%; specificity, 100%). CONCLUSIONS: The prospective validation of the clinical criteria for DLBs showed poor accuracy in this series. We believe that current criteria for DLBs are useful when DLBs occur in isolation, but have low sensitivity when Lewy bodies coexist with the pathological abnormalities of Alzheimer disease. Li, J. Y., P. Henning Jensen, et al. (2002). "Differential localization of alpha-, beta- and gamma-synucleins in the rat CNS." Neuroscience 113(2): 463-78. alpha-Synuclein is a presynaptic protein that normally participates in the homeostasis of synaptic vesicles. Missense mutations in its gene cause the protein to participate actively in the development of heritable forms of Parkinson's disease. Moreover, its metabolism is perturbed in all cases of Parkinson's disease where alpha-synuclein accumulates in a filamentous form in the Lewy body nerve cell lesion. Lewy bodies also develop in other common neurodegenerative disorders, like dementia with Lewy bodies and Lewy body variant of Alzheimer's disease. In the present study, we have studied the detailed distribution of alpha-, beta- and gamma-synuclein in the rat CNS.alpha-Synuclein was not observed in perikarya, but was distributed with high intensity in nerve terminals in the caudate and putamen and ventral pallidum, where beta-synuclein was much weaker and less densely distributed in the caudate and putamen. gamma-Synuclein was not found in the caudate and putamen. alpha-Synuclein was robustly distributed in the substantia nigra pars reticulata, but was very weak or virtually absent from the perikarya of the neurons in the pars compacta. In contrast, beta-synuclein was very weak or absent from the substantia nigra. gamma-Synuclein was absent from the terminals of substantia nigra pars reticulata, but sparsely distributed gamma-synuclein-containing neurons were detected in the substantia nigra pars compacta. In the brainstem, alpha-synuclein as well as gamma-synuclein were present in the locus coeruleus with high intensity, while beta-synuclein was very weak. In addition, alpha-synuclein was intense in the vagus nucleus, but weak in the oculomotor, facial, hypoglossal, accessory and ambiguous nuclei, where beta-synuclein was very intensely present. Furthermore, gamma-synuclein was localized in the terminals and in cell bodies of the Edinger-Westphal nucleus, the red nucleus, locus coeruleus, and most cranial nerve-related nuclei. In the spinal cord, alpha- and gamma-synucleins were intensely present in laminae I and II and in the preganglionic sympathetic nuclei, whereas beta-synuclein was very weak.These results indicate that alpha-synuclein is abundant in central catecholaminergic regions. beta-Synuclein is more localized in the somatic cholinergic components, while it is particularly weak or absent from catecholaminergic neurons. gamma-Synuclein appears to be present in both cholinergic and catecholaminergic regions, but very weak in the forebrain. Lang, C. J. and M. Bergmann (2002). "[Dementias with lewy bodies]." Fortschr Neurol Psychiatr 70(9): 476-94. Dementias with Lewy bodies are no rare cause of cognitive and motor impairments in old age. Neuropathologically, they must be distinguished into diffuse Lewy body disease resp. dementia with Lewy bodies, Parkinson's disease with concomitant Alzheimer's pathology, and the Lewy body variant of Alzheimer's disease according to extent and concomitant pathology. The most reliable diagnostic features of dementia with Lewy bodies are fluctuating disturbances of cognition and consciousness, visual disorders (hallucinations, visuoperceptive and visuoconstructive impairments), and early extrapyramidal signs of the hypokinetic-rigid type with a propensity to frequent falls. The pertinent diagnostic criteria are the consensus criteria according to McKeith et al. Additional contributions are to be expected by functional neuroimaging (SPECT, PET) and CSF examination (homovanillic acid). However, even assuming the most favorable conditions a diagnostic accuracy of 85 % is presently hard to achieve. Particularly, as is demonstrated using a case example, reliable antemortem diagnosis of Lewy body variant of Alzheimer's disease is hardly possible. Clinically, this group of diseases is important, since increased neuroleptic sensitivity must be taken into account and modern central cholinergic agents seem to be a promising therapeutic option. Kurosinski, P., M. Guggisberg, et al. (2002). "Alzheimer's and Parkinson's disease--overlapping or synergistic pathologies?" Trends Mol Med 8(1): 3-5. Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most common neurodegenerative disorders in humans. They are characterized by insoluble protein deposits; beta-amyloid plaques and tau-containing neurofibrillary lesions in AD, and alpha-synuclein-containing Lewy bodies in PD. As a significant percentage of patients have clinical and pathological features of both diseases, the patho-cascades of the two diseases might overlap. For the first time, new animal models that express multiple transgenes provide the tools to dissect the pathogenic pathways and to differentiate between additive and synergistic effects. Kim, K. S., S. Y. Choi, et al. (2002). "Aggregation of alpha-synuclein induced by the Cu,Zn-superoxide dismutase and hydrogen peroxide system." Free Radic Biol Med 32(6): 544-50. Alpha-synuclein is a major component of the abnormal protein aggregation in Lewy bodies of Parkinson's disease (PD) and senile plaques of Alzheimer's disease (AD). Previous studies have shown that the aggregation of alpha-synuclein was induced by copper (II) and H(2)O(2) system. Since copper ions could be released from oxidatively damaged Cu,Zn-superoxide dismutase (SOD), we investigated the role of Cu,Zn-SOD in the aggregation of alpha-synuclein. When alpha-synuclein was incubated with both Cu,Zn-SOD and H(2)O(2), alpha-synuclein was induced to be aggregated. This process was inhibited by radical scavengers and spin trapping agents such as 5,5'-dimethyl 1-pyrolline N-oxide and tert-butyl-alpha-phenylnitrone. Copper chelators, diethyldithiocarbamate and penicillamine, also inhibited the Cu,Zn-SOD/H(2)O(2) system-induced alpha-synuclein aggregation. These results suggest that the aggregation of alpha-synuclein is mediated by the Cu,Zn-SOD/H(2)O(2) system via the generation of hydroxyl radical by the free radical-generating function of the enzyme. The Cu,Zn-SOD/H(2)O(2)-induced alpha-synuclein aggregates displayed strong thioflavin-S reactivity, reminiscent of amyloid. These results suggest that the Cu,Zn-SOD/H(2)O(2) system might be related to abnormal aggregation of alpha-synuclein, which may be involved in the pathogenesis of PD and related disorders. Khotianov, N., R. Singh, et al. (2002). "Lewy body dementia: case report and discussion." J Am Board Fam Pract 15(1): 50-4. BACKGROUND: Lewy body dementia is a common but frequently underdiagnosed cause of dementia often mistaken for the more familiar entity of Alzheimer disease. Clinically the distinction is important, because it can have profound implications for management. METHODS: The medical literature was searched using the keywords "Lewy bodies," "Lewy body dementia," "Alzheimer dementia," and "parkinsonian disorders." A case of Lewy body dementia is described. RESULTS: An elderly man had long-standing diagnoses of Alzheimer disease and Parkinson disease. After he was evaluated thoroughly, the diagnosis was revised to Lewy body dementia, leading to changes in treatment that were associated with dramatic improvement in the patient's mental status. Evidence from the literature suggests that Lewy body dementia can be diagnosed in primary care settings based on clinical criteria. The physician should be alert to this diagnosis, and special attention should be paid to dementia patients who exhibit parkinsonism, hallucinations, fluctuating cognition, or prominent visuosperceptual deficits. CONCLUSIONS: The diagnosis of Lewy body dementia has important implications. It is associated with a high incidence of neuroleptic sensitivity, necessitating great caution in the use of these common antipsychotic agents. Early studies indicate cholinesterase inhibitors can be beneficial for treating the hallucinations and behavior disturbances that afflict these patients and might also improve cognition. Jellinger, K. A. (2002). "Disturbance of the nigro-amygdaloid connections in dementia with Lewy bodies." J Neurol Sci 193(2): 157-8. Harding, A. J., B. Lakay, et al. (2002). "Selective hippocampal neuron loss in dementia with Lewy bodies." Ann Neurol 51(1): 125-8. Hippocampal volume and neuron number were measured using stereological techniques in pathologically confirmed dementia with Lewy bodies (n = 8), Parkinson's disease only (n = 4), and controls (n = 9). We, and others, have previously shown considerable cell loss in the CA1 and subiculum subregions in Alzheimer's disease. In contrast, these regions were spared in dementia with Lewy bodies where a selective loss of lower presubiculum pyramidal neurons was found. These findings suggest a selective loss of frontally projecting hippocampal neurons in dementia with Lewy bodies versus those projecting to temporal lobe regions in Alzheimer's disease. Gu, G., P. E. Reyes, et al. (2002). "Mitochondrial DNA deletions/rearrangements in parkinson disease and related neurodegenerative disorders." J Neuropathol Exp Neurol 61(7): 634-9. Inhibition of mitochondrial respiratory chain function may contribute to dopaminergic neurodegeneration in the substantia nigra (SN) of patients with Parkinson disease (PD). Since large-scale structural changes (e.g. deletions and rearrangements in mitochondrial DNA [mtDNA]) have been associated with mitochondrial dysfunction, we tested the hypothesis that increased total mtDNA deletions/rearrangements are associated with neurodegeneration in PD. This study employed a well-established technique, long-extension polymerase chain reaction (LX-PCR), to detect the multiple mtDNA deletions/rearrangements in the SN of patients with PD, multiple system atrophy (MSA), dementia with Lewy bodies (DLB), Alzheimer disease (AD), and age-matched controls. We also compared the total mtDNA deletions/rearrangements in different brain regions of PD patients. The results demonstrated that both the number and variety of mtDNA deletions/rearrangements were selectively increased in the SN of PD patients compared to patients with other movement disorders as well as patients with AD and age-matched controls. In addition, increased mtDNA deletions/rearrangements were observed in other brain regions in PD patients, indicating that mitochondrial dysfunction is not just limited to the SN of PD patients. These data suggest that accumulation of total mtDNA deletions/rearrangements is a relatively specific characteristic of PD and may be one of the contributing factors leading to mitochondrial dysfunction and neurodegeneration in PD. Freo, U., G. Pizzolato, et al. (2002). "A short review of cognitive and functional neuroimaging studies of cholinergic drugs: implications for therapeutic potentials." J Neural Transm 109(5-6): 857-70. In the last 20 years a cholinergic dysfunction has been the major working hypothesis for the pharmacology of memory disorders. Cholinergic antagonists and lesions impair and different classes of cholinomimetics (i.e. acetylcholine precursors, cholinergic agonists and acetylcholinesterase inhibitors) enhance attention and memory in experiment animals, healthy human subjects and Alzheimer disease patients. In addition, acetylcholinesterase inhibitors improve different cognitive (i.e. visuospatial and verbal) functions in a variety of unrelated disorders such as dementia with Lewy bodies, Parkinson disease, multiple sclerosis, schizoaffective disorders, iatrogenic memory loss, traumatic brain injury, hyperactivity attention disorder and, as we recently reported, vascular dementia and mild cognitive impairment. In animals, different cholinomimetics dose-dependently increased regional cerebral metabolic rates for glucose (rCMRglc) and regional blood flow (rCBF), two indices of neuronal function, more markedly in subcortical regions (i.e. thalamus, hippocampus and visual system nuclei). In both healthy human subjects and Alzheimer disease patients acetylcholinesterase inhibitors increased rCMRglc and rCBF in subcortical and cortical brain regions at rest but attenuated rCBF increases during cognitive performances. Hence, acetylcholinesterase inhibitors may enhance cognition and rCMRglc by acting primarily on subcortical regions that are involved in attentional (i.e. thalamus) and memory (i.e. hippocampus) processes; such an effect probably is not specific for Alzheimer disease and can be beneficial in patients suffering from a wide array of neuropsychiatric disorders. Bergman, J. and V. Lerner (2002). "Successful use of donepezil for the treatment of psychotic symptoms in patients with Parkinson's disease." Clin Neuropharmacol 25(2): 107-10. The risk of psychosis among patients with Parkinson's disease (PD) is high, and the management of these patients remains a substantial problem for physicians. Atypical antipsychotics, despite their advantages over conventional antipsychotics, can cause different side effects and deterioration of PD. Several reports have suggested that donepezil can be helpful in the treatment of psychotic conditions in patients with dementia with Lewy bodies and Alzheimer's disease. This report presents the results of preliminary study of six patients (four women, two men; age range, 60-75 years) with PD (range of duration, 3-7 years) and dementia complicated by psychosis. All patients were treated with antiparkinsonian therapy, and donepezil was added to their regular treatment. The severity of the psychotic symptoms was assessed using the Scale for the Assessment of Positive Symptoms, and extrapyramidal symptoms were assessed using the Simpson-Angus Scale. With the addition of donepezil (as much as 10 mg/day) to their constant antiparkinsonian treatment, five patients had clinically significant (more than 53%) improvement on the assessment scale, and one patient had minimal (24%) improvement after 6 weeks of the treatment. None of the patients had side effects or deterioration of parkinsonian symptoms. The results suggest that donepezil may ameliorate psychotic symptoms in patients with PD, but this will need to be tested further in controlled, double-blind trials. Barber, R., I. McKeith, et al. (2002). "Volumetric MRI study of the caudate nucleus in patients with dementia with Lewy bodies, Alzheimer's disease, and vascular dementia." J Neurol Neurosurg Psychiatry 72(3): 406-7. OBJECTIVES: To determine whether parkinsonian symptoms in dementia with Lewy bodies (DLB) are associated with greater atrophy of the caudate nucleus in comparison with patients with Alzheimer's disease (AD) and vascular dementia (VaD). METHODS: T1weighted MR scans were acquired in elderly patients with DLB, AD, VaD, and healthy controls. Normalised volumetric measurements of the caudate nucleus were obtained and parkinsonian symptoms rated using Hoehn and Yahr staging. RESULTS: There were no significant differences in the volume of the caudate nucleus between patients with dementia. However, the left caudate volume was significantly reduced in AD and DLB compared with controls. Parkinsonian symptoms did not correlate with caudate nucleus volume. CONCLUSIONS: Parkinsonian symptoms in DLB may be more closely coupled to neurochemical rather than structural changes in the caudate nucleus, and volumetric MRI analysis of caudate nucleus does not discriminate between patients with DLB, AD, and VaD. 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. Yoshita, M., J. Taki, et al. (2001). "A clinical role for [(123)I]MIBG myocardial scintigraphy in the distinction between dementia of the Alzheimer's-type and dementia with Lewy bodies." J Neurol Neurosurg Psychiatry 71(5): 583-8. OBJECTIVE: Scintigraphy with [(123)I]metaiodobenzyl guanidine ([(123)I]MIBG) enables the quantification of postganglionic sympathetic cardiac innervation. Recently, myocardial [(123)I]MIBG scintigraphy has been found to be useful in distinguishing Parkinson's disease, a Lewy body disease, from other akinetic rigid syndromes. Some patients initially diagnosed with dementia of the Alzheimer's type (DAT) are discovered to have an alternative disease such as dementia with Lewy bodies (DLB), despite the application of stringent diagnostic criteria. In the present study, examinations were performed to clarify the usefulness of myocardial [(123)I]MIBG scintigraphy in improving the differential diagnosis between patients with DLB and DAT. METHODS: Fourteen patients with DLB and 14 patients with DAT underwent scintigraphy with [(123)I]MIBG, combined with orthostatic tests and cardiac examinations. RESULTS: In all patients with DLB, the heart to mediastinum (H/M) ratio of MIBG uptake was pathologically impaired in both early and delayed images, independently of the duration of disease and autonomic failure. All patients with DAT had successful MIBG uptake in the heart regardless of duration of disease and autonomic failure. Orthostatic hypotension was seen in four patients with DAT and 13 patients with DLB. CONCLUSIONS: [(123)I]MIBG myocardial scintigraphy might detect early disturbances of the sympathetic nervous system in DLB and might provide useful diagnostic information to discriminate DLB from DAT. The distinction between DLB and DAT may be improved by greater emphasis on cardiac sympathetic disturbances. Tabner, B. J., S. Turnbull, et al. (2001). "Production of reactive oxygen species from aggregating proteins implicated in Alzheimer's disease, Parkinson's disease and other neurodegenerative diseases." Curr Top Med Chem 1(6): 507-17. The deposition of abnormal protein fibrils is a prominent pathological feature of many different 'protein conformational' diseases, including some important neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), motor neurone disease and the 'prion' dementias. Some of the fibril-forming proteins or peptides associated with these diseases have been shown to be toxic to cells in culture. A clear understanding of the molecular mechanisms responsible for this toxicity should shed light on the probable link between protein deposition and cell loss in these diseases. In the case of the beta-amyloid (Abeta), which accumulates in the brain in AD, there is good evidence that the toxic mechanism involves the production of reactive oxygen species (ROS). By means of an electron spin resonance (ESR) spin-trapping method, we have shown recently that solutions of Abeta liberate readily detectable amounts of hydroxyl radicals upon incubation in vitro followed by the addition of small amounts of Fe(II). We have also obtained similar results with alpha-synuclein, which accumulates in Lewy bodies in PD. Our data suggest that hydrogen peroxide accumulates during Abeta or alpha-synuclein incubation and that this is subsequently converted to hydroxyl radicals, on addition of Fe (II), by Fenton's reaction. Consequently, we now support the idea that one of the fundamental molecular mechanisms underlying the pathogenesis of cell death in AD, PD, and possibly some other protein conformational diseases, could be the direct production of ROS during formation of the abnormal protein aggregates. This hypothesis suggests a novel approach to the therapy of this group of diseases. Sung, J. Y., J. Kim, et al. (2001). "Induction of neuronal cell death by Rab5A-dependent endocytosis of alpha-synuclein." J Biol Chem 276(29): 27441-8. The presynaptic alpha-synuclein is a prime suspect for contributing to Lewy pathology and clinical aspects of diseases, including Parkinson's disease, dementia with Lewy bodies, and a Lewy body variant of Alzheimer's disease. Here we examined the pathogenic mechanism of neuronal cell death induced by alpha-synuclein. The exogenous addition of alpha-synuclein caused a marked decrease of cell viability in primary and immortalized neuronal cells. The neuronal cell death appeared to be correlated with the Rab5A-specific endocytosis of alpha-synuclein that subsequently caused the formation of Lewy body-like intracytoplasmic inclusions. This was further supported by the fact that the expression of GTPase-deficient Rab5A resulted in a significant decrease of its cytotoxicity as a result of incomplete endocytosis of alpha-synuclein. Strubel, D., J. M. Jacquot, et al. (2001). "[Dementia and falls]." Ann Readapt Med Phys 44(1): 4-12. INTRODUCTION: Dementia is now a frequent disease in elderly and may be a major risk of falling. Usually these falls are multiple and serious, but their consequences are not specific. All types of dementia (Alzheimer's disease, dementia with Lewy bodies, dementia in Parkinson's disease, fronto-temporal dementia, vascular dementiaellipsis) and all stages of evolution are concerned.Discussion: These falls result from cognitive and behavioural disorders, visual and motor problems, gait and balance disturbances, malnutrition, adverse effects of medication and fear of falling. CONCLUSION: Prevention is possible. Attention must be given on the patient himself (keeping in good health, limitation in sedative treatment and mechanical restraintsellipsis) and on his environment (lighting, obstacles on the ground, stress levelellipsis). After a fall, especially after a complicated fall, rehabilitation modalities and aims must be adapted but caring must not be defeatist. Randomized studies need to be realized. Shiozaki, K., E. Iseki, et al. (2001). "Distribution of m1 muscarinic acetylcholine receptors in the hippocampus of patients with Alzheimer's disease and dementia with Lewy bodies-an immunohistochemical study." J Neurol Sci 193(1): 23-8. Of the five subtypes (m1-m5) of muscarinic acetylcholine receptors (mAChR), the m1 subtype is the most abundant in the human cerebral cortex and hippocampus. Impairment of the muscarinic cholinergic system in the brain may cause cognitive dysfunction in patients with Alzheimer's disease (AD), and choline esterase inhibitors (ChE-I) are used to improve cognitive dysfunction. Severe impairment of the cholinergic system has also been reported in the brains of subjects with dementia with Lewy bodies (DLB). There have been a few reports about the distribution of mAChR subtypes in the human brain. In the present study, we investigated the distribution of m1 mAChR in the human hippocampus using an antibody against the m1 subtype.In the control brains, m1 immunoreactivity was observed in the apical dendrites and cell bodies of granular neurons of the dentate gyrus and pyramidal neurons of CA1-3 and the subiculum. The dendrites and the cell bodies of the pyramidal neurons in layers III and V of the parahippocampal cortex and other temporal cortices were also positive for m1 immunoreactivity. This m1 immunoreactivity was markedly reduced in AD and DLB brains. Sharma, N., J. Hewett, et al. (2001). "A close association of torsinA and alpha-synuclein in Lewy bodies: a fluorescence resonance energy transfer study." Am J Pathol 159(1): 339-44. TorsinA, a novel protein in which a mutation causes dominant, early onset torsion dystonia, may serve as a chaperone for misfolded proteins that require refolding or degradation. It has been hypothesized that misfolded alpha-synuclein, a protein in which two mutations cause autosomal dominantly inherited Parkinson's disease, serves as a nidus for the development of a Lewy body. We hypothesized that torsinA plays a role in the cellular processing of alpha-synuclein. We demonstrate that anti-torsin antibodies stain Lewy bodies and Lewy neurites in the substantia nigra and cortex. Using sensitive fluorescent resonance energy transfer (FRET) techniques, we find evidence of a close association between torsinA and alpha-synuclein in Lewy bodies. Preobrazhenskaia, I. S., V. P. Chekhonin, et al. (2001). "[Permeability of hemato-encephalic barrier in Alzheimer's disease and parkinsonism with cognitive disorders]." Zh Nevrol Psikhiatr Im S S Korsakova 101(5): 39-42. The study was made of 17 patients with expected Alzheimer's disease (AD), 29 patients with Parkinson's disease (PD) and 7 with a expected dementia with Levy bodies (DLB). The severity of cognitive disorders was determined according to the following scales: Global Deterioration Rating Scale, Mini-mental State Examination, Mattis Dementia Rating Scale. Besides, the patients state was evaluated, in the whole, according to some scales. Permeability of hemato-encephalic barrier was evaluated according to the blood serum levels of 3 neurospecific proteins--neuron specific enolase, glial fibrillary protein and alpha-glycoprotein. Their determination was performed by ELISA method. The significant elevation of the levels of the proteins studied was found already on the early stages of the disease. Their levels were higher in the patients with the dementia as compared with the individuals without it. There were no differences in cortical, subcortical and combined types of dementia. The authors believe, that some of the proteins studied (neuron specific enolase, for example) may serve as non specific markers of cerebral degeneration. Muma, N. A., J. M. Lee, et al. (2001). "6-hydroxydopamine-induced lesions of dopaminergic neurons alter the function of postsynaptic cholinergic neurons without changing cytoskeletal proteins." Exp Neurol 168(1): 135-43. The neuropathological hallmarks of many neurodegenerative diseases are intraneuronal inclusions containing cytoskeletal proteins such as neurofilaments in Lewy bodies in Parkinson's disease and tau in neurofibrillary tangles in Alzheimer's disease. Dysfunction in dopaminergic and cholinergic systems also exist in both Alzheimer's disease and Parkinson's disease. Because the primary pathology in Parkinson's disease is localized to the dopaminergic system, we set out to determine if perturbations in cholinergic systems are a consequence of dopaminergic neuron loss. Therefore, following intracerebral microinjections of 6-hydroxydopamine in rats, the activity of cholinergic neurons was measured by hemicholinium binding in cholinergic terminal fields and perturbations in cytoskeletal proteins were examined in dopaminoceptive neurons using immunocytochemistry. The 6-hydroxydopamine injections robustly reduced the number of monoaminergic cell bodies in the lateral midbrain and dramatically decreased dopamine and its major metabolites in dopaminergic projection sites. This treatment increased hemicholinium binding in the prefrontal cortex (200%) and amygdala (284%); however, despite previous reports to the contrary, there were no increases in immunoreactivity for phosphorylated neurofilaments, microtubule-associated protein (MAP) 2, tau or paired helical filament (PHF) tau. This lack of an increase in cytoskeletal proteins was observed following either injections of moderate doses of the toxin directly into the medial forebrain bundle or after high doses were administered intracerebroventricularly. These results suggest that removal of dopaminergic inputs to the forebrain results in hyperactivity of the cholinergic systems but is not sufficient to induce postsynaptic perturbations in cytoskeletal proteins which occur in neurodegenerative diseases. McShane, R. H., Z. Nagy, et al. (2001). "Anosmia in dementia is associated with Lewy bodies rather than Alzheimer's pathology." J Neurol Neurosurg Psychiatry 70(6): 739-43. OBJECTIVES: To assess olfactory function of patients with dementia. Odour detection ability is impaired in clinical Parkinson's disease. Evidence of impaired detection in patients with clinically diagnosed Alzheimer's disease is inconsistent. No studies of olfaction have been neuropathologically validated. METHODS: The olfactory function of 92 patients with dementia and 94 controls was assessed using a simple bedside test as part of the Oxford Project To Investigate Memory and Ageing (OPTIMA). Neuropathological assessment was made of cortical Lewy bodies and substantia nigra (SN) cell counts and of Alzheimer's disease in all 92 patients, 22 of whom had SN Lewy bodies and 43 of whom had only Alzheimer's disease. RESULTS: Patients with Lewy bodies were more likely to be anosmic than those with Alzheimer's disease or controls. Patients with Alzheimer's disease were not more likely to be anosmic than controls. Nor was anosmia associated with degree of neurofibrillary tangles, as assessed by Braak stage. Among subjects with Lewy bodies, overall cortical Lewy body scores and Lewy body density in the cingulate were higher in those who were anosmic. Consensus clinical criteria for dementia with Lewy bodies had a sensitivity of 64% and specificity of 89%. In the absence of definite Alzheimer's disease, the criteria had sensitivity of 100%. In patients with definite Alzheimer's disease, anosmia was slightly more sensitive (55%) than the consensus criteria (33%). However, the addition of anosmia to the consensus criteria did not improve their overall performance. CONCLUSION: Dementia with Lewy bodies is associated with impaired odour detection. Misdiagnosis may have accounted for some previous reports of impaired odour detection in Alzheimer's disease. Simple but more sensitive tests of anosmia are required if they are to be clinically useful in identifying patients with dementia with Lewy bodies. McLean, P. J., H. Kawamata, et al. (2001). "Alpha-synuclein-enhanced green fluorescent protein fusion proteins form proteasome sensitive inclusions in primary neurons." Neuroscience 104(3): 901-12. Alpha-synuclein accumulates in the brains of sporadic Parkinson's disease patients as a major component of Lewy bodies, and mutations in alpha-synuclein are associated with familial forms of Parkinson's disease. The pathogenic mechanisms that precede and promote the aggregation of alpha-synuclein into Lewy bodies in neurons remain to be determined. Here, we constructed a series of alpha-synuclein-enhanced green fluorescent protein (alpha-synucleinEGFP, SynEGFP) fusion proteins to address whether the Parkinson's disease-associated mutations alter the subcellular distribution of alpha-synuclein, and to use as a tool for experimental manipulations to induce aggregate formation. When transfected into mouse cultured primary neurons, the 49-kDa alpha-synucleinEGFP fusion proteins are partially truncated to a approximately 27-kDa form. This non-fluorescent carboxy-terminally modified fusion protein spontaneously forms inclusions in the neuronal cytoplasm. A marked increase in the accumulation of inclusions is detected following treatment with each of three proteasome inhibitors, n-acetyl-leu-leu-norleucinal, lactacystin and MG132. Interestingly, Ala30Pro alpha-synucleinEGFP does not form the cytoplasmic inclusions that are characteristic of wild-type and Ala53Thr alpha-synucleinEGFP, supporting the idea that the Ala30Pro alpha-synuclein protein conformation differs from wild-type alpha-synuclein. Similar inclusions are formed if alpha-synuclein carboxy-terminus is modified by the addition of a V5/6xHistidine epitope tag. By contrast, overexpression of unmodified alpha-synuclein does not lead to aggregate formation. Furthermore, synphilin-1, an alpha-synuclein interacting protein also found in Lewy bodies, colocalizes with the carboxy-terminally truncated alpha-synuclein fusion protein in discrete cytoplasmic inclusions.Our finding that manipulations of the carboxy-terminus of alpha-synuclein lead to inclusion formation may provide a model for studies of the pathogenic mechanisms of alpha-synuclein aggregation in Lewy bodies. Mattila, P. M., M. Roytta, et al. (2001). "Choline acetytransferase activity and striatal dopamine receptors in Parkinson's disease in relation to cognitive impairment." Acta Neuropathol (Berl) 102(2): 160-6. Brain tissue from 44 patients with Parkinson's disease (PD) and 36 age-matched controls was examined for choline acetyltransferase (ChAT) activity, and for densities of D1 and D2 dopamine receptors. Brain samples were examined for Alzheimer' disease (AD) type changes and for Lewy bodies (LBs), and for apolipoprotein E genotype. Patients were evaluated for the stage of cognitive impairment using Reisberg's global deterioration scale. ChAT activity in PD was reduced in all brain areas examined, being 51% of the control mean in the hippocampus (P<0.001), 57% in the prefrontal cortex (P< 0.001) and 64% in the temporal cortex (P<0.001). The number of LBs had a significant negative correlation with ChAT activity in both prefrontal (r=-0.33, P<0.05) and temporal cortex (r=-0.32, P<0.05). The reduction in ChAT activity in the prefrontal cortex had a significant negative correlation (r=-0.38, P=0.012) with the extent of cognitive impairment. When the CERAD class 'C' was excluded, cognitive impairment correlated significantly with both prefrontal ChAT activity (r=-0.52, P=0.0051) and the density of D1 dopamine receptors in the caudate nucleus (r=-0.40, P=0.037). The number of D1 and D2 dopamine receptors was reduced in both caudate nucleus and putamen in PD patients without neuroleptics as compared to controls. An increased D2 receptor number was found in the caudate nucleus and putamen in PD patients treated with neuroleptics. The present study showed that cognitive decline in PD is associated with reduced ChAT activity in the prefrontal cortex and the D1 dopamine receptor number in the caudate nucleus, even in the absence of AD-type pathology. Lippa, C. F., M. L. Schmidt, et al. (2001). "Alpha-synuclein in familial Alzheimer disease: epitope mapping parallels dementia with Lewy bodies and Parkinson disease." Arch Neurol 58(11): 1817-20. BACKGROUND: Alpha-synuclein is a major component of Lewy bodies (LBs) in Parkinson disease and dementia with LBs and of glial cytoplasmic inclusions in multiple system atrophy. However, epitope mapping for alpha-synuclein is distinctive in different neurodegenerative diseases. The reasons for this are poorly understood but may reflect fundamental differences in disease mechanisms. OBJECTIVE: To investigate the alpha-synuclein epitope mapping properties of LBs in familial Alzheimer disease. DESIGN AND SETTING: We compared LBs in familial Alzheimer disease with those in synucleinopathies by probing 6 brains of persons with familial Alzheimer disease using a panel of antibodies to epitopes spanning the alpha-synuclein protein. Results were compared with data from brains of persons with Parkinson disease, dementia with LBs, and multiple system atrophy. RESULTS: The brains of persons with familial Alzheimer disease showed consistent staining of LBs with all antibodies, similar to Parkinson disease and dementia with LBs but different from alpha-synuclein aggregates that occurred in multiple system atrophy. CONCLUSIONS: These data suggest that the epitope profiles of alpha-synuclein in LBs are similar, regardless of whether the biological trigger is related to synuclein or a different genetic pathway. These findings support the hypothesis that the mechanism of alpha-synuclein aggregation is the same within cell types but distinctive between cell types. Kuusisto, E., A. Salminen, et al. (2001). "Ubiquitin-binding protein p62 is present in neuronal and glial inclusions in human tauopathies and synucleinopathies." Neuroreport 12(10): 2085-90. We examined the immunoreactivity of ubiquitin-binding protein p62 and its association with ubiquitin (Ub), alpha-synuclein, and paired helical filament (PHF)-tau in the affected brain areas of human tauopathies and synucleinopathies. Ubiquitin-binding protein p62 is a widely expressed protein that can bind to Ub noncovalently and is involved in several signalling pathways, making p62 a candidate regulator of Ub-mediated proteolysis. We show that p62 immunoreactivity co-localizes with neuronal and glial Ub-containing inclusions in Alzheimer's disease, Pick's disease, dementia with Lewy bodies, Parkinson's disease, and multiple system atrophy. This is the first demonstration of a common protein component, apart from Ub, that is present in both PHF-tau and alpha-synuclein inclusions. In both tauo- and synucleinopathies, the staining patterns for p62 and Ub were markedly similar, suggesting that a common mechanism which requires interaction of p62 and Ub contributes to the formation of PHF-tau and alpha-synuclein inclusions. Kotzbauer, P. T., J. Q. Trojanowsk, et al. (2001). "Lewy body pathology in Alzheimer's disease." J Mol Neurosci 17(2): 225-32. Lewy bodies, the characteristic pathological lesion of substantia nigra neurons in Parkinson's disease (PD), are frequently observed to accompany the amyloid plaque and neurofibrillary tangle pathology of Alzheimer's disease (AD). However the typical anatomic distribution of Lewy bodies in AD is distinct from PD. The most common site of occurrence is the amygdala, where Lewy bodies are observed in approximately 60% of both sporadic and familial AD. Other common sites of occurrence include the periamygdaloid and entorhinal cortex, while neocortical and brainstem areas develop Lewy bodies in a lower percentage of cases. In contrast, dementia with Lewy bodies (DLB), defined by widespread neocortical and brainstem Lewy bodies but frequently accompanied by variable levels of AD-type pathology, represents the other end of a spectrum of pathology associated with dementia. The observation of Lewy bodies in familial AD cases suggests that like neurofibrillary tangles, the formation of Lewy bodies can be induced by the pathological state caused by Abeta-amyloid overproduction. The role of Lewy body formation in the dysfunction and degeneration of neurons remains unclear. The protein alpha-synuclein appears to be an important structural component of Lewy bodies, an observation spurred by the discovery of point mutations in the alpha-synuclein gene linked to rare cases of autosomal dominant PD. Further investigation of alpha-synuclein and its relationship to pathological conditions promoting Lewy body formation in AD, PD, and DLB may yield further insight into pathogenesis of these diseases. Kawamata, H., P. J. McLean, et al. (2001). "Interaction of alpha-synuclein and synphilin-1: effect of Parkinson's disease-associated mutations." J Neurochem 77(3): 929-34. alpha-Synuclein is a major component of Lewy bodies, a neuropathological feature of Parkinson's disease. Two alpha-synuclein mutations, Ala53Thr and Ala30Pro, are associated with early onset, familial forms of the disease. Recently, synphilin-1, a protein found to interact with alpha-synuclein by yeast two hybrid techniques, was detected in Lewy bodies. In this study we report the interaction of alpha-synuclein and synphilin-1 in human neuroglioma cells using a sensitive fluorescence resonance energy transfer technique. We demonstrate that the C-terminus of alpha-synuclein is closely associated with the C-terminus of synphilin-1. A weak interaction occurs between the N-terminus of alpha-synuclein and synphilin-1. The familial Parkinson's disease associated mutations of alpha-synuclein (Ala53Thr and Ala30Pro) also demonstrate a strong interaction between their C-terminal regions and synphilin-1. However, compared with wild-type alpha-synuclein, significantly less energy transfer occurs between the C-terminus of Ala53Thr alpha-synuclein and synphilin-1, suggesting that the Ala53Thr mutation alters the conformation of alpha-synuclein in relation to synphilin-1. Kanazawa, I. (2001). "How do neurons die in neurodegenerative diseases?" Trends Mol Med 7(8): 339-44. Given that neurons are post-mitotic cells, their life span is generally long enough to reach that of humans. However, sometimes neurons die without recognizable causes, as a result of a process called neurodegeneration. Apart from when gene mutations can be correlated with disease, it is difficult to pinpoint molecules that are responsible for neuronal death. Therefore, neurons living in a 'sick state' for many years might reveal important information about neuronal death. Systematic and extensive single-neuron analysis of 'sick' neurons is expected to provide clues to the mechanisms of neurodegeneration. Moreover, the elimination of putative triggering and promoting factors involved in neurodegenerative disease might prevent disease progression. Kahle, P. J., M. Neumann, et al. (2001). "Selective insolubility of alpha-synuclein in human Lewy body diseases is recapitulated in a transgenic mouse model." Am J Pathol 159(6): 2215-25. alpha-Synuclein (alpha-SYN) is deposited in intraneuronal cytoplasmic inclusions (Lewy bodies, LBs) characteristic for Parkinson's disease (PD) and LB dementias. alpha-SYN forms LB-like fibrils in vitro, in contrast to its homologue beta-SYN. Here we have investigated the solubility of SYNs in human LB diseases and in transgenic mice expressing human wild-type and PD-associated mutant [A30P]alpha-SYN driven by the brain neuron-specific promoter, Thy1. Distinct alpha-SYN species were detected in the detergent-insoluble fractions from brains of patients with PD, dementia with LBs, and neurodegeneration with brain iron accumulation type 1 (formerly known as Hallervorden-Spatz disease). Using the same extraction method, detergent-insolubility of human alpha-SYN was observed in brains of transgenic mice. In contrast, neither endogenous mouse alpha-SYN nor beta-SYN were detected in detergent-insoluble fractions from transgenic mouse brains. The nonamyloidogenic beta-SYN was incapable of forming insoluble fibrils because amino acids 73 to 83 in the central region of alpha-SYN are absent in beta-SYN. In conclusion, the specific accumulation of detergent-insoluble alpha-SYN in transgenic mice recapitulates a pivotal feature of human LB diseases. Jellinger, K. A. and C. Stadelmann (2001). "Problems of cell death in neurodegeneration and Alzheimer's Disease." J Alzheimers Dis 3(1): 31-40. Progressive cell loss in specific neuronal populations is a pathological hallmark of neurodegenerative diseases, but its mechanisms remain unresolved. Apoptosis or alternative pathways of neuronal death have been discussed in Alzheimer disease (AD) and other disorders. However, DNA fragmentation in human brain as a sign of neuronal injury is too frequent to account for the continuous loss in these slowly progressive diseases. In autopsy cases of AD, Parkinson's disease (PD), related disorders, and age-matched controls, DNA fragmentation using the TUNEL method and an array of apoptosis-related proteins (ARP), proto-oncogenes, and activated caspase 3, the key enzyme of late-stage apoptosis, were examined. In AD, a considerable number of hippocampal neurons and glial cells showed DNA fragmentation with a 3- to 6-fold increase related to amyloid deposits and neurofibrillary tangles, but only one in 2.600 to 5.650 neurons displayed apoptotic morphology and cytoplasmic immunoreactivity for activated caspase~3, whereas no neurons were labeled in age-matched controls. Caspase~3 immunoreactivity was seen in granules of cells with granulovacuolar degeneration, in around 25% In progressive supranuclear palsy, only single neurons but oligodendrocytes in brainstem, around 25% TUNEL-positive and expressed both ARPs and activated caspase 3. In PD, dementia with Lewy bodies, and multisystem atrophy (MSA), TUNEL-positivity and expression of ARPs or activated caspase~3 were only seen in microglia and oligodendrocytes with cytoplasmic inclusions in MSA, but not in neurons. These data provide evidence for extremely rare apoptotic neuronal death in AD and PSP compatible with the progression of neuronal degeneration in these chronic diseases. Apoptosis mainly involves reactive microglia and oligodendroglia, the latter occasionally involved by deposits of insoluble fibrillary proteins, while alternative mechanisms of neuronal death may occur. Susceptible cell populations in a proapoptotic environment, particularly in AD, show increased vulnerability towards metabolic or other noxious factors, with autophagy as a possible protective mechanism in early stages of programmed cell death. The intracellular cascade leading to cell death still awaits elucidation. Iseki, E., M. Kato, et al. (2001). "A neuropathological study of the disturbance of the nigro-amygdaloid connections in brains from patients with dementia with Lewy bodies." J Neurol Sci 185(2): 129-34. We neuropathologically and immunohistochemically investigated characteristics of the central amygdaloid nucleus lesion and its relationship with the substantia nigra lesion in dementia with Lewy bodies (DLB) brains. Nine DLB, four Parkinson's disease (PD) and four Alzheimer-type dementia (ATD) cases were examined. The degree of neuronal loss in the substantia nigra was (+)-(+++) in DLB cases, (+++) in PD cases and (+) in ATD cases. All DLB cases showed spongy change and ubiquitin-positive spheroids in the central nucleus. The degree of spongy change was (+)-(+++) in DLB cases, (+) in PD cases and (-)-(+) in ATD cases, which was correlated with the degree of neuronal loss in the substantia nigra in DLB cases. The number of ubiquitin-positive spheroids was parallel to the degree of spongy change. The central nucleus receives dense dopaminergic fibers from the substantia nigra. Many ubiquitin-positive spheroids were also positive to alpha-synuclein and tyrosine-hydroxylase, suggesting that they derive from the degeneration of terminal or distal axons of Lewy body-bearing dopaminergic neurons in the substantia nigra. The disturbance of the dopaminergic connections from the substantia nigra to the central nucleus may be responsible for psychotic symptoms in DLB patients. Imamura, T., K. Ishii, et al. (2001). "Occipital glucose metabolism in dementia with lewy bodies with and without Parkinsonism: a study using positron emission tomography." Dement Geriatr Cogn Disord 12(3): 194-7. Reduction of glucose metabolism in the occipital lobe is reported in dementia with Lewy bodies (DLB) and Parkinson's disease. If dysfunction of the nigrostriatal system is responsible for occipital hypometabolism, (1) DLB patients with parkinsonism would show a lower occipital metabolism than do patients without parkinsonism, and (2) DLB patients without parkinsonism would show an occipital metabolism comparable to those of normal subjects and patients with Alzheimer's disease (AD). To examine these hypotheses, we studied the regional cerebral metabolic rate of glucose (rCMRglc) in patients with a clinical diagnosis of DLB or AD, using (18)F-fluorodeoxyglucose and positron emission tomography. The subjects consisted of 15 DLB patients with parkinsonism, 7 DLB patients without parkinsonism and 7 AD patients without parkinsonism. The medial and lateral occipital rCMRglc was significantly lower in the DLB patients without parkinsonism than in the AD patients. There were no significant differences in occipital metabolic rates between the DLB groups with and without parkinsonism. DLB patients without parkinsonism showed a significant reduction of occipital glucose metabolism which is comparable with that of DLB patients with parkinsonism. The neurobiological bases of occipital hypometabolism in DLB may be pathological processes in the brainstem or basal forebrain structures other than the nigrostriatal system. Hsu, Y. Y., A. T. Du, et al. (2001). "Magnetic resonance imaging and magnetic resonance spectroscopy in dementias." J Geriatr Psychiatry Neurol 14(3): 145-66. This article reviews recent studies of magnetic resonance imaging and magnetic resonance spectroscopy in dementia, including Alzheimer's disease, frontotemporal dementia, dementia with Lewy bodies, idiopathic Parkinson's disease, Huntington's disease, and vascular dementia. Magnetic resonance imaging and magnetic resonance spectroscopy can detect structural alteration and biochemical abnormalities in the brain of demented subjects and may help in the differential diagnosis and early detection of affected individuals, monitoring disease progression, and evaluation of therapeutic effect. Hossain, S., A. Alim, et al. (2001). "Limited proteolysis of NACP/alpha-synuclein." J Alzheimers Dis 3(6): 577-584. The NAC region of NACP/alpha-synuclein is a secondary component of Alzheimer's disease amyloid. alpha-Synuclein is a major component of Lewy bodies, a typical neuropathological feature of Parkinson's disease. However, the physiological role and deposition mechanisms of alpha-synuclein are unknown. Structural analyses of alpha-synuclein should provide a better understanding of its biochemical characteristics. We investigated the digestion of alpha-synuclein withalpha-chymotrypsin and cathepsin D, which are reported to be involved in amyloidogenesis, under various conditions in vitro. There are many putative cleavage sites for these enzymes in alpha-synuclein, including in the NAC region. However, most of the predicted sites remained undigested, and the NAC region was found to be intact even after extensive digestion. This peculiar characteristic of alpha-synuclein may be relevant to the abnormal deposition of this molecule in alpha-synuclein-associated neurodegenerative diseases. Galvin, J. E., T. M. Schuck, et al. (2001). "Differential expression and distribution of alpha-, beta-, and gamma-synuclein in the developing human substantia nigra." Exp Neurol 168(2): 347-55. Although the functions of alpha-, beta-, and gamma-synuclein (alphaS, betaS, gammaS, respectively) are unknown, these synaptic proteins are implicated in the pathogenesis of Parkinson's disease (PD) and related disorders. For example, alphaS forms Lewy bodies (LBs) in substantia nigra (SN) neurons of PD. However, since it is not known how these hallmark PD lesions contribute to the degeneration of SN neurons or what the normal function of alphaS is in SN neurons, we studied the developing human SN from 11 weeks gestational age (GA) to 16 years of age using immunohistochemistry and antibodies to alphaS, betaS, gammaS, other synaptic proteins, and tyrosine hydoxylase (TH). SN neurons expressed TH at 11 weeks GA and alphaS, betaS, and gammaS appeared initially at 15, 17, and 18 weeks GA, respectively. These synucleins first appeared in perikarya of SN neurons after synaptophysin, but about the same time as synaptotagmin and synaptobrevin. Redistribution of alphaS from perikarya to processes of SN neurons occurred by 18 weeks GA in parallel with synaptophysin, while betaS and synaptotagmin were redistributed similarly between 20 and 28 weeks GA and this also occurred with gammaS and synaptobrevin between 33 weeks GA and 9 months postnatal. These data suggest that alphaS, betaS, and gammaS may play a functional role in the development and maturation of SN neurons, but it remains to be determined how sequestration of alphaS as LBs in PD contributes to the degeneration of SN neurons. Ferrer, I. (2001). "[Alpha-synucleinopathies]." Neurologia 16(4): 163-70. The term alpha-synucleinopathy is used to name a group of disorders having in common the abnormal deposition of alpha-synuclein in the cytoplasm of neurons or glial cells, as well as in extracellular deposits of amyloid. In Parkinson's disease and Lewy body dementia, alpha-synuclein is the main component of Lewy bodies and dystrophic neurites; alpha-synuclein also accumulates in the cytoplasm of glial cells. In multiple system atrophy, alpha-synuclein conforms the cytoplasmic oligodendroglial inclusions and the neuronal inclusions which are the hallmark of this disease. Finally, the amyloidogenic fragment 61-95 amino acids of alpha-synuclein is the non-Abeta component of senile plaque amyloid in Alzheimer disease. Accumulations of alpha-synuclein in all these disorders have in common a fibrilar configuration, but they differ in the binding of alpha-synuclein to distinct proteins with the exception of ubiquitin whose binding to alpha-synuclein is common to all alpha-synuclein inclusions. The mechanisms leading to alpha-synuclein fragmentation and aggegation into extracellular amyloid are not known, although alpha-synuclein fragment and betaA4 aggregates are the result of abnormal cleavage of large precursors. On the other hand, several studies have shown that alpha-synuclein may adopt a fibrilar conformation and give rise to insoluble forms and high molecular weight aggregates in vitro. Similar complexes have also been observed in alpha-synucleinopathies. Although studies in vitro and in vivo have shown toxic effects of alpha-synuclein, the consequence of alpha-synuclein deposition on cell survival in alpha-synucleinopathies is not known. Ferrer, I., R. Blanco, et al. (2001). "Active, phosphorylation-dependent mitogen-activated protein kinase (MAPK/ERK), stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), and p38 kinase expression in Parkinson's disease and Dementia with Lewy bodies." J Neural Transm 108(12): 1383-96. The expression of mitogen-activated protein kinases, extracellular signal-regulated kinases (MAPK/ERK), stress-activated protein kinases, c-Jun N-terminal kinases (SAPK/JNK), and p38 kinases is examined in Parkinson disease (PD), in Dementia with Lewy bodies (DLB), covering common and pure forms, and in age-matched controls. The study is geared to gaining understanding about the involvement of these kinases in the pathogenesis of Lewy bodies (LBs) and associated tau deposits in Alzheimer changes in the common form of DLB. Active, phosphorylation dependent MAPK (MAPK-P) is found as granular cytoplasmic inclusions in a subset of cortical neurons bearing abnormal tau deposits in common forms of DLB. Phosphorylated p-38 (p-38-P) decorates neurons with neurofibrillary tangles and dystrophic neurites of senile plaques in common forms of DLB. Phosphorylated SAPK/JNK (SAPK/JNK-P) expression occurs in cortical neurons with neurofibrillary tangles in the common form of DLB. Lewy bodies (LBs) in the brain stem of PD and DLB are stained with anti-ERK-2 antibodies, but they are not recognized by MAPK-P, SAPK/JNK-P and p-38-P. Yet MAPK-P, p-38-P and SAPK/JNK-P immunoreactivity is found in cytoplasmic granules in the vicinity of LBs or in association with irregular-shaped or diffuse alpha-synuclein deposits in a small percentage of neurons, not containing phosphorylated tau, of the brain stem in PD and DLB. MAPK-P, p-38-P and SAPK-P are not expressed in cortical LBs or in cortical neurons with alpha-synuclein-only inclusions in DLB. MAPK-P, p-38-P and SAPK/JNK-P are not expressed in alpha-synuclein-positive neurites (Lewy neurites) in PD and DLB as revealed by double-labeling immunohistochemistry. These results show that MAPKs are differentially regulated in neurons with alpha-synuclein-related inclusions and in neurons with abnormal tau deposits in DLB. Moreover, different kinase expression in brain stem and cortical LBs suggest a pathogenesis of brain stem and cortical LBs in LB diseases. Finally, no relationship has been observed between MAPK-P, p-38-P and SAPK/JNK-P expression and increased nuclear DNA vulnerability, as revealed with the method of in situ end-labeling of nuclear DNA fragmentation, and active, cleaved caspase-3 expression in neurons and glial cells in the substantia nigra in PD and DLB. Ebadi, M., P. Govitrapong, et al. (2001). "Ubiquinone (coenzyme q10) and mitochondria in oxidative stress of parkinson's disease." Biol Signals Recept 10(3-4): 224-53. Parkinson's disease is the second most common neurodegenerative disorder after Alzheimer's disease affecting approximately1% of the population older than 50 years. There is a worldwide increase in disease prevalence due to the increasing age of human populations. A definitive neuropathological diagnosis of Parkinson's disease requires loss of dopaminergic neurons in the substantia nigra and related brain stem nuclei, and the presence of Lewy bodies in remaining nerve cells. The contribution of genetic factors to the pathogenesis of Parkinson's disease is increasingly being recognized. A point mutation which is sufficient to cause a rare autosomal dominant form of the disorder has been recently identified in the alpha-synuclein gene on chromosome 4 in the much more common sporadic, or 'idiopathic' form of Parkinson's disease, and a defect of complex I of the mitochondrial respiratory chain was confirmed at the biochemical level. Disease specificity of this defect has been demonstrated for the parkinsonian substantia nigra. These findings and the observation that the neurotoxin 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP), which causes a Parkinson-like syndrome in humans, acts via inhibition of complex I have triggered research interest in the mitochondrial genetics of Parkinson's disease. Oxidative phosphorylation consists of five protein-lipid enzyme complexes located in the mitochondrial inner membrane that contain flavins (FMN, FAD), quinoid compounds (coenzyme Q10, CoQ10) and transition metal compounds (iron-sulfur clusters, hemes, protein-bound copper). These enzymes are designated complex I (NADH:ubiquinone oxidoreductase, EC 1.6. 5.3), complex II (succinate:ubiquinone oxidoreductase, EC 1.3.5.1), complex III (ubiquinol:ferrocytochrome c oxidoreductase, EC 1.10.2.2), complex IV (ferrocytochrome c:oxygen oxidoreductase or cytochrome c oxidase, EC 1.9.3.1), and complex V (ATP synthase, EC 3.6.1.34). A defect in mitochondrial oxidative phosphorylation, in terms of a reduction in the activity of NADH CoQ reductase (complex I) has been reported in the striatum of patients with Parkinson's disease. The reduction in the activity of complex I is found in the substantia nigra, but not in other areas of the brain, such as globus pallidus or cerebral cortex. Therefore, the specificity of mitochondrial impairment may play a role in the degeneration of nigrostriatal dopaminergic neurons. This view is supported by the fact that MPTP generating 1-methyl-4-phenylpyridine (MPP(+)) destroys dopaminergic neurons in the substantia nigra. Although the serum levels of CoQ10 is normal in patients with Parkinson's disease, CoQ10 is able to attenuate the MPTP-induced loss of striatal dopaminergic neurons. Boeve, B. F., M. H. Silber, et al. (2001). "Association of REM sleep behavior disorder and neurodegenerative disease may reflect an underlying synucleinopathy." Mov Disord 16(4): 622-30. Our objective was to examine whether rapid eye movement (REM) sleep behavior disorder occurs in disproportionally greater frequency in multiple system atrophy (MSA), Parkinson's disease (PD), and dementia with Lewy bodies (DLB), collectively known as the synucleinopathies, compared to other nonsynucleinopathy neurodegenerative disorders. In study 1, we reviewed the clinical records of 398 consecutive patients evaluated at Mayo Clinic Rochester for parkinsonism and/or cognitive impairment. The frequency of suspected and polysomnogram (PSG)-confirmed REM sleep behavior disorder (RBD) among subjects with the synucleinopathies MSA, PD, or DLB was compared to the frequency among subjects with the nonsynucleinopathies Alzheimer's disease (AD), frontotemporal dementia (FTD), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), mild cognitive impairment (MCI), primary progressive aphasia (PPA), and posterior cortical atrophy (PCA). In study 2, we reviewed the clinical records of 360 consecutive patients evaluated at Mayo Clinic Jacksonville for parkinsonism and/or cognitive impairment. The frequency of probable RBD among patients with PD and DLB was compared to the frequency among patients with AD and MCI. In study 3, we reviewed the brain biopsy or postmortem autopsy diagnoses of 23 Mayo Clinic Rochester patients who had been clinically examined for possible RBD and a neurodegenerative disorder. In study 1, patients with MSA, PD, or DLB were more likely to have probable and PSG-confirmed RBD compared to subjects with the nonsynucleinopathies (probable RBD 77/120=64% vs. 7/278=3%, p < 0.01; PSG-confirmed RBD 47/120=39% vs. 1/278=0%, p < 0.01). In study 2, patients with PD and DLB were more likely to have probable RBD compared to those with AD and MCI (56% vs. 2%, p < 0.01). In study 3, of the 23 autopsied patients who had been questioned about possible RBD, 10 were clinically diagnosed with RBD. The neuropathologic diagnoses in these 10 included Lewy body disease in nine, and MSA in one. Of the other 13 cases, 12 did not have a history suggesting RBD, and the one case who did had normal electromyographic atonia during REM sleep on PSG and autopsy findings of PSP. Only one of these 13 had a synucleinopathy. The positive predictive values for RBD indicating a synucleinopathy for studies 1-3 were 91.7%, 94.3%, and 100.0%, respectively. Clinically suspected and PSG-proven RBD occurs with disproportionally greater frequency in MSA, PD, and DLB compared to other neurodegenerative disorders. In the setting of degenerative dementia and/or parkinsonism, we hypothesize that RBD is a manifestation of an evolving synucleinopathy. Barbieri, S., K. Hofele, et al. (2001). "Mouse models of alpha-synucleinopathy and Lewy pathology. Alpha-synuclein expression in transgenic mice." Adv Exp Med Biol 487: 147-67. Arai, Y., M. Yamazaki, et al. (2001). "Alpha-synuclein-positive structures in cases with sporadic Alzheimer's disease: morphology and its relationship to tau aggregation." Brain Res 888(2): 287-296. Alzheimer's disease (AD) and Parkinson's disease share common clinical and pathological features. In this study, we examined the relationship between AD pathology and alpha-synuclein aggregation. The frequency and distribution of alpha-synuclein-positive structures were systematically investigated in 27 cases with sporadic AD by alpha-synuclein immuno-histochemistry. Thirteen (48.2%) of 27 cases had various alpha-synuclein-positive structures as well as Lewy bodies. The frequency and density of senile plaques and neurofibrillary tangles were not significantly different between cases with alpha-synuclein structures and those without. alpha-Synuclein-positive structures were found most frequently in the amygdala. The alpha-synuclein-positive inclusions that are different from Lewy bodies were observed at the highest rate in the hippocampus. The discovery of alpha-synuclein as the constituent of Lewy bodies facilitated the detection of Lewy-related structures even in AD cases with widespread and numerous neurofibrillary tangles. alpha-Synuclein-positive inclusions except for Lewy bodies are exposed, and the distribution of them indicates that Lewy body formation may be influenced by the degree of tau aggregation. This study also supports the suggestion that cases with AD pathology can be classified into two groups according to the existence or absence of alpha-synuclein aggregation. Wakabayashi, K., S. Hayashi, et al. (2000). "NACP/alpha-synuclein-positive filamentous inclusions in astrocytes and oligodendrocytes of Parkinson's disease brains." Acta Neuropathol (Berl) 99(1): 14-20. The precursor of the non-Abeta component of Alzheimer's disease amyloid (NACP), also called alpha-synuclein, is a major component of Lewy bodies in Parkinson's disease (PD) as well as of neuronal and oligodendroglial cytoplasmic inclusions in multiple system atrophy. We previously reported argyrophilic, tau-negative glial inclusions in the midbrains of patients with PD and have now conducted immunocytochemical and ultrastructural examinations. The PD glial inclusions also are immunoreactive for NACP/alpha-synuclein, but not for beta-synuclein, and ultrastructurally are composed of filamentous structures about 25-40 nm in diameter. Double immunolabeling showed that the inclusions were present in both astrocytic and oligodendroglial cells. They were located within the substantia nigra in 13 of 30 patients with PD and outside the nigra in 24. The number of inclusions was correlated with the severity of nigral neuronal loss. These findings indicate that abnormal accumulation of NACP/alpha-synuclein in glial cells is a pathological feature of PD related to its progression. Waite, L. M., G. A. Broe, et al. (2000). "Motor function and disability in the dementias." Int J Geriatr Psychiatry 15(10): 897-903. Epidemiological and neuropathological series have identified three predominant dementing processes; Alzheimer's disease (AD), vascular dementia (VaD) and dementia associated with Lewy bodies (termed Parkinson's disease dementia (PDD) in this paper). While each has its own distinguishing features and by definition all impact upon day to day functioning, no random community derived sample has examined clinical features as defined by gait and balance abnormalities and compared disability ratings of the three dementias simultaneously. Six hundred and forty-seven community dwelling subjects participated in the Sydney Older Persons Study and of these 537 participated in a medical assessment. Of these 537,482 informants rated disability. Gait and balance abnormalities of the three major dementias were identified and the association of the dementias with disability examined. The three major dementias showed evidence of both slowing and ataxia in gait and balance tests. This was maximal in those with PDD. Similarly, all showed evidence of disability that was maximal in those with PDD. In conclusion, this study has identified that gait abnormalities are present in all three dementias to a varying degree. It is hypothesised that the varying levels of disability observed are a consequence of the varying levels of motor impairment, resulting in greater levels of disability in those with PDD. van der Putten, H., K. H. Wiederhold, et al. (2000). "Neuropathology in mice expressing human alpha-synuclein." J Neurosci 20(16): 6021-9. The presynaptic protein alpha-synuclein is a prime suspect for contributing to Lewy pathology and clinical aspects of diseases, including Parkinson's disease, dementia with Lewy bodies, and a Lewy body variant of Alzheimer's disease. alpha-Synuclein accumulates in Lewy bodies and Lewy neurites, and two missense mutations (A53T and A30P) in the alpha-synuclein gene are genetically linked to rare familial forms of Parkinson's disease. Under control of mouse Thy1 regulatory sequences, expression of A53T mutant human alpha-synuclein in the nervous system of transgenic mice generated animals with neuronal alpha-synucleinopathy, features strikingly similar to those observed in human brains with Lewy pathology, neuronal degeneration, and motor defects, despite a lack of transgene expression in dopaminergic neurons of the substantia nigra pars compacta. Neurons in brainstem and motor neurons appeared particularly vulnerable. Motor neuron pathology included axonal damage and denervation of neuromuscular junctions in several muscles examined, suggesting that alpha-synuclein interfered with a universal mechanism of synapse maintenance. Thy1 transgene expression of wild-type human alpha-synuclein resulted in similar pathological changes, thus supporting a central role for mutant and wild-type alpha-synuclein in familial and idiotypic forms of diseases with neuronal alpha-synucleinopathy and Lewy pathology. These mouse models provide a means to address fundamental aspects of alpha-synucleinopathy and test therapeutic strategies. Tiraboschi, P., L. A. Hansen, et al. (2000). "Cholinergic dysfunction in diseases with Lewy bodies." Neurology 54(2): 407-11. OBJECTIVE: To evaluate cholinergic activity in diseases with Lewy bodies (LB; LB variant of AD [LBV], diffuse LB disease [DLBD], and Parkinson's disease [PD]) to determine if 1) AD changes are requisite to cholinergic dysfunction, 2) cholinergic activity declines to the same extent in neocortical and archicortical areas, and 3) cholinergic loss is influenced by APOE genotype. BACKGROUND: Like AD, diseases with LB are associated with decreased choline acetyltransferase (ChAT) activity. Increased APOE epsilon4 allele frequency has been reported in LBV. Whether APOE genotype affects cholinergic function in LBV remains unclear. METHODS: An autopsy series of 182 AD (National Institute on Aging and Consortium to Establish a Registry for Alzheimer's Disease criteria), 49 LBV, 11 PD, 6 DLBD, and 16 normal control (NC) subjects. APOE genotype and ChAT activity (nmol/h/100 mg) in the midfrontal and hippocampal cortices were determined. RESULTS: Mean midfrontal ChAT activity was markedly reduced in diseases with LB (LBV: 53.3 +/- 39.0; PD: 54.8 +/- 35.7; DLBD: 41.3 +/- 24.8) compared to NC (255.4 +/- 134.6; p < 0.001) and AD (122.6 +/- 78.9; p < 0.05). Among diseases with LB, midfrontal ChAT activity was decreased to a similar extent in patients with (LBV) and without (DLBD and PD) AD pathology. Although mean ChAT activity for LBV was less than half that for AD in the midfrontal cortex, it was similar to that for AD in the hippocampus (LBV: 243.5 +/- 189.7; AD: 322.8 +/- 265.6; p > 0.05). However, hippocampal ChAT activity for both AD and LBV was lower than that for NC (666.5 +/- 360.3; p < 0.001). The epsilon4 allele dosage did not influence midfrontal ChAT activity in LBV. CONCLUSION: Marked losses in midfrontal ChAT activity occur in diseases with LB, independent of coexistent AD changes. A greater midfrontal, as opposed to hippocampal, cholinergic deficit may differentiate LBV from AD. The lack of a relationship between epsilon4 allele dosage and midfrontal ChAT activity suggests that other factors may play a role in its decline in LBV. Terry, R. D. (2000). "Do neuronal inclusions kill the cell?" J Neural Transm Suppl 59: 91-3. Neurofibrillary tangles, Pick bodies and Lewy bodies are considered quantitatively in relation to neuron loss. It would seem that the inclusions are not themselves the cause of neuron death. Spillantini, M. G. and M. Goedert (2000). "The alpha-synucleinopathies: Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy." Ann N Y Acad Sci 920: 16-27. Parkinson's disease is the second most common neurodegenerative disease, after Alzheimer's disease. Neuropathologically, it is characterized by the degeneration of populations of nerve cells that develop filamentous inclusions in the form of Lewy bodies and Lewy neurites. Recent work has shown that the filamentous inclusions of Parkinson's disease are made of the protein alpha-synuclein and that rare, familial forms of Parkinson's disease are caused by missense mutations in the alpha-synuclein gene. Besides Parkinson's disease, the filamentous inclusions of two additional neurodegenerative diseases, namely, dementia with Lewy bodies and multiple system atrophy, have also been found to be made of alpha-synuclein. Recombinant alpha-synuclein has been shown to assemble into filaments with similar morphologies to those found in the human diseases and with a cross-beta fiber diffraction pattern. The new work has established the alpha-synucleinopathies as a major class of neurodegenerative disease. Sommer, B., S. Barbieri, et al. (2000). "Mouse models of alpha-synucleinopathy and Lewy pathology." Exp Gerontol 35(9-10): 1389-403. The discovery of two missense mutations (A53T and A30P) in the gene encoding the presynaptic protein alpha-synuclein (alphaSN) that are genetically linked to rare familial forms of Parkinson's disease and its accumulation in Lewy bodies and Lewy neurites has triggered several attempts to generate transgenic mice overexpressing human alphaSN. Analogous to a successful strategy for the production of transgenic animal models for Alzheimer's disease we generated mice expressing wildtype and the A53T mutant of human alphaSN in the nervous system under control of mouse Thy1 regulatory sequences. These animals develop neuronal alpha-synucleinopathy, striking features of Lewy pathology, neuronal degeneration and motor defects. Neurons in brainstem and motor neurons appeared particularly vulnerable. Motor neuron pathology included axonal damage and denervation of neuromuscular junctions, suggesting that alphaSN may interfere with a universal mechanism of synapse maintenance. Thy1-transgene expression of wildtype human alphaSN resulted in comparable pathological changes thus supporting a central role for mutant and wildtype alphaSN in familial and idiopathic forms of diseases with neuronal alpha-synucleinopathy and Lewy pathology. The mouse models provide means to address fundamental aspects of alpha-synucleinopathy and to test therapeutic strategies. Simard, M., R. van Reekum, et al. (2000). "A review of the cognitive and behavioral symptoms in dementia with Lewy bodies." J Neuropsychiatry Clin Neurosci 12(4): 425-50. Dementia with Lewy bodies is a relatively common cause of dementia. Much has been learned about this disorder, yet much remains to be elucidated, especially in regard to early clinical diagnosis. To clarify the future research agenda in this area, the authors critically appraise the literature on cognitive and behavioral changes in DLB and provide a brief overview of the history of DLB, the main pathological changes, and the findings related to extrapyramidal symptoms and treatment issues. Twenty-one studies on cognition and 47 on behavioral changes in DLB are reviewed. Impairments of working memory and visuospatial functions, visual hallucinations, and depression (or symptoms of depression such as apathy and anxiety) have been identified as early indicators of DLB. However, longitudinal and cross-sectional data are lacking, particularly for different aspects of working memory, visual perception, and non-psychotic behavioral symptoms. Shoji, M., Y. Harigaya, et al. (2000). "Accumulation of NACP/alpha-synuclein in lewy body disease and multiple system atrophy." J Neurol Neurosurg Psychiatry 68(5): 605-8. OBJECTIVES: NACP/alpha-synuclein is an aetiological gene product in familial Parkinson's disease. To clarify the pathological role of NACP/alpha-synuclein in sporadic Parkinson's disease and other related disorders including diffuse Lewy body disease (DLBD) and multiple system atrophy (MSA), paraffin sections were examined immunocytochemically using anti-NACP/alpha-synuclein antibodies. METHODS: A total of 58 necropsied brains, from seven patients with Parkinson's disease, five with DLBD, six with MSA, 12 with Alzheimer's disease, one with Down's syndrome, one with amyotrophic lateral sclerosis (ALS), three with ALS and dementia, one with Huntington's disease, two with progressive supranuclear palsy (PSP), one with Pick's disease, one with myotonic dystrophy, and three with late cerebellar cortical atrophy (LCCA), and 15 elderly normal controls were examined. RESULTS: In addition to immunoreactive Lewy bodies, widespread accumulation of NACP/alpha-synuclein was found in neurons and astrocytes from the brainstem and basal ganglia to the cerebral cortices in Parkinson's disease/DLBD. NACP/alpha-synuclein accumulates in oligodendrocytes from the spinal cord, the brain stem to the cerebellar white matter, and inferior olivary neurons in MSA. These widespread accumulations were not seen in other types of dementia or spinocerebellar ataxia. CONCLUSION: Completely different types of NACP/alpha-synuclein accumulation in Parkinson's disease/DLBD and MSA suggest that accumulation is a major step in the pathological cascade of both diseases and provides novel strategies for the development of therapies. Shimura, H., N. Hattori, et al. (2000). "Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase." Nat Genet 25(3): 302-5. Autosomal recessive juvenile parkinsonism (AR-JP), one of the most common familial forms of Parkinson disease, is characterized by selective dopaminergic neural cell death and the absence of the Lewy body, a cytoplasmic inclusion body consisting of aggregates of abnormally accumulated proteins. We previously cloned PARK2, mutations of which cause AR-JP (ref. 2), but the function of the gene product, parkin, remains unknown. We report here that parkin is involved in protein degradation as a ubiquitin-protein ligase collaborating with the ubiquitin-conjugating enzyme UbcH7, and that mutant parkins from AR-JP patients show loss of the ubiquitin-protein ligase activity. Our findings indicate that accumulation of proteins that have yet to be identified causes a selective neural cell death without formation of Lewy bodies. Our findings should enhance the exploration of the molecular mechanisms of neurodegeneration in Parkinson disease as well as in other neurodegenerative diseases that are characterized by involvement of abnormal protein ubiquitination, including Alzheimer disease, other tauopathies, CAG triplet repeat disorders and amyotrophic lateral sclerosis. Schwab, C., A. J. DeMaggio, et al. (2000). "Casein kinase 1 delta is associated with pathological accumulation of tau in several neurodegenerative diseases." Neurobiol Aging 21(4): 503-10. The distribution of casein kinase 1 delta (Cki delta) was studied by immunohistochemistry and correlated with other pathological hallmarks in Alzheimer's disease (AD), Down syndrome (DS), progressive supranuclear palsy (PSP), parkinsonism dementia complex of Guam (PDC), Pick's disease (PiD), pallido-ponto-nigral degeneration (PPND), Parkinson's disease (PD), dementia with Lewy bodies (DLB), amyotrophic lateral sclerosis (ALS), and elderly controls. Cki delta was found to be associated generally with granulovacuolar bodies and tau-containing neurofibrillary tangles in AD, DS, PSP, PDC, PPND, and controls, and Pick bodies and ballooned neurons in PiD. It was not associated with tau-containing inclusions in astroglia and oligodendroglia in PPND, PSP, and PDC. It was also not associated with tau-negative Lewy bodies in PD and DLB, Hirano bodies in PDC, Marinesco bodies in PD, AD, and controls and "skein"-like inclusions in anterior motor neurons in ALS. The colocalization of the kinase Cki delta and its apparent substrate tau suggests a function for Cki delta in the abnormal processing of tau. Schipper, H. M. (2000). "Heme oxygenase-1: role in brain aging and neurodegeneration." Exp Gerontol 35(6-7): 821-30. The mechanisms responsible for excessive iron deposition and mitochondrial insufficiency in the aging and degenerating nervous system remain poorly understood. Heme oxygenase-1 (HO-1) is a 32kDa stress protein that degrades heme to biliverdin, free iron and carbon monoxide. Our laboratory has shown that cysteamine, dopamine, beta-amyloid, IL-1beta and TNF-alpha up-regulate HO-1 followed by mitochondrial sequestration of non-transferrin-derived 55Fe in cultured rat astroglia. In these cells and in rat astroglia transfected with the human HO-1 gene, mitochondrial iron trapping is abrogated by the HO-1 inhibitors, tin-mesoporphyrin and dexamethasone. We determined that HO-1 immunoreactivity is enhanced greatly in neurons and astrocytes of the hippocampus and cerebral cortex of Alzheimer subjects and co-localizes to senile plaques and neurofibrillary tangles (NFT). HO-1 staining is also augmented in astrocytes and decorates neuronal Lewy bodies in the Parkinson nigra. Collectively, our findings suggest that HO-1 over-expression contributes to the pathological iron deposition and mitochondrial damage documented in these aging-related neurodegenerative disorders. We recently observed that, paradoxically, HO-1 mRNA levels are markedly suppressed in peripheral lymphocytes of patients with early sporadic Alzheimer disease and may thus provide a useful biological marker of this condition. Rozemuller, A. J., P. Eikelenboom, et al. (2000). "Activated microglial cells and complement factors are unrelated to cortical Lewy bodies." Acta Neuropathol (Berl) 100(6): 701-8. Inflammatory mechanisms have been demonstrated in Alzheimer's disease (AD) but their presence in other neurodegenerative disorders is not well documented. Complement factors and activated microglia have been reported in the substantia nigra of Parkinson's disease (PD). In the present study we investigated the cingulate gyrus of 25 autopsied patients with clinically and neuropathologically well-documented PD, with or without dementia, for the presence of (activated) microglial cells and their relation with Lewy body (LB)-bearing neurons. In addition, we studied the presence of complement factors in LBs. Of the 25 patient, 15 were clinically demented, fulfilling criteria for dementia with LBs (DLB); 7 also fulfilled CERAD morphological criteria for probable or definite Alzheimer type of dementia. Microglia clustering was seen around congophilic plaques with or without tau pathology. Microglial cells were not associated with LB-bearing neurons or noncongophilic plaques. The cortex of DLB patients without AD plaques did not show more microglial cells than the cortex of non-demented controls. The number of microglia was the lowest in young control patients who died immediately after trauma. Complement factor C3d was occasionally seen in diffusely ubiquinated neurons but late complement factors were not detected in these neurons. Double staining for complement and alpha-synuclein was negative, suggesting the absence of complement in LBs. In contrast, AD plaques in the same sections showed complement factors C3c, C3d, C1q and C5-9. In conclusion, we have found no evidence that inflammatory mechanism are involved in LB formation in cerebral cortex. Ransmayr, G., G. K. Wenning, et al. (2000). "[Dementia with Lewy bodies]." Nervenarzt 71(12): 929-35. Dementia with Lewy bodies (DLB) is the second most frequent neuropathologically diagnosed degenerative dementing illness. The clinical characteristics are progressive dementia, parkinsonian syndrome, fluctuations of cognitive functions, alertness, and attention, visual hallucinations (usually detailed and well described), depression, REM sleep behavior disorder, adverse responses to standard neuroleptics doses, falls, syncopes, systematized delusions, and other modalities of hallucinations. Specificity of the clinical diagnostic criteria is high (95%), and sensitivity is considerably lower. Mean age at disease onset ranges between 60 and 68 years. The male gender prevails. Disease duration is 6 to 8 years. The differential diagnoses of DLB are dementia of the Alzheimer type, Parkinson's disease, subcortical arteriosclerotic encephalopathy, progressive supranuclear palsy, multiple system atrophy, and rarely Creutzfeldt-Jakob disease. The genetic background of the disease is unclear. Magnetic resonance imaging and single photon emission tomography can contribute to the diagnosis. Controlled pharmacological studies have so far not been published. The disease is treated with L-dopa, atypical neuroleptics, acetylcholine esterase inhibitors, antihypotensive agents, and peripheral anticholinergic and alpha receptor-blocking medications to improve neurogenic bladder dysfunction. Ransmayr, G. (2000). "Dementia with Lewy bodies: prevalence, clinical spectrum and natural history." J Neural Transm Suppl(60): 303-14. The article summarises history, terminology, the clinical and neuropathological diagnostic criteria, neurochemical and genetic findings, sensitivity and specificity of the clinical diagnostic criteria, prevalence, demographical data and nosology, differential diagnosis, and therapy of dementia with Lewy bodies (DLB). DLB shares clinical symptoms of Parkinson's disease and dementia of the Alzheimer-type (DAT). However, DLB is also different to PD and DAT (less tremor and asymmetry of the motor symptoms, more falls, and less favourable response to L-Dopa than PD; in contrast to DAT marked cognitive fluctuations and phases of reduced alertness, hallucinations and delirium). There are genetic similarities to DAT and PD in terms of common genetic risk factors. A genetic cause of the disease has so far not been detected. Whether or not DLB is a disease entity or an association of diseases (Lewy body disease and DAT) has so far not been elucidated. Clinical distinction from DAT and PD has clinical importance because of different therapeutic and prognostic implications. Studies are needed to standardize the treatment of motor, cognitive, psychiatric and vegetative symptoms. Paik, S. R., H. J. Shin, et al. (2000). "Metal-catalyzed oxidation of alpha-synuclein in the presence of Copper(II) and hydrogen peroxide." Arch Biochem Biophys 378(2): 269-77. alpha-Synuclein is a component of abnormal protein depositions of Lewy bodies and senile plaques found in Parkinson's and Alzheimer's diseases, respectively. By using chemical coupling reagents such as dicyclohexylcarbodiimide or N-(ethoxycarbonyl)-2-ethoxy-1, 2-dihydroquinoline, the protein was shown to experience self-oligomerization in the presence of either copper(II) or Abeta25-35. The oligomers which appeared as a ladder on a 10-20% Tricine/SDS-PAGE have been suggested to participate in the formation of protein aggregations by possibly providing a nucleation center. Since oxidatively modified protein could increase its own tendency toward protein aggregation, metal-catalyzed oxidation of alpha-synuclein has been examined with copper(II) and hydrogen peroxide in the absence of the coupling reagent. Intriguingly, the protein was also self-oligomerized into an SDS-resistant ladder on the gel. This biochemically specific copper-mediated oxidative oligomerization was shown to be dependent upon the acidic C-terminus of alpha-synuclein because the C-terminally truncated proteins such as alpha-syn114 and alpha-syn97 were not affected by the metal and hydrogen peroxide. More importantly, the oxidative oligomerization was synergistically enhanced by the presence of Abeta25-35, indicating that the peptide interaction with alpha-synuclein facilitated the copper(II) binding to the acidic C-terminus and subsequent oxidative crosslinking. It has been, therefore, suggested that abnormalities in copper and H(2)O(2) homeostasis and certain pathological factors functionally similar to the Abeta25-35 could play critical roles in the metal-catalyzed oxidative oligomerization of alpha-synuclein, which may lead to possible protein aggregation and neurodegenerations. Ogawa, K., T. Yamada, et al. (2000). "Localization of a novel type trypsin-like serine protease, neurosin, in brain tissues of Alzheimer's disease and Parkinson's disease." Psychiatry Clin Neurosci 54(4): 419-26. Neurosin, a novel type of trypsin-like serine protease, has been shown to be preferentially expressed in human brain by northern blotting. We examined neurosin immunolabeling in the brains of neurologically normal persons and patients with Alzheimer's disease (AD) and with Parkinson's disease. We also identified the expression of the mRNA for neurosin by in situ hybridization histochemistry and reverse transcription-polymerase chain reaction (RT-PCR). The neurosin antibody stained all of the nuclei of various cell types. In neurons, there was also staining of neuronal cytoplasm, nucleoli and their processes. In AD, staining of neurons with processes was rare in the damaged areas. Some senile plaques, extracellular tangles and Lewy bodies were also positive for neurosin. Expression of the mRNA for neurosin was seen in neurons in the gray matter, and in microglial cells in the white matter. In AD, the intensity of the signal for neurosin mRNA in the gray matter was decreased compared with normal control brains. The relative levels of neurosin mRNA in AD brains, measured by RT-PCR, were lower than those in controls. These results suggest that in human brain neurosin plays various physiological roles, and that in AD this molecule, like other serine proteases, may have a role in the degradation of such substances as beta-amyloid protein. Nores, J. M., B. Biacabe, et al. (2000). "[Olfactory disorders in Alzheimer's disease and in Parkinson's disease. Review of the literature]." Ann Med Interne (Paris) 151(2): 97-106. Olfactory disorders in Alzheimer's disease and Parkinson's disease have been the topic of a large body of work over the last decades. Work devoted to olfactory disorders in Alzheimer's disease includes over 300 papers providing clinical and fundamental data. Anatomy studies in Alzheimer's disease have demonstrated a specific concentration of lesions in peripheral and central olfactory structures (senile plaques, neurofibrillary degeneration) as well as lesions in layers II and III of the entorhinal cortex. These neuropathological findings led to the development of the hypothesis that olfactory disorders in Alzheimer's disease would result from a toxic process. Observed olfactory deficits involve both identification and recognition of odors and detection thresholds. Nevertheless, patients with Alzheimer's disease rarely consult for sensorial deficits as the other signs of the disease predominate. Neuropath