Lewy body dementia

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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.

Wszolek, Z. K., K. Gwinn-Hardy, et al. (2002). "Neuropathology of two members of a German-American kindred (Family C) with late onset parkinsonism." Acta Neuropathol (Berl) 103(4): 344-50.
We present genealogical and longitudinal clinical observations and autopsy findings of a previously reported kindred, Family C (German-American), with late-onset autosomal dominant parkinsonism with evidence for linkage on chromosome 2p13. The clinical phenotype includes the cardinal features of idiopathic Parkinson's disease. In addition, postural tremor and dementia are detected in some individuals. Two members of the kindred, one affected and one unaffected have recently come to autopsy. The unaffected family member was an 82-year-old woman whose brain showed only mild age-related pathology and no evidence of subclinical Lewy body disease. In contrast, the affected family member was an 83-year-old man whose brain had neuronal loss, gliosis and Lewy bodies in the substantia nigra and other monoaminergic brain stem nuclei, as well as the basal forebrain and amygdala. Lewy bodies and Lewy neurites had a distribution typical of cases of idiopathic Parkinson's disease. Thus, the clinical and pathological findings in this family with autosomal dominant parkinsonism are similar to those of sporadic Parkinson's disease.

Wang, L., M. Zhu, et al. (2002). "[The application of Gallyas-Braak stainings in pathologic diagnosis of neurodegenerative diseases]." Zhonghua Nei Ke Za Zhi 41(2): 120-3.
OBJECTIVE: To evaluate the role of Gallyas silver staining in the diagnosis of neurodegenerative diseases. METHOD: Modified Gallyas-Braak staining method was used to investigate samples of the brain and spinal cord of 22 cases with neurodegenerative disease including Alzheimer's disease (AD), Parkinson's diseas (PD), Pick's disease, diffuse Lewy body disease (DLBD), progressive supranuclear palsy (PSP), diagnosed by clinical and routine pathologic method. 10 cases without clinical symptoms and pathologic abnormalities of the nervous system served as control. RESULT: As compared with Bodian staining, Gallyas-Braak staining demonstrated clearly neurofibrillary tangles in the hippocampus and the cortex of frontal and temperal lobe in all the cases with Alzheimer's disease, 6 cases with dementia of other causes and 3 normal aged. However, global neurofibrillary tangles in the midbrain and the basal ganglia were found only with Gallyas-Braak staining in 4 cases with both dementia and extrapyramidal features. In addition, tuft-shaped astrocytes were shown with this method in the motor cortex, basal ganglia, midbrain of the above 4 cases and astrocytic plaques in the same area in 2 cases of the 4 cases. In this connexion, pathologic findings in 2 of the 4 cases corresponded to PSP and those of the other two cases fufiled the diagnostic criteria of corticobasal degeneration (CBD) Oligodendroglial cytoplasmic inclusions in the white matter of the brain and the spinal cord were founded in 3 of the 4 cases with multiple system atrophy (MSA). This silver staining demonstrated as well a lot of argyrophilic grains in the neuropil of the temporal lobe and the hippocampus in one case with AD. CONCLUSION: Gallyas silver staining could better reveal not only Alzheimer-like neurofibrillary tangles but also different glial inclusions in other neurodegenerative diseases such as PSP, CBD and MSA. Consequently, it is of great value in the pathologic diagnosis and study of such degenerative diseases.

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.

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.

Scott, H. L., D. V. Pow, et al. (2002). "Aberrant expression of the glutamate transporter excitatory amino acid transporter 1 (EAAT1) in Alzheimer's disease." J Neurosci 22(3): RC206.
Glutamate-mediated toxicity has been implicated in the neurodegeneration observed in Alzheimer's disease. In particular, glutamate transport dysfunction may increase susceptibility to glutamate toxicity, thereby contributing to neuronal cell injury and death. In this study, we examined the cellular localization of the glial glutamate transporter excitatory amino acid transporter 1 (EAAT1) in the cerebral cortex of control, Alzheimer's disease, and non-Alzheimer dementia cases. We found that EAAT1 was strongly expressed in a subset of cortical pyramidal neurons in dementia cases showing Alzheimer-type pathology. In addition, tau (which is a marker of neurofibrillary pathology) colocalized to those same pyramidal cells that expressed EAAT1. These findings suggest that EAAT1 changes are related to tau expression (and hence neurofibrillary tangle formation) in dementia cases showing Alzheimer-type pathology. This study implicates aberrant glutamate transporter expression as a mechanism involved in neurodegeneration in Alzheimer's disease.

Schlossmacher, M. G., M. P. Frosch, et al. (2002). "Parkin localizes to the Lewy bodies of Parkinson disease and dementia with Lewy bodies." Am J Pathol 160(5): 1655-67.
Mutations in alpha-synuclein (alpha S) and parkin cause heritable forms of Parkinson disease (PD). We hypothesized that neuronal parkin, a known E3 ubiquitin ligase, facilitates the formation of Lewy bodies (LBs), a pathological hallmark of PD. Here, we report that affinity-purified parkin antibodies labeled classical LBs in substantia nigra sections from four related human disorders: sporadic PD, inherited alphaS-linked PD, dementia with LBs (DLB), and LB-positive, parkin-linked PD. Anti-parkin antibodies also detected LBs in entorhinal and cingulate cortices from DLB brain and alphaS inclusions in sympathetic gangliocytes from sporadic PD. Double labeling with confocal microscopy of DLB midbrain sections revealed that approximately 90% of anti-alpha S-reactive LBs were also detected by a parkin antibody to amino acids 342 to 353. Accordingly, parkin proteins, including the 53-kd mature isoform, were present in affinity-isolated LBs from DLB cortex. Fluorescence resonance energy transfer and immunoelectron microscopy showed that alphaS and parkin co-localized within brainstem and cortical LBs. Biochemically, parkin appeared most enriched in cytosolic and postsynaptic fractions of adult rat brain, but also in purified, alpha S-rich presynaptic elements that additionally contained parkin's E2-binding partner, UbcH7. We conclude that parkin and UbcH7 are present with alphaS in subcellular compartments of normal brain and that parkin frequently co-localizes with alpha S aggregates in the characteristic LB inclusions of PD and DLB. These results suggest that functional parkin proteins may be required during LB formation.

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.

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.

Power, J. H., J. M. Shannon, et al. (2002). "Nonselenium glutathione peroxidase in human brain : elevated levels in Parkinson's disease and dementia with lewy bodies." Am J Pathol 161(3): 885-94.
Nonselenium glutathione peroxidase (NSGP) is a new member of the antioxidant family. Using antibodies to recombinant NSGP we have examined the distribution of this enzyme in normal, Parkinson's disease (PD), and dementia with Lewy body disease (DLB) brains. We have also co-localized this enzyme with alpha-synuclein as a marker for Lewy bodies. In normal brains there was a very low level of NSGP staining in astrocytes. In PD and DLB there were increases in the number and staining intensity of NSGP-positive astrocytes in both gray and white matter. Cell counting of NSGP cells in PD and DLB frontal and cingulated cortices indicated there was 10 to 15 times more positive cells in gray matter and three times more positive cells in white matter than in control cortices. Some neurons were positive for both alpha-synuclein and NSGP in PD and DLB, and double staining indicated that NSGP neurons contained either diffuse cytoplasmic alpha-synuclein deposits or Lewy bodies. In concentric Lewy bodies, alpha-synuclein staining was peripheral whereas NSGP staining was confined to the central core. Immunoprecipitation indicated there was direct interaction between alpha-synuclein and NSGP. These results suggest oxidative stress conditions exist in PD and DLB and that certain cells have responded by up-regulating this novel antioxidant enzyme.

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.

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.

Kawamoto, Y., I. Akiguchi, et al. (2002). "14-3-3 proteins in Lewy bodies in Parkinson disease and diffuse Lewy body disease brains." J Neuropathol Exp Neurol 61(3): 245-53.
Several components of Lewy bodies have been identified, but the precise mechanism responsible for the formation of Lewy bodies remains undetermined. The 14-3-3 protein family is involved in numerous signal transduction pathways and interacts with alpha-synuclein, which is a major constituent of Lewy bodies. To elucidate the role of 14-3-3 proteins in neuro-degenerative disorders associated with Lewy bodies, we performed immunohistochemical studies on 14-3-3 in brains from 5 elderly control subjects and from 10 patients with Parkinson disease (PD) or diffuse Lewy body disease (DLBD). In the normal controls, 14-3-3-like immunoreactivity was mainly observed in the neuronal somata and processes in various cortical and subcortical regions. In the PD and DLBD cases, a similar immunostaining pattern was found and immunoreactivity was generally spared in the surviving neurons from the severely affected regions. In addition, both classical and cortical Lewy bodies were intensely immunolabeled and some dystrophic neurites were also immunoreactive for 14-3-3. Our results suggest that 14-3-3 proteins may be associated with Lewy body formation and may play an important role in the pathogenesis of PD and DLBD.

Kahle, P. J., C. Haass, et al. (2002). "Structure/function of alpha-synuclein in health and disease: rational development of animal models for Parkinson's and related diseases." J Neurochem 82(3): 449-57.

Jellinger, K. A. (2002). "Disturbance of the nigro-amygdaloid connections in dementia with Lewy bodies." J Neurol Sci 193(2): 157-8.

Jellinger, K. A., K. Seppi, et al. (2002). "Impact of coexistent Alzheimer pathology on the natural history of Parkinson's disease." J Neural Transm 109(3): 329-39.
OBJECTIVE: To assess the impact of coexisting Alzheimer (AD) pathology on the natural history of Parkinson's disease (PD). BACKGROUND: AD changes are frequently present in brains of demented PD patients. Assessing the relative contribution of AD pathology to the natural history of PD is difficult and the impact of both AD and cortical Lewy body (LB) pathologies on cognitive dysfunction is still under discussion. From clinical experience, dementia in PD patients, mainly related to AD pathology, is associated with a poor outcome, but the impact of AD pathology on the natural history of PD has not been studied systematically. MATERIAL AND METHODS: In 200 consecutive autopsy cases of PD (sex (m/f) ratio 1:1.1), age at death 58-98 (mean 77.0 +/- 9.5) years, from a specialized Austrian brain bank, retrospectively assessed major initial clinical symptoms (tremor, akinesia), moderate/severe dementia, and duration of illness were correlated with associated AD pathologies using CERAD, Braak and NIA-Reagan criteria. Mann-Whitney U-test, Cox-regression were used for statistical analysis. RESULTS: While gender had no influence on the clinical motor symptoms and outcome, tremor dominant type had a significantly better outcome than akinetic forms (p = 0.022), even after adjustment with age at onset and associated AD pathology (CERAD and Braak criteria). Patients with late onset showed significantly shorter duration of illness irrespective of dementia. Moderate to severe dementia, reported in 33% of the sample, was significantly correlated with AD pathology (all 3 criteria) that showed significantly negative correlation with survival: between CERAD 0-A vs. B and C there was a significant difference of odd ratios (p < 0.001), as was between Braak stages 0-2, 3-4.5, and 5, but not between Braak stages 3-4 and 5. CONCLUSIONS: The present data confirm previous studies suggesting better outcome of tremor-dominant than akinetic-rigid type of PD, significantly worse outcome in PD with late onset and dementia that is significantly correlated with coexistent neuritic Alzheimer pathology, particularly when using the CERAD and NIA-R criteria for the diagnosis of AD. Further studies are needed to elucidate the relative impact of cortical LB and AD pathologies on the natural history of PD.

Iwatsubo, T. (2002). "[alpha-synuclein and Parkinson's disease]." Seikagaku 74(6): 477-82.

Holdorff, B. (2002). "Friedrich Heinrich Lewy (1885-1950) and his work." J Hist Neurosci 11(1): 19-28.
In 1912, Friedrich Heinrich Lewy first described the inclusion bodies named after him and seen in paralysis agitans (p.a.). Tretiakoff had found (1919) that the nucleus niger is most likely to be affected but in a subsequent large-scale series of post-mortem examinations (1923). Lewy was able to confirm this for a minority of cases only, with the exception of those that displayed postencephalitic Parkinsonism (and an unknown number of atypical Parkinson syndrome cases not identified until the 1960s). In a speculative paper (1932), he saw similarities between inclusion bodies in p.a. and viral diseases like lyssa and postulated a viral genesis of p.a. In a historical review of basal ganglia diseases (1942), he did not mention the putative significance of the inclusion bodies for the post-mortem diagnosis. It seems that their importance was seen only after Lewy's death, long after Tretiakoff's initial naming of the 'corps de Lewy'. Lewy, however, had already described their diffuse and cortical distribution (1923). An identification of diffuse Lewy body disease or dementia followed much later. Lewy's career in many diverse branches of neurology and internal medicine was strongly affected by World War I and the difficult situation faced by Jews in Germany. Shortly after the Neurological Institute was founded in Berlin in 1932 (as a clinic and research institute), he was forced, in 1933, to emigrate. His exile in England and the United States mirrors the fate of many German Jews and academics in the first half of the 20th century.

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.

Harding, A. J., G. A. Broe, et al. (2002). "Visual hallucinations in Lewy body disease relate to Lewy bodies in the temporal lobe." Brain 125(Pt 2): 391-403.
Consensus opinion characterizes dementia with Lewy bodies (DLB) as a progressive dementing illness, with significant fluctuations in cognition, visual hallucinations and/or parkinsonism. When parkinsonism is an early dominant feature, consensus opinion recommends that dementia within the first year is necessary for a diagnosis of DLB. If dementia occurs later, a diagnosis of Parkinson's disease with dementia (PDD) is recommended. While many previous studies have correlated the neuropathology in DLB with dementia and parkinsonism, few have analysed the relationship between fluctuating cognition and/or well-formed visual hallucinations and the underlying neuropathology in DLB and PDD. The aim of the present study was to determine any relationship between these less-studied core clinical features of DLB, and the distribution and density of cortical Lewy bodies (LB). The brains of 63 cases with LB were obtained over 6 years following population-based studies of dementia and parkinsonian syndromes. Annual, internationally standardized, clinical assessment batteries were reviewed to determine the presence and onset of the core clinical features of DLB. The maximal density of LB, plaques and tangles in the amygdala, parahippocampal, anterior cingulate, superior frontal, inferior temporal, inferior parietal and visual cortices were determined. Current clinicopathological diagnostic criteria were used to classify cases into DLB (n = 29), PDD (n = 18) or parkinsonism without dementia (n = 16) groups. Predictive statistics were used to ascertain whether fluctuating cognition or visual hallucinations predicted the clinicopathological group. Analysis of variance and regressions were used to identify any significant relationship(s) between the presence and severity of neuropathological and clinical features. Cognitive fluctuations and/or visual hallucinations were not good predictors of DLB in pathologically proven patients, although the absence of these features early in the disease course was highly predictive of PDD. Cases with DLB had higher LB densities in the inferior temporal cortex than cases with PDD. There was no association across groups between any neuropathological variable and the presence or absence of fluctuating cognition. However, there was a striking association between the distribution of temporal lobe LB and well-formed visual hallucinations. Cases with well-formed visual hallucinations had high densities of LB in the amygdala and parahippocampus, with early hallucinations relating to higher densities in parahippocampal and inferior temporal cortices. These temporal regions have previously been associated with visual hallucinations in other disorders. Thus, our results suggest that the distribution of temporal lobe LB is more related to the presence and duration of visual hallucinations in cases with LB than to the presence, severity or duration of dementia.

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.

Fernandez, H. H., M. E. Trieschmann, et al. (2002). "Quetiapine for psychosis in Parkinson's disease versus dementia with Lewy bodies." J Clin Psychiatry 63(6): 513-5.
BACKGROUND: Most clinicians perceive psychosis in dementia with Lewy bodies (DLB) as more difficult to treat than Parkinson's disease, yet there are no reports comparing the antipsychotic response between the 2 disorders. METHOD: All charts of Parkinson's disease and DLB patients at our Movement Disorders Center, Memorial Hospital of Rhode Island, Pawtucket, given quetiapine for psychosis were reviewed. Demographic data, including type and severity of psychosis, before and after Unified Parkinson's Disease Rating Scale (UPDRS)-motor scores, motor worsening, and treatment response (recorded as poor/none, partial, or total), were obtained. The chi-square test was used to assess differences in efficacy and tolerability of quetiapine between Parkinson's disease and DLB patients. RESULTS: Eighty-seven Parkinson's disease and 11 DLB patients with psychosis were analyzed. No significant difference in mean age, levodopa dose, quetiapine dose, duration of quetiapine use, or baseline UPDRS-motor score was noted between Parkinson's disease and DLB patients. Eighty percent (70/87) of Parkinson's disease patients and 90% (10/11) of DLB patients had partial to complete resolution of psychosis using quetiapine (p = .40). Motor worsening was noted at one point in 32% (28/87) of Parkinson's disease and 27% (3/11) of DLB patients over the duration of quetiapine use (p = .74). CONCLUSION: Long-term quetiapine use was generally well tolerated in this geriatric Parkinson's disease and DLB population. Mild motor worsening occurred in some patients. No significant difference in long-term efficacy and motor worsening associated with quetiapine treatment was noted between the 2 disorders.

Christen, Y. (2002). "[Proteins and mutations: a new vision (molecular) of neurodegenerative diseases]." J Soc Biol 196(1): 85-94.
Neurodegenerative diseases have long been considered to be poorly defined, misunderstood, and inadequately treated. In recent years, research on Alzheimer's disease has led to numerous advances that have improved our understanding of this form of dementia and also of the entire category of neurodegenerative diseases. It now appears that numerous neurodegenerative diseases of the central nervous system correspond to the aggregation of specific proteins: beta-amyloid in Alzheimer disease, tau protein in Alzheimer disease, fronto-temporal dementia, progressive supranuclear palsy and corticobasal degeneration, alpha-synuclein in Parkinson disease and Lewy body dementia, PrP protein in prion diseases, SOD in amyotrophic lateral sclerosis, polyglutamine expansions in Huntington's disease and other diseases, etc. It is remarkable that in all these cases mutations have been identified for genes coding for these proteins and able to cause the disease and, moreover, that the introduction of the corresponding gene into transgenic mice (or other transgenic animals) has made it possible to create animal models of these conditions. This suggests that the proteins in question play a determinative role in the pathogenesis of these diseases and are not simply consequences of it. Neurodegenerative diseases are proteinopathies. But they are also networkopathies because the neuronal proteins are organized in functional networks. We must also note that all these diseases are associated with the process of aging, for they do not appear in the young. This fact suggests that the anomaly (genetic or otherwise) concerning a given protein does not suffice by itself to induce the disease process. Many observations suggest that the additional event involved, common to all neurodegenerative conditions, may be the intervention of free radicals. We thus propose here the theory that the diversity of neurodegenerative diseases is explained by the combination of two pathogenic events: one specific and associated with the aggregation of a particular protein in the nervous system, the other, non-specific and associated with aging and with the production and harmful actions of free radicals. This unified interpretation leads directly to treatment hypotheses: the development of drugs capable either of inhibiting the production or aggregation of proteins specifically implicated in diverse diseases (or promoting their elimination) or of inhibiting the production or action of free radicals in the nervous system. The former should target one of these various diseases, and the latter should act on a wide range of diseases. The two approaches may conceivably be combined.

Ceballos-Baumann, A. O. (2002). "[Dopaminergic agents, COMT inhibitors or amantadine? Proper treatment for your Parkinson patient]." MMW Fortschr Med Suppl 2: 37-43.
Over the last six years, eight new substances for the treatment of idiopathic parkinsonism (IP) have been approved for use: four oral and one parenteral dopamine agonist (apomorphine), two COMT-inhibitors and budipine. The old drug amantadine has experienced a renaissance in the treatment of a complication occurring during long-term treatment of IP, namely levodopa-induced dyskinesia. Deep brain stimulation with programmable pulse generators and stereotactically implanted electrodes are increasingly being used in patients with severe on-off phases and levodopa dyskinesia. The treatment of Parkinson's disease unresponsive to dopaminergic substances and that associated with dementia remains problematical. In combinations of parkinsonism and dementia, the cholinesterase inhibitors are being used in particular for Lewy body dementia.

Castellani, R. J., G. Perry, et al. (2002). "Hydroxynonenal adducts indicate a role for lipid peroxidation in neocortical and brainstem Lewy bodies in humans." Neurosci Lett 319(1): 25-8.
Multiple lines of evidence indicate that oxidative stress is a critical pathogenic factor in Parkinson disease (PD) and diffuse Lewy body disease (DLBD). Previously, we demonstrated increased levels of redox-active iron in Lewy bodies, and that Lewy bodies accumulate advanced glycation end-products. To further characterize the role of oxidative stress in diseases with Lewy body formation, we examined immunocytochemically eight cases of PD and five cases of DLBD for adducts of the lipid peroxidation adduct 4-hydroxy-2-nonenal, and for N(epsilon)-(carboxymethyl)lysine (CML). Our findings demonstrate immunolocalization of 4-hydroxynonenal and CML to Lewy bodies in PD and DLBD. These findings not only support prior studies indicating that lipid peroxidation is increased in patients with PD and DLBD but that oxidative damage may play a critical role in Lewy body formation.

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.

Al-Sarraj, S., S. Maekawa, et al. (2002). "Ubiquitin-only intraneuronal inclusion in the substantia nigra is a characteristic feature of motor neurone disease with dementia." Neuropathol Appl Neurobiol 28(2): 120-8.
Two types of ubiquitinated inclusions have been described in motor neurone disease (MND). (1) Skein or globular ubiquitinated inclusions in the motor neurones (more frequently in the lower motor neurones). This is a characteristic feature of all motor neurone disease categories. (2) Dot-shape or crescentric ubiquitinated inclusions in the upper layers of cortex and dentate gyrus described in cases of motor neurone disease with dementia (DMND). We investigated the substantia nigra (SN) in MND cases; two cases of motor neurone disease inclusion body (MND-IB) dementia, six cases of DMND, 14 cases of MND (including one case from Guam and two cases of familial SOD1 mutation), four cases of Parkinson's disease (PD), and 10 cases of age-matched normal controls. SN and spinal cord sections were stained with ubiquitin (alpha-synuclein, tau, PGM1, SMI-31 and SOD1 antibodies). The neuronal density in SN was quantified by using a computer-based image analysis system. Four out of six DMND cases showed rounded ubiquitin positive inclusions with irregular frayed edges, associated with neuronal loss, reactive astrocytosis and a large number of activated microglia cells. These inclusions are negative with antibodies to (alpha-synuclein, tau, SMI-31 and SOD1). The SN in cases from MND-IB dementia and MND showed occasional neuronal loss and no inclusions. The ubiquitin-only inclusions in SN of DMND cases are similar (but not identical) to the ubiquitinated inclusions described previously in the spinal cord of MND cases and are distinct from Lewy bodies (LBs). The degeneration of SN is most likely a primary neurodegenerative process of motor neurone disease type frequently involving the DMND cases. MND disease is a spectrum and multisystem disorder with DMND located at the extreme end of a spectrum affecting the CNS more widely than just the motor system.

(2002). "Understanding changes in cholinergic function: implications for treating dementia." J Clin Psychiatry 63(3): 259-69.

Zesiewicz, T. A., M. J. Baker, et al. (2001). "Diffuse Lewy Body Disease." Curr Treat Options Neurol 3(6): 507-518.
Diffuse Lewy body disease (DLB) is a neurodegenerative disorder characterized by dementia, fluctuations in mental status, hallucinations, and parkinsonism. Diffuse Lewy body disease is the second most common cause of dementia, following Alzheimer's disease. The treatment of DLB includes cholinergic therapy for cognitive impairment, atypical neuroleptics to alleviate hallucinations, and levodopa/carbidopa to improve parkinsonism. The recognition and diagnosis of DLB has critical treatment implications. Centrally acting cholinesterase inhibitors, such as rivastigmine, donepezil, and galantamine partially reverse decreased cortical cholinergic activity and may improve cognition and neuropsychiatric symptoms in DLB. Rivastigmine has been demonstrated to improve cognition and neuropsychiatric symptoms in patients with DLB without worsening parkinsonian features. Due to the potential adverse events associated with neuroleptics in this population, treatment with cholinesterase inhibitors is currently considered first-line therapy in the treatment of hallucinations and mental status fluctuations in DLB. Exquisite sensitivity to neuroleptic medications is a hallmark of DLB and life-threatening complications have been reported. Caution should be exercised when implementing antipsychotic therapy for the treatment of behavioral disturbances of DLB. When required, atypical neuroleptics with the least extrapyramdial side effects, such as quetiapine, should be used. The parkinsonian features of DLB may respond to dopaminergic therapy with levodopa. If parkinsonian symptoms result in clinical disability, a trial of levodopa is warranted. Unfortunately, dopaminergic medications may worsen hallucinations. Because dopamine agonists have a greater tendency to induce hallucinations and somnolence, levodopa is the treatment of choice for parkinsonism in DLB. Rapid eye movement (REM) sleep behavior disorder (RBD) is now recognized as a feature of DLB. Awareness of the presence of this symptom in patients with DLB is important and treatment with low dose clonazepam may help. Cholinergic aumentation may also improve these symptoms in patients with DLB.

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.

Wirdefeldt, K., N. Bogdanovic, et al. (2001). "Expression of alpha-synuclein in the human brain: relation to Lewy body disease." Brain Res Mol Brain Res 92(1-2): 58-65.
Alpha-synuclein is mutated in some hereditary cases of Parkinson's disease and the protein precipitates in Lewy bodies, the pathological hallmark of both Parkinson's disease and Lewy body disease. Transgenic mice overexpressing human wild-type alpha-synuclein develop alpha-synuclein-immunoreactive inclusions in brain regions typically affected with Lewy body disease. We used in situ hybridization to characterize alpha-synuclein expression and examine mRNA levels in patients affected with Lewy body disease and controls. Substantia nigra was avoided because of the extensive neuronal loss and cingulate gyrus was chosen as it is one of the diagnostic regions in Lewy body disease where Lewy bodies most frequently are demonstrated. beta-tubulin was used to control for neuronal degeneration. The alpha-synuclein probe showed intense labeling of pyramidal cells in lamina III and V in both patients and controls. We found no difference in alpha-synuclein mRNA levels and beta-tubulin mRNA was not significantly altered (P=0.06) in patient brains. There was no difference in the ratio of alpha-synuclein and beta-tubulin mRNA levels between patients and controls. Further, we found no relationship between alpha-synuclein mRNA levels and Lewy bodies. Great variability in alpha-synuclein mRNA levels among patients indicates that Lewy body disease may be a heterogeneous disorder with regard to alpha-synuclein involvement.

Uversky, V. N., H. J. Lee, et al. (2001). "Stabilization of partially folded conformation during alpha-synuclein oligomerization in both purified and cytosolic preparations." J Biol Chem 276(47): 43495-8.
Aggregation of alpha-synuclein is tightly associated with many neurodegenerative diseases, such as Parkinson's disease, dementia with Lewy body, Lewy body variant of Alzheimer's disease, multiple system atrophy, and Hallervorden-Spatz disease, implicating a crucial role of aggregated forms of alpha-synuclein in the pathogenesis. Here, we examined the effect of elevated temperature on the oligomerization and structural changes of alpha-synuclein in the early stage of aggregation and show that self-assembly is crucial for the stabilization of a partially folded conformation. The efficiency of alpha-synuclein oligomerization increased proportional to the temperature increase, both in purified form and in crude cytosolic preparation. This oligomerization coincided with a small but reproducible change in the circular dichroism spectrum and an increase in the 1-anilinonaphthalene-8-sulfonic acid binding. The hydrodynamic dimensions of the dimer measured by size exclusion chromatography suggest a pre-molten globule-like structure. These data suggest that partially folded alpha-synuclein, which is unstable in the monomeric form, is stabilized by self-assembly and that these oligomers may evolve into the fibril nucleus.

Suzuki, A., S. Ikebe, et al. (2001). "[A 64-year-old man with parkinsonism as an initial symptom followed by dementia associated with marked abnormal behaviours]." No To Shinkei 53(11): 1075-87.
We report a 64-year-old man with parkinsonism as an initial symptom, which was followed by dementia and abnormal behaviours. He was well until 1985, when he was 49 years old, when he noted rest tremor in his right hand. Soon tremor appeared in his left hand as well. He was seen in our clinic and levodopa was prescribed. He was doing well with this medication, however, in 1993, he started to suffer from on-off phenomenon. He also noted visual hallucination. In 1994, he stole a watermelon and ate it in the shop. He repeated such abnormal behaviours. In 1995, he was admitted to the neurology service of Hatsuishi Hospital. On admission, he was alert and oriented. He did not seem to be demented; however, he admitted stealing and hypersexual behaviours. No aphasia, apraxia, or agnosia was noted. In the cranial nerves, downward gaze was markedly restricted. He showed masked and seborrhoic face, and small voice. No motor palsy was noted, but he walked in small steps with freezing and start hesitation. Marked neck and axial rigidity was noted. Tremor was absent except for in the tongue. No cerebellar ataxia was noted. Deep tendon reflexes were diminished. Plantar response was extensor bilaterally. Forced grasp was noted also bilaterally. He was treated with levodopa and pergolide, but he continued to show on-off phenomenon. His balance problem and akinesia became progressively worse; still he showed hypersexual behaviour problems. He also showed progressive decline in cognitive functions. In 1997, he started to show dysphagia. He developed aspiration pneumonia in July of 1998. In 1999, he developed emotional incontinence and became unable to walk. He also developed repeated aspiration pneumonia. He died on March 1, 2000. He was discussed in a neurological CPC and the chief discussant arrived at a conclusion that the patient had corticobasal degeneration. Other diagnoses entertained included dementia with Lewy bodies, diffuse Lewy body disease, and frontotemporal dementia. Majority of the participants thought that diffuse Lewy body disease was most likely. Post-mortem examination revealed marked nigral neuronal loss, gliosis and Lewy bodies in the remaining neurons. Abundant Lewy bodies of cortical type were seen wide spread in the cortical areas, but particularly many in the amygdaloid nucleus. Lewy bodies were also seen in the subcortical structures such as the dorsal motor nucleus, oculomotor nucleus, Meynert nucleus, putamen, and thalamus. What was interesting was marked neuronal loss of the pontine nuclei, demyelination of the pontocerebellar fiber, and moderate neuronal loss of the cerebellar Purkinje neurons, a reminiscent of pontocerebellar atrophy. However, the inferior olivary nucleus was intact.

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.

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.

Serby, M. and S. C. Samuels (2001). "Diagnostic criteria for dementia with lewy bodies reconsidered." Am J Geriatr Psychiatry 9(3): 212-6.
The validity of the consensus criteria for dementia with Lewy bodies (DLB) has been questioned. The authors, therefore, performed analyses of 242 published cases with clinicopathological correlation of DLB. The prevalence of specific consensus criteria in 69 patients reported on by the Newcastle and Nottingham groups in England (Group N) were compared with their prevalence in papers from all other investigators (Group O). Analysis of the entire sample (Groups N and O combined) revealed 64% with parkinsonism, 66% with co-occurring parkinsonism and dementia, 39% with visual hallucinations (VH), and 30% with cognitive fluctuations (CF). Group N had significantly more CF and co-occurring parkinsonism and dementia. Dopaminergic drugs were associated with the presence of VH. Although selection factors may have contributed to investigator differences, parkinsonism and co-occurrence with dementia appear to be the most consistent diagnostic criteria for DLB.

Schweitzer, I. (2001). "Does risperidone have a place in the treatment of nonschizophrenic patients?" Int Clin Psychopharmacol 16(1): 1-19.
There is a now a substantial body of evidence that suggests the new antipsychotic agent, risperidone, may be safe and effective for treating psychotic, affective or behavioural symptoms associated with various disorders other than schizophrenia, schizophreniform disorder or schizo-affective disorder. These conditions include bipolar disorder, obsessive-compulsive disorder, Tourette's syndrome, dementia, Lewy body disease, mental retardation, Parkinson's disease, idiopathic segmental dystonia and organic catatonia. Although much of the data is anecdotal or in the form of open studies, there is now emerging a small number of well controlled investigations supporting efficacy for mania, dementia, behavioural disturbance in mental retardation and conduct disorder. Conventional antipsychotics have long been used, either in a primary capacity or as an adjunct to treat these disorders; however, they have limited benefit, pose significant risks of extrapyramidal side-effects, and may cause the potentially life-threatening neuroleptic malignant syndrome. In contrast, risperidone at the recommended low doses may be efficacious and pose reduced risk of motor side-effects. This article reviews the evidence that risperidone may be an effective new treatment for disorders other than schizophrenia.

Sayre, L. M., M. A. Smith, et al. (2001). "Chemistry and biochemistry of oxidative stress in neurodegenerative disease." Curr Med Chem 8(7): 721-38.
The age-related neurodegenerative diseases exemplified by Alzheimer&hyp;s disease (AD), Lewy body diseases such as Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington&hyp;s disease are characterized by the deposition of abnormal forms of specific proteins in the brain. Although several factors appear to underlie the pathological depositions, the cause of neuronal death in each disease appears to be multifactorial. In this regard, evidence in each case for a role of oxidative stress is provided by the finding that the pathological deposits are immunoreactive to antibodies recognizing protein side-chains modified either directly by reactive oxygen or nitrogen species, or by products of lipid peroxidation or glycoxidation. Although the source(s) of increased oxidative damage are not entirely clear, the findings of increased localization of redox-active transition metals in the brain regions most affected is consistent with their contribution to oxidative stress. It is tempting to speculate that free radical oxygen chemistry plays a pathogenetic role in all these neurodegenerative conditions, though it is as yet undetermined what types of oxidative damage occur early in pathogenesis, and what types are secondary manifestations of dying neurons. Delineation of the profile of oxidative damage in each disease will provide clues to how the specific neuronal populations are differentially affected by the individual disease conditions.

Rideout, H. J., K. E. Larsen, et al. (2001). "Proteasomal inhibition leads to formation of ubiquitin/alpha-synuclein-immunoreactive inclusions in PC12 cells." J Neurochem 78(4): 899-908.
Proteasomal dysfunction has been recently implicated in the pathogenesis of several neurodegenerative diseases, including Parkinson's disease and diffuse Lewy body disease. We have developed an in vitro model of proteasomal dysfunction by applying pharmacological inhibitors of the proteasome, lactacystin or ZIE[O-tBu]-A-leucinal (PSI), to dopaminergic PC12 cells. Proteasomal inhibition caused a dose-dependent increase in death of both naive and neuronally differentiated PC12 cells, which could be prevented by caspase inhibition or CPT-cAMP. A percentage of the surviving cells contained discrete cytoplasmic ubiquitinated inclusions, some of which also contained synuclein-1, the rat homologue of human alpha-synuclein. However the total level of synuclein-1 was not altered by proteasomal inhibition. The ubiquitinated inclusions were present only within surviving cells, and their number was increased if cell death was prevented. We have thus replicated, in this model system, the two cardinal pathological features of Lewy body diseases, neuronal death and the formation of cytoplasmic ubiquitinated inclusions. Our findings suggest that inclusion body formation and cell death may be dissociated from one another.

Ransmayrl, G., K. Seppi, et al. (2001). "Striatal dopamine transporter function in dementia with Lewy bodies and Parkinson's disease." Eur J Nucl Med 28(10): 1523-8.
The aim of this study was to compare parkinsonian features and loss of striatal dopamine transporter (DAT) function in patients with dementia with Lewy bodies (DLB) and Parkinson's disease (PD), matched for age and disease duration. Twenty patients with DLB. 24 PD patients and 10 matched controls were examined with SPET using a dual-head camera and the dopamine-transporter ligand 123I-beta-CIT (148 MBq). Moreover, in a subgroup of patients (16 DLB and 20 PD patients), subscores of the Unified Parkinson's Disease Rating Scale (UPDRS)-motor examination (ME) subscale were obtained during "practical off", i.e. 12 h following withdrawal of antiparkinsonian therapy. Compared with controls, striatal/cerebellar (S/C) ratios of DAT binding were significantly reduced in both DLB and PD, deficits being more marked in DLB patients (controls 7.2 +/- 1.2, DLB 3.3 +/- 1, PD 4.2 +/- 1.4; means +/- SD). The side-to-side differences in the S/C ratios were lower in the DLB group and the controls than in PD patients (0.4 +/- 0.4. 0.2 +/- 0.2 and 0.6 +/- 0.3, respectively, P<0.05). The total UPDRS-ME scores during practical-off were significantly higher in the DLB than in the PD group (41.2 +/- 12.7 vs 26.6 +/- 15.3, P<0.01). The side-to-side differences of the summed UPDRS extremity subscores were smaller in the DLB than in the PD group (2.2 +/- 2.3 vs 7.4 +/- 3.9, P<0.0001). Our findings suggest that parkinsonism evolves largely symmetrically and progresses more rapidly with more severe loss of striatal dopamine transporter function in DLB compared to PD. Whether these findings are helpful in the differential diagnosis of DLB and PD needs to be examined in further studies.

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.

Masson, C. (2001). "[Parkinson's disease]." Presse Med 30(8): 386-8.

Masliah, E., E. Rockenstein, et al. (2001). "beta-amyloid peptides enhance alpha-synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer's disease and Parkinson's disease." Proc Natl Acad Sci U S A 98(21): 12245-50.
Alzheimer's disease and Parkinson's disease are associated with the cerebral accumulation of beta-amyloid and alpha-synuclein, respectively. Some patients have clinical and pathological features of both diseases, raising the possibility of overlapping pathogenetic pathways. We generated transgenic (tg) mice with neuronal expression of human beta-amyloid peptides, alpha-synuclein, or both. The functional and morphological alterations in doubly tg mice resembled the Lewy-body variant of Alzheimer's disease. These mice had severe deficits in learning and memory, developed motor deficits before alpha-synuclein singly tg mice, and showed prominent age-dependent degeneration of cholinergic neurons and presynaptic terminals. They also had more alpha-synuclein-immunoreactive neuronal inclusions than alpha-synuclein singly tg mice. Ultrastructurally, some of these inclusions were fibrillar in doubly tg mice, whereas all inclusions were amorphous in alpha-synuclein singly tg mice. beta-Amyloid peptides promoted aggregation of alpha-synuclein in a cell-free system and intraneuronal accumulation of alpha-synuclein in cell culture. beta-Amyloid peptides may contribute to the development of Lewy-body diseases by promoting the aggregation of alpha-synuclein and exacerbating alpha-synuclein-dependent neuronal pathologies. Therefore, treatments that block the production or accumulation of beta-amyloid peptides could benefit a broader spectrum of disorders than previously anticipated.

Masliah, E., M. Alford, et al. (2001). "Cholinergic deficits in the brains of patients with parkinsonism-dementia complex of Guam." Neuroreport 12(18): 3901-3.
Patients with parkinsonism-dementia complex (PDC) of Guam showed moderate loss of choline acetyl transferase activity in the midfrontal and inferior parietal cortex, and severe loss in the superior temporal cortex. This deficit was similar to that seen in Alzheimer's disease and less severe than Lewy body disease. Thus, cholinergic deficits in the neocortex might contribute to some of the cognitive alterations in PDC of Guam.

Mark, M. H. (2001). "Lumping and splitting the Parkinson Plus syndromes: dementia with Lewy bodies, multiple system atrophy, progressive supranuclear palsy, and cortical-basal ganglionic degeneration." Neurol Clin 19(3): 607-27, vi.
The atypical parkinsonian or Parkinson Plus syndromes are often difficult to differentiate from Parkinson's disease and each other. In this article, the clinicopathological characteristics of dementia with Lewy bodies, multiple system atrophy, progressive supranuclear palsy, and cortical-basal ganglionic degeneration are discussed. These disorders, although clinically distinct, may have more similarities than previously thought, based on modern immunocytochemical techniques and new genetic findings. These intriguing interconnections at a basic molecular level have provided the scientific rationale for lumping these diseases into two groups, the synucleinopathies and the tauopathies.

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.

Leech, R. W., R. A. Brumback, et al. (2001). "Dementia: the University of Oklahoma autopsy experience." J Okla State Med Assoc 94(11): 507-11.
The brain from 98 consecutive patients with the clinical diagnosis of dementia were examined at autopsy in a standardized fashion. Alzheimer's Disease was present in 79 of the cases, 76%, but represented the only diagnosis in 41%. Thus, almost 60% had another associated pathologic disorder. Cerebral amyloid angiopathy (CAA) represented the single largest subset, present in 25 cases. 40% were accompanied by either 1) small, microscopic infarcts or cortical scars, or 2) small collections of macrophages containing hemosiderin or small hemorrhages. CAA occurred with both atherosclerotic cortical infarcts and arteriolosclerotic subcortical pallor or lacunar infarcts. Alzheimer's Disease occurred with Diffuse Lewy Body (DLB) Disease in 13 cases. DLB Disease did not occur as a distinct entity, and thus may represent the second largest subset of Alzheimer's Disease. Both Alzheimer's Disease and DLB Disease accounted for dementia in Parkinson's Disease. Almost 25% of all cases had a disorder other than Alzheimer's Disease.

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.

Kosel, S., E. M. Grasbon-Frodl, et al. (2001). "Inter-laboratory comparison of DNA preservation in archival paraffin-embedded human brain tissue from participating centres on four continents." Neurogenetics 3(3): 163-70.
DNA extracted from formalin-fixed and paraffin-embedded brain tissue is known to contain as yet ill-characterized inhibitors of the PCR process. As part of a project that aims to clarify the role of mitochondrial DNA sequence variation in human neurodegenerative diseases using DNA from various ethnic backgrounds, we have investigated factors that influence the preservation of archival DNA and its suitability for PCR. In this study, neuropathological tissue samples were analysed that had been routinely processed in 18 international centres on four continents. Following DNA extraction, PCR amplification of mitochondrial and nuclear DNA sequences was performed with and without additional purification of the template DNA. In addition, the DNA used for PCR was analysed by HPLC. Phosphate-buffered formalin proved to be a superior fixative compared with unbuffered aldehyde: DNA extraction resulted in greater yields, the molecular weight of the isolated DNA was higher and PCR was more successful. PCR inhibitors were identified as (1) high concentrations of small (<300 bp) DNA fragments that competitively compete with template DNA and (2) contaminants of the DNA template solution including denatured protein that cannot be completely removed by phenolic extraction. HPLC analysis did not reveal significant qualitative differences between DNA isolated from fresh-frozen tissue samples and DNA recovered from formalin-fixed, paraffin-embedded brain tissue. The fact that DNA could be amplified from the majority of tissue specimens in this study suggests that rare diseases and diseases where ethnic background plays an important role can be sampled for genetic polymorphism analysis on a global scale using archival neuropathological collections.

Korczyn, A. D. (2001). "Dementia in Parkinson's disease." J Neurol 248 Suppl 3: III1-4.
Advanced Parkinson's disease (PD) is frequently associated with dementia. The pathogenesis of this dementia is complex, related to deficiency of several biogenic amines and cortical Lewy body deposition, as well as co-existent age-related brain changes, both of the Alzheimer's type and vascular. However, degeneration of the cholinergic neurons in the nucleus basalis of Meynert may have an important contribution to the cognitive decline. The dementia of PD has a grave effect on the quality of life of the patients and their caregivers, as well as negative effect on their survival. The treatment of dementia associated with PD therefore must encompass several agents. We have treated several patients with the cholinesterase inhibitor rivastigmine which produced gratifying results. Future studies should define the exact role of this agent in the treatment of the dementia of PD.

Kofler, M., J. Muller, et al. (2001). "The auditory startle reaction in parkinsonian disorders." Mov Disord 16(1): 62-71.
The auditory startle reaction to an unexpected loud stimulus is regarded as a brainstem reflex originating in the nucleus reticularis pontis caudalis and being distributed up the brainstem and down the spinal cord along slowly conducting pathways. Auditory startle responses (ASR) have been reported absent or reduced in progressive supranuclear palsy (PSP), and delayed in Parkinson's disease (PD), but normal in multiple-system atrophy (MSA). For the first time we studied ASR in patients fulfilling the clinical criteria of dementia with Lewy bodies (DLB) (n = 8), a neurodegenerative disorder characterized by cortical and subcortical depositions of Lewy bodies resulting in parkinsonism and progressive cognitive decline. For comparison, we also investigated patients with PD (n = 10), MSA (n = 7), PSP (n = 10), and age-matched healthy controls (n = 10). ASR were elicited by binaural high-intensity auditory stimuli. Surface electromyographic activity was simultaneously recorded from facial, upper, and lower extremity muscles. For each muscle, we assessed response probability and measured latency, amplitude, duration, and habituation rate. Patients with DLB had fewer and abnormally delayed ASR of low amplitude and short duration in extremity muscles compared to healthy controls. Furthermore, we confirm and extend previous findings of abnormal ASR in PSP and PD, and also demonstrate exaggerated ASR in extremity muscles of MSA patients. The different patterns of ASR abnormalities may reflect distinct types of brainstem dysfunction in DLB.

Kanazawa, A., S. Ikebe, et al. (2001). "[An 84-year-old woman with progressive mental deterioration and abnormal behavior]." No To Shinkei 53(2): 199-209.
We report an 84-year-old woman with progressive mental deterioration. She was well until January 1994, when she was 80 years of the age. At that time she developed a delusional ideation, in that she stated that she would be killed by her fellow members of the society for elderly, in which she was belonging. At times, she closed the shutter of her house saying that a stranger was wandering outside of her house. In 1995, she could not identify the face of her son's wife. When she went out for shopping, she lost her way to the home. She prowled about in and out of her home. In 1996, she had to be admitted to a nursing home, where quarrelled with other patients and behaved violently. She was admitted to the neurology service of Hatsuishi Hospital on November 20th, 1997. Family history revealed that her mother was said to be demented. On admission, she was alert and behaved in a good manner. She was disoriented to the time and unable to do serial 7. Her memory was very poor. She did not show aphasia or apraxia. Cranial nerves appeared to be intact. She showed no weakness or muscle atrophy. Gait was normal for her age. Plastic rigidity was noted in four limbs more on the right side. No ataxia was noted. Deep tendon reflexes were exaggerated, however, no Babinski sign was noted. Sensory examination was intact. Her hospital course was characterized by the development of progressive gait disturbance, violent behaviour, and prowling around. On November 30th, 1998, she fell down and suffered from a fracture in the neck of her femur. Although replacement of the femur head was performed, she became unable to walk after this episode. Her mental functions deteriorated further. She developed pneumonia and expired on February 2, 1999. She was discussed in a neurological CPC and the chief discussant arrived at a conclusion that the patient probably had diffuse Lewy body disease, because of the combination of dementia and parkinsonism. Other possibilities discussed in the CPC included Pick's disease, frontotemporal dementia and parkinsonism, and Alzheimer's disease. Post-mortem examination revealed moderate atrophy in the frontal and temporal cortices. Microscopic examination showed atrophy and gliosis in the hippocampus. Many diffuse plaque and neuritic plaques were seen in the frontal cortex by methenamine silver staining. Neurofibrillary tangles were also found. The Meynert nucleus was preserved. The putamen and the substantia nigra were also intact. Pathologic diagnosis was consistent with Alzheimer's disease.

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.

Iwata, A., S. Miura, et al. (2001). "alpha-Synuclein forms a complex with transcription factor Elk-1." J Neurochem 77(1): 239-52.
alpha-Synuclein has been identified as a component of Lewy bodies in Parkinson's disease and diffuse Lewy body disease, and glial cytoplasmic inclusions (GCIs) in multiple system atrophy (MSA). To explore the role of alpha-synuclein in the pathogenesis, we searched for molecules interacting with alpha-synuclein and discovered that GCIs are stained by anti-Elk-1 antibody. To seek the role of Elk-1 in synucleinopathies, we cotransfected alpha-synuclein and Elk-1 to cultured cells, and found small granular structure complexes where the two molecules colocalized. Moreover, alpha-synuclein and Elk-1 were co-immunoprecipitated from the cell lysates. For formation of the complex, the presence of both ETS and B-box domains of Elk-1 was required. Although there was no evidence of direct binding between alpha-synuclein and Elk-1, we discovered that alpha-synuclein and Elk-1 both bind to ERK-2, a MAP kinase. The effect of alpha-synuclein on the MAP kinase pathway was assessed using the Pathdetect system, which showed prominent attenuation of Elk-1 phosphorylation with alpha-synuclein, and especially A53T mutant. Our results suggest that alpha-synuclein reacts with the MAP kinase pathway, which might cause dysfunction of neurons and oligodendrocytes and lead to neurodegeneration in Parkinson's disease and MSA.

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.

Hishikawa, N., Y. Hashizume, et al. (2001). "Widespread occurrence of argyrophilic glial inclusions in Parkinson's disease." Neuropathol Appl Neurobiol 27(5): 362-72.
Argyrophilic glial inclusions, which are immunohistochemically positive for alpha-synuclein but negative for tau protein, were examined in the brain of Parkinson's disease (PD) patients. Autopsied brains of 10 individuals who died from PD, of two incidental Lewy body disease cases and of five age-matched individuals whose deaths were caused by non-neurological diseases were studied, histopathologically, by Gallyas-Braak staining and, immunohistochemically, with anti-alpha-synuclein antibody, anti-ubiquitin, and anti-tyrosine hydroxylase. All postmortem PD brains showed a significant number of argyrophilic glial inclusions, but no glial inclusions were found in control brains. The inclusions were found not only in the regions showing neuronal loss and gliosis, such as the substantia nigra, locus ceruleus and dorsal vagal nucleus, but also in regions without neuronal loss and gliosis, such as the cerebral cortex, cerebral white matter, striatum, globus pallidus, thalamus, cerebellum and spinal cord. The distribution and density of glial inclusions in PD brains varied from case to case but, in the cerebral cortex, the number of glial inclusions were fairly well correlated with the number of Lewy bodies. The distribution pattern of glial inclusions also showed a striking resemblance to that of catecholaminergic neurones and fibres. The abnormal accumulation of alpha-synuclein in glial cells was more widespread than neurone loss, and appears to be an important pathological feature of PD.

Henderson, J. M., W. P. Gai, et al. (2001). "Parkinson's disease with late Pick's dementia." Mov Disord 16(2): 311-9.
We report a case in which typical clinical features of idiopathic Parkinson's disease existed for seven years prior to the development of significant behavioral and cognitive changes and severe dementia. The patient presented with right-sided resting tremor, bradykinesia, and rigidity, which were highly responsive to levodopa. Serial neuropsychological evaluation revealed no evidence of dementia until late in the disease. The patient deteriorated rapidly eight years into the disease, requiring full care. She died 16 years after symptom onset and post-mortem neuropathological analysis revealed Lewy body Parkinson's disease and Pick's disease. To our knowledge, this is the first non-familial case with this combination of clinical history and pathologically confirmed disease to be reported in the literature. The absence of a family history of any neurological disease sets this case apart from the recently described genetic cases of frontotemporal dementia with Parkinsonism linked to chromosome 17. In addition, the relatively late onset of dementia in frontotemporal dementia is atypical. While there is considerable debate regarding the cause of dementia in idiopathic Parkinson's disease, our case illustrates that Pick's disease is one such cause.

Harding, A. J. and G. M. Halliday (2001). "Cortical Lewy body pathology in the diagnosis of dementia." Acta Neuropathol (Berl) 102(4): 355-63.
Dementia with Lewy bodies (DLB) and Parkinson's disease (PD) are distinguishable clinically but often not neuropathologically. This study aims to test whether the distribution of cortical Lewy bodies differs in these clinicopathological groups and to develop diagnostic protocols for their differentiation. Brains were obtained at autopsy from cases recruited from prospective clinical studies of dementia or movement disorders. All cases with significant pathologies other than Lewy bodies or plaques were excluded. Cases were categorised into either PD without dementia, DLB (dementia first or within 2 years of disease onset), or PD with a later onset of dementia (PDD). The distribution and density of Lewy bodies and Lewy neurites was determined using antibodies to ubiquitin and alpha-synuclein. Cortical Lewy body densities could not separate cases of DLB from those with PDD. However, semiquantitative thresholds in the parahippocampus could separate demented from non-demented cases with high sensitivity and specificity. Interactions between multiple pathologies were determined using factor analysis. Although many cases had CA2 Lewy neurites, this was not associated with severity or duration of either dementia or parkinsonism. Most DLB cases had significant plaque pathology, and severity and duration of dementia was related to both increasing parahippocampal Lewy body densities and neuritic plaque grade. Weighted kappa statistics revealed that the combination of these pathologies indicated a more severe dementia. These results suggest that dual pathologies cause DLB, and high densities of parahippocampal Lewy bodies indicate dementia regardless of additional pathologies.

Goedert, M. (2001). "Parkinson's disease and other alpha-synucleinopathies." Clin Chem Lab Med 39(4): 308-12.
Parkinson's disease is the most common movement disorder and the second most common neurodegenerative disease. Neuropathologically, it is characterized by the degeneration of nerve cells that develop filamentous inclusions in the form of Lewy bodies and Lewy neurites. Recent work has shown that rare, familial forms of Parkinson's disease are caused by missense mutations in the alpha-synuclein gene and that the filamentous lesions of Parkinson's disease are made of alpha-synuclein. The same is true of the Lewy body pathology that is associated with other neurodegenerative diseases, such as dementia with Lewy bodies. The filamentous inclusions of multiple system atrophy have also been found to be made of alpha-synuclein, thus providing an unexpected molecular link with Lewy body diseases. Recombinant alpha-synuclein assembles into filaments with similar morphologies to those found in the human diseases and with a cross-beta diffraction pattern characteristic of amyloid. The related proteins beta-synuclein and gamma-synuclein are poor at assembling into filaments. They are not present in the pathological filamentous lesions and have not been found to be linked to genetic disease. The new work has established the alpha-synucleinopathies as a major class of neurodegenerative disease.

Goedert, M. (2001). "Alpha-synuclein and neurodegenerative diseases." Nat Rev Neurosci 2(7): 492-501.

Galvin, J. E., V. M. Lee, et al. (2001). "Synucleinopathies: clinical and pathological implications." Arch Neurol 58(2): 186-90.
The synucleinopathies are a diverse group of neurodegenerative disorders that share a common pathologic lesion composed of aggregates of insoluble alpha-synuclein protein in selectively vulnerable populations of neurons and glia. Growing evidence links the formation of abnormal filamentous aggregates to the onset and progression of clinical symptoms and the degeneration of affected brain regions in neurodegenerative disorders. These disorders may share an enigmatic symmetry, i.e., missense mutations in the gene encoding for the disease protein (alpha-synuclein) cause familial variants of Parkinson disease as well as its hallmark brain lesions, but the same brain lesions also form from the corresponding wild-type brain protein in the more common sporadic varieties of Parkinson disease. It is likely that clarification of this enigmatic symmetry in 1 form of synucleinopathy will have a profound impact on understanding the mechanisms underlying all these disorders. Furthermore, these efforts will likely lead to novel diagnostic and therapeutic strategies in regard to the synucleinopathies.

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.

Demakis, G. J., T. P. Sawyer, et al. (2001). "Incidental recall on WAIS-R digit symbol discriminates Alzheimer's and Parkinson's diseases." J Clin Psychol 57(3): 387-94.
The purpose of this study was to examine how Alzheimer's (n = 37) and Parkinson's (n = 21) patients perform on the incidental recall adaptation to the Digit Symbol of the Wechsler Adult Intelligence Scale-Revised (WAIS-R) and how such performance is related to established cognitive efficiency and memory measures. This adaptation requires the examinee to complete the entire subtest and then, without warning, to immediately recall the symbols associated with each number. Groups did not differ significantly on standard Digit Symbol administration (90 seconds), but on recall Parkinson's patients recalled significantly more symbols and symbol-number pairs than Alzheimer's patients. Using only the number of symbols recalled, discriminate function analysis correctly classified 76% of these patients. Correlations between age-corrected scaled score, symbols incidentally recalled, and established measures of cognitive efficiency and memory provided evidence of convergent and divergent validity. Age-corrected scaled scores were more consistently and strongly related to cognitive efficiency, whereas symbols recalled were more consistently and strongly related to memory measures. These findings suggest that the Digit Symbol recall adaptation is actually assessing memory and that it can be another useful way to detect memory impairment.

Chan, D. K. (2001). "Parkinson disease and its differentials. Diagnoses made easy." Aust Fam Physician 30(11): 1053-6.
BACKGROUND: Parkinson disease is a common neurological disorder that is both underdiagnosed and inaccurately diagnosed. There is no reliable biological marker or test that can differentiate between causes of parkinsonism. Even for experienced clinicians, the clinical diagnostic accuracy compared to post mortem findings is about 80%. OBJECTIVE: To discuss the clinical features that differentiate Parkinson disease from other important causes of parkinsonism. DISCUSSION: Although Parkinson disease is a common cause of parkinsonism, other candidates such as drug reactions, benign essential tremor, vascular disease and Lewy body dementia need to be differentiated. Incorrect diagnosis can result in complications related particularly to the use of levodopa and antipsychotic agents. Diagnostic accuracy is important to ensure appropriate management, to avoid complications and to assist patients to have realistic expectations and prognostic information about their condition.

Campbell, B. C., C. A. McLean, et al. (2001). "The solubility of alpha-synuclein in multiple system atrophy differs from that of dementia with Lewy bodies and Parkinson's disease." J Neurochem 76(1): 87-96.
Intracellular inclusions containing alpha-synuclein (alpha SN) are pathognomonic features of several neurodegenerative disorders. Inclusions occur in oligodendrocytes in multiple system atrophy (MSA) and in neurons in dementia with Lewy bodies (DLB) and Parkinson's disease (PD). In order to identify disease-associated changes of alpha SN, this study compared the levels, solubility and molecular weight species of alpha SN in brain homogenates from MSA, DLB, PD and normal aged controls. In DLB and PD, substantial amounts of detergent-soluble and detergent-insoluble alpha SN were detected compared with controls in grey matter homogenate. Compared with controls, MSA cases had significantly higher levels of alpha SN in the detergent-soluble fraction of brain samples from pons and white matter but detergent-insoluble alpha SN was not detected. There was an inverse correlation between buffered saline-soluble and detergent-soluble levels of alpha SN in individual MSA cases suggesting a transition towards insolubility in disease. The differences in solubility of alpha SN between grey and white matter in disease may result from different processing of alpha SN in neurons compared with oligodendrocytes. Highly insoluble alpha SN is not involved in the pathogenesis of MSA. It is therefore possible that buffered saline-soluble or detergent-soluble forms of alpha SN are involved in the pathogenesis of other alpha SN-related diseases.

Bogdanovic, N. (2001). "Intraneuronal Lewy body inclusions in Parkinson and diffuse Lewy body disease." J Cell Mol Med 5(3): 318-9.

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.

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.

Arahata, H., Y. Ohyagi, et al. (2001). "[A patient with probable dementia with Lewy bodies, who showed improvement of dementia and parkinsonism by the administratim of donepezil]." Rinsho Shinkeigaku 41(7): 402-6.
We present a 73-year-old man with probable dementia with Lewy bodies(DLB). At 65 years of age, he gradually developed bradykinesia, gait disturbance and mild amnesia. At 71 years of age, he noted resting tremor in bilateral hands, and amnesia and disorientation were exacerbated. He was diagnosed as having parkinsonism and took L-dopa/carbidopa at 100 mg/day. Since he developed hallucination and abnormal behavior 2 days after the initiation of the drug, he stopped taking L-dopa and was admitted to our hospital. A neurological examination on admission revealed moderate amnesia, disorientation, finger agnosia, constitutional apraxia, mask-like face, cogwheel rigidity, resting tremor in bilateral hands, and bradykinesia. Brain MRI showed mild brain atrophy, and single photon emission computerized tomography(SPECT) showed diffuse moderate hypoperfusion in bilateral cerebral cortex. As he had fluctuating cognitive dysfunction and parkinsonism, he was diagnosed to have probable DLB. As his dementia was exacerbated by trihexyphenidyl, an anti-cholinergic agent, at 2 mg/day, we treated him with donepezil, an anti-choline esterase agent, at 3-5 mg/day. His parkinsonism, including rigidity and bradykinesia, was markedly improved his dementia, consisting of amnesia and disorientation. Electroencephalography (EEG) improved in the organization of the dominant rhythm. The SPECT improved in the blood perfusion of the bilateral frontal lobe as well as cognitive function and parkinsonism were maintained by donepezil for 6 months after discharge. A therapeutic efficacy of donepezil for DLB has recently been reported. It is notable that donepezil was beneficial not only for cognitive dysfunction but also for parkinsonism in the present case with probable DLB.

Aarsland, D., C. Ballard, et al. (2001). "A comparative study of psychiatric symptoms in dementia with Lewy bodies and Parkinson's disease with and without dementia." Int J Geriatr Psychiatry 16(5): 528-36.
OBJECTIVES: To compare the frequency and clinical correlates of neuropsychiatric symptoms in patients with Parkinson's disease (PD) with and without dementia and in those with dementia with Lewy bodies (DLB). METHODS: Neuropsychiatric symptoms during the month prior to assessment were assessed in clinically diagnosed PD patients with dementia (PDD; n = 48) and without dementia (PDND; n = 83) and in 98 DLB patients (33% autopsy confirmed) using standardized instruments. RESULTS: Delusions and hallucinations were significantly more common in DLB (57% and 76%) than PDD (29% and 54%) and PDND (7% and 14%) patients (p < 0.001). In all groups, auditory and visual hallucinations and paranoid and phantom boarder delusions were the most common psychotic symptoms. Frequency of major depression and less than major depression did not differ significantly between the three groups. Clinical correlates of hallucinations in PD were dementia (odds ratio (OR) = 3.9; 95% confidence interval (CI) 1.5-10.4) and Hoehn-Yahr stage 3 or more (OR 3.4; 95% CI 1.0-12.0), whereas no significant clinical correlates of hallucinations were found in DLB patients. CONCLUSIONS: Delusions and hallucinations occur with increasing frequency in PDND, PDD and DLB patients, but the presentation of these symptoms is similar. These findings support the hypothesis that psychiatric symptoms are associated with cortical Lewy bodies or cholinergic deficits in the two disorders.

Aarsland, D., C. Ballard, et al. (2001). "Comparison of extrapyramidal signs in dementia with Lewy bodies and Parkinson's disease." J Neuropsychiatry Clin Neurosci 13(3): 374-9.
Extrapyramidal signs (EPS) were compared in 98 dementia with Lewy bodies (DLB) and 130 medication-responsive Parkinson's disease (PD) patients. DLB patients were older at assessment and at disease onset, were cognitively more impaired, and had a shorter duration of disease than PD patients. Sixty-seven DLB patients (68%) showed EPS. The 58 DLB patients with complete data had more severe action tremor, body bradykinesia, difficulty arising from a chair, and facial expression, gait, and rigidity symptoms than PD patients (all P<0.001). Abnormal posture and tremor at rest did not differ. Severity of EPS correlated with age, duration of disease, and cognitive impairment in PD patients but not in DLB patients. Studies of the clinical significance and management of EPS in DLB patients are needed.

(2001). "[Parkinson disease: diagnostic and therapeutic criteria]." Presse Med 30(8): 379-85.

Yamamura, Y., N. Hattori, et al. (2000). "Autosomal recessive early-onset parkinsonism with diurnal fluctuation: clinicopathologic characteristics and molecular genetic identification." Brain Dev 22 Suppl 1: S87-91.
Autosomal recessive early-onset parkinsonism with diurnal fluctuation (AR-EPDF, syn. autosomal recessive juvenile parkinsonism, PARK2) is one of the hereditary parkinsonian syndromes. We examined subjects consisting of 43 patients from 22 families with AR-EPDF. The clinical features were relatively homogeneous, including the average age at onset of 26.1 years, beginning with dystonic gait disturbance, diurnal fluctuation of the symptoms (sleep benefit) unrelated to medication, dystonia (mainly foot dystonia), hyperactive tendon reflex, remarkable effect of levodopa and other antiparkinsonism drugs, susceptibility to dopa-induced dyskinesia, mild autonomic symptoms, absence of dementia, and slow progression of disease. Some patients had hysteric character or psychic symptoms provoked by medication. Pathologic study revealed neuronal loss in the substantia nigra pars compacta and locus coeruleus without Lewy body formation. We performed extensive molecular genetic analysis of the parkin gene in 16 families to identify a total of six different deletional mutations. In AR-EPDF loss of newly discovered 'Parkin' protein is responsible for selective degeneration of the pigmented neurons in the substantia nigra and locus coeruleus. Compared with autosomal dominant Parkinson's disease, AR-EPDF appears to be more prevalent and present in several ethnic groups.

Woulfe, J., H. Hoogendoorn, et al. (2000). "Monoclonal antibodies against Epstein-Barr virus cross-react with alpha-synuclein in human brain." Neurology 55(9): 1398-401.
Using antibodies generated against the latent membrane protein 1 of Epstein-Barr virus, intense immunoreactivity of Lewy bodies (in PD and dementia with Lewy bodies) and glial cytoplasmic inclusions (in multiple system atrophy) was demonstrated. ELISA and Western blotting techniques confirmed that this immunolabeling was due to cross-reactivity of the antiviral antibody with alpha-synuclein, a neuronal protein implicated in the pathogenesis of PD. This example of cross-reactivity between Epstein-Barr virus and alpha-synuclein may bear implications for further elucidating infectious or autoimmune mechanisms in PD.

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.

Vazquez-Alen, P., Y. Perez-Gilabert, et al. (2000). "[A study made on a data base of 2,471 patients with Parkinson disease and disorders of movement in Health District 1 of the autonomous region of Madrid. Observed demographic changes over 8 year-period]." Rev Neurol 30(7): 635-40.
INTRODUCTION: A specialised unit may influence favourably primary levels of health system by alerting physicians and patients on the existence of those pathologies most commonly seen. OBJECTIVES: To determine demographic changes and referral patterns observed in a hospital-based monographic outpatient clinic on Parkinson's disease and movement disorders along an eight-year period (1991-1998). PATIENTS AND METHODS: Database analysis of 2,471 patients attending a specialised unit covering an urban and rural population of 630,000 people in South-East Madrid city and county. RESULTS: We observed a slight, albeit non-significant reduction in the incidence of secondary parkinsonisms (40% of all parkinsonisms observed). This occurred despite a drastic reduction in drug-induced parkinsonisms, particularly those caused by cinnarizine/flunarizine and flupentixol. The reduction was balanced by a relative increase in neurodegenerative parkinsonisms, particularly Lewy body dementia. There was a sustained decrease in the time elapsed between onset of symptoms and identification of parkinsonisms as well as identification of its primary or symptomatic nature. The incidence of tardive dystonia (46.7%) of all symptomatic dystonias) remained unchanged. Essential tremor referrals markedly increased along the study period. CONCLUSIONS: Demographics features of patients attending a Parkinson's disease and movement disorder unit are submitted to changes over time. These probably reflect better awareness about these conditions by patients and physicians, ready access to hospital-based specialised units, and a greater demand for specialised care by the aged.

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.

Tatlidil, R., P. New, et al. (2000). "FDG positron emission tomography in diffuse Lewy body disease: a case report." Clin Nucl Med 25(12): 1004-6.
Lewy body disease is a clinicopathologic condition that includes Parkinson's disease at one end and diffuse Lewy body disease at the other hand. The latter is often associated with progressive cognitive deterioration, levodopa-responsive parkinsonism, fluctuations of cognitive and motor functions, and visual and auditory hallucinations. In addition, it can be a familial disease. Clinical and positron emission tomographic findings are described in a patient with atypical dementia and movement disorder and a pathologically proved diagnosis of diffuse Lewy body disease.

Stefanova, N., K. Seppi, et al. (2000). "Depression in alpha-synucleinopathies: prevalence, pathophysiology and treatment." J Neural Transm Suppl(60): 335-43.
Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA) are increasingly recognized as alpha-synucleinopathies, i.e. neurodegenerative disorders that share a common subcellular pathology characterized by alpha-synuclein abnormal aggregation. In the present review we focus on depression in alpha-synucleinopathies, discussing epidemiological, pathophysiological and treatment aspects of this frequently disabling clinical feature which may occur in PD, DLB and MSA alike.

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.

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.

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.

Piao, Y. S., K. Wakabayashi, et al. (2000). "Aggregation of alpha-synuclein/NACP in the neuronal and glial cells in diffuse Lewy body disease: a survey of six patients." Clin Neuropathol 19(4): 163-9.
BACKGROUND : alpha-Synuclein is now known to be a major component of Lewy bodies (LBs) in Parkinson's disease (PD) and diffuse Lewy body disease (DLBD). Recently, cytoplasmic aggregation of alpha-synuclein has also been reported to occur in glial cells in these diseases. METHODS: We have conducted an immunohistochemical survey to clarify in detail the distribution of alpha-synuclein aggregates in the central nervous system of patients with DLBD. The cerebrum, brainstem, cerebellum and spinal cord of six patients with DLBD were examined immunohistochemically using anti-alpha-synuclein antibodies. RESULTS: In all patients, alpha-synuclein-immunoreactive cytoplasmic inclusions, including those with profiles of typical LBs, were visualized in neurons of the cerebral neocortex, hippocampus, amygdaloid nucleus, hypothalamus, brainstem pigmented nuclei and reticular formation. In some of these patients, similar spherical cytoplasmic inclusions were also detected in neurons of the olfactory bulb, basal ganglia, thalamus, the subthalamic, pontine, inferior olivary and cerebellar dentate nuclei, and in the spinal gray matter. Moreover, alpha-synuclein-immunoreactive cytoplasmic inclusions, which appeared circular or coil-like in shape, were found in glial cells. In four patients with longstanding DLBD, these cytoplasmic inclusions were distributed widely in brain areas, including brainstem, basal ganglia, and cerebral and cerebellar white matter. CONCLUSION: The widespread occurrence of alpha-synuclein aggregates in both neuronal and glial cells is a pathological feature in patients suffering from DLBD.

Perry, E., C. Martin-Ruiz, et al. (2000). "Nicotinic receptor subtypes in human brain ageing, Alzheimer and Lewy body diseases." Eur J Pharmacol 393(1-3): 215-22.
Human brain ageing is associated with reductions in a variety of nicotinic receptors subtypes, whereas changes in age-related disorders including Alzheimer's disease or Parkinson's disease are more selective. In Alzheimer's disease, in the cortex there is a selective loss of the alpha4 (but not alpha3 or 7) subunit immunoreactivity and of nicotine or epibatidine binding but not alpha-bungarotoxin binding. Epibatidine binding is inversely correlated with clinical dementia ratings and with the level of Abeta1-42, but not related to plaque or tangle densities. In contrast, alpha-bungarotoxin binding is positively correlated with plaque densities in the entorhinal cortex. In human temporal cortex loss of acetylcholinesterase catalytic activity is positively correlated with decreased epibatidine binding and in a transgenic mouse model over expressing acetylcholinesterase, epibatidine binding is elevated. In Parkinson's disease, loss of striatal nicotine binding appears to occur early but is not associated with a loss of alpha4 subunit immunoreactivity. Tobacco use in normal elderly individuals is associated with increased alpha4 immunoreactivity in the cortex and lower densities of amyloid-beta plaques, and with greater numbers of dopaminergic neurons in the substantia nigra pars compacta. These findings indicate an early involvement of the alpha4 subunit in beta-amyloidosis but not in nigro-striatal dopaminergic degeneration.

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. Neuropathology data on the olfactory system are much more sparse in Parkinson's disease. Lewy bodies suggestive of Parkinson's disease have been observed in the olfactory bulb and pathways, but, unlike Alzheimer's disease, the olfactory disorders appear to be stable, changing little over time, as opposed to the evolution of neurological symptoms and cognition impairment. Clinicians should be aware that olfactory disorders are an integral part of Alzheimer's disease and Parkinson's disease. Screening for sensorial impairment however is a secondary objective in the context of these neurodegenerative diseases.

Mukaetova-Ladinska, E. B., J. Hurt, et al. (2000). "Alpha-synuclein inclusions in Alzheimer and Lewy body diseases." J Neuropathol Exp Neurol 59(5): 408-17.
Alpha-synuclein has assumed particular neuropathological interest in the light both of its identification as a non-beta-amyloid plaque constituent in Alzheimer disease (AD), and the recent association between dominant inheritance of Parkinson disease (PD) and 2 missense mutations at positions 30 and 53 of the synuclein protein. We report a systematic study of alpha-synuclein, tau, and ubiquitin immunoreactivity in representative neurodegenerative disorders of late life. The alpha-synuclein association with Lewy bodies is variable, peripheral, and is not stable with respect to proteases or acid treatment, whereas there is no association with Pick bodies. Stable patterns of immunoreactivity included neurites and a novel inclusion body. Although there is an overlap between the presence of Lewy bodies and stable alpha-synuclein immunoreactivity, this is seen only in the presence of concomitant neuropathological features of AD. The novel alpha-synuclein inclusion body identified in pyramidal cells of the medial temporal lobe in particular was found in AD and in the Lewy body variant of AD, and was associated neither with ubiquitin nor tau protein. The inclusion is therefore neither a Lewy body nor a PHF-core body, but may be confused with the Lewy body, particularly in the Lewy body variant of AD. Abnormal processing of alpha-synuclein leading to its deposition in the form of proteolytically stable deposits is a particular feature of the intermediate stages of AD.

Mori, E. (2000). "[Dementia with Lewy bodies]." Nippon Ronen Igakkai Zasshi 37(10): 772-6.
Dementia with Lewy bodies (DLB), the second most frequent cause of primary degenerative dementias following Alzheimer's disease, has been increasingly recognized since the proposal of the consensus name and clinical diagnostic criteria. Although DLB overlaps in clinical, pathological, and genetic features with Alzheimer's disease and Parkinson's disease, DLB should be understood as an entity with the essential feature of the presence of Lewy bodies in the brain stem and cerebral cortex. From the clinical point of view, DLB is characterized by the presence of progressive dementia without severe memory disorders at the early stage, with significant cognitive fluctuations, well-formed recurrent visual hallucinations, and spontaneous Parkinsonism. This article reviews recent clinical and research findings, including our own, to facilitate clinical recognition of DLB. In addition to the supportive features described in the consortium clinical diagnostic criteria for DLB such as falls and great sensitivity to neuroleptic drugs, our studies found other frequent disorders including disproportionately severe visuoconstructive and visuoperceptual disturbances, transitory alterations in consciousness with reduplication phenomena, misidentification delusions, and non-aphasic misnamings. Neuroimaging features include relatively preserved hippocampal volume on MRI and occipital involvement on metabolic and blood flow imagings. The correct diagnosis of DLB is important to administer adequate treatment, to avoid adverse effects with neuroleptic drugs, and to establish precise prognosis. The present summary of the clinical features is hopefully helpful for clinical diagnosis of DLB. From a therapeutic point of view, cholinesterase inhibitors seemingly show some efficacy in the treatment of cognitive alterations. Further research would result in advances in diagnostic methods and therapeutic approaches in the near future.

Mizutani, T. (2000). "[Diagnostic criteria of diffuse Lewy body disease]." Nippon Rinsho 58(10): 2044-8.
DLBD is also called Dementia with Lewy bodies(DLB) which was proposed by the consortium on DLB international workshop(CDLB) in 1995. CDLB criteria of clinical diagnosis contain progressive cognitive decline as a mandatory feature, and fluctuating cognition, recurrent visual hallucinations and parkinsonism as 3 core features. Supportive features include repeated falls, syncope, transient loss of consciousness, neuroleptic sensitivity, and systematized delusions. CDLB pathologic criteria include the presence of Lewy bodies as the only essential feature, and associated features included Lewy-related neurites, senile plaques, neurofibrillary tangles, and regional neuronal loss in the areas vulnerable to Parkinson's disease. Lewy bodies are counted and scored from 0 to 2 in 5 designated cortical areas. Total Lewy body score of 7-10 indicates DLBD.

McLean, P. J., S. Ribich, et al. (2000). "Subcellular localization of alpha-synuclein in primary neuronal cultures: effect of missense mutations." J Neural Transm Suppl(58): 53-63.
Numerous recent observations have implicated alpha-synuclein in the pathogenesis of several neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, dementia with Lewy bodies and multiple-system atrophy. Two missense mutations in the gene for alpha-synuclein have been identified in some cases of familial Parkinson's disease and it is thought that these may disrupt the normal structure of the protein and thus promote aggregation into Lewy body filaments. Here, we examine the subcellular localization of alpha-synuclein in primary cortical neurons maintained in a monolayer culture. The protein has widespread expression throughout neurons, including the nucleus, and has a discete localization in the neurites of more mature neurons, reminiscent of synaptic specializations. Interestingly, in a subpopulation of cortical neurons transfected at 13 days in vitro, we find that alpha-synuclein appears to aggregate into distinct punctate inclusions in the cytoplasm and proximal neurites. Unlike Lewy bodies, these structures are not ubiquitin positive. These regions of alpha-synuclein accumulation are observed following transfections with wild-type, Ala30Pro or Ala53Thr alpha-synuclein; neither mutation alters their frequency.

McKeith, I. G., J. B. Grace, et al. (2000). "Rivastigmine in the treatment of dementia with Lewy bodies: preliminary findings from an open trial." Int J Geriatr Psychiatry 15(5): 387-92.
The objective of this study was to assess the tolerability and efficacy of rivastigmine in a group of patients with probable dementia with Lewy bodies (DLB), using an open label study. Open label treatment was with rivastigmine up to maximum tolerated dose (mean 9.6 mg daily, range 3-12 mg). Eleven patients with DLB, mean age 78.5 years, were treated with this cholinesterase inhibitor. After 12 weeks of treatment, mean Neuropsychiatric Inventory scores fell by 73% for delusions, 63% for apathy, 45% for agitation and 27% for hallucinations. Five of the patients (45%) experienced very significant clinical improvements that had not been achieved with other treatments, including low dose neuroleptics. Medication was well tolerated and parkinsonian symptoms tended to improve. Cholinesterase inhibition may be a safe and effective alternative to neuroleptic treatment in DLB. Such effects may also prove to be applicable to the management of neuropsychiatric symptoms in Parkinson's disease and Alzheimer's disease.

McKeith, I. G. (2000). "Spectrum of Parkinson's disease, Parkinson's dementia, and Lewy body dementia." Neurol Clin 18(4): 865-902.
Dementia occurs more commonly in individuals with Parkinson's disease (PD) than in the age-matched general population. Dementia in PD may result from a mixture of cortical and subcortical dementia syndromes caused by a variety of underlying pathologic processes and neurochemical deficits. A primary dementia syndrome has been described that shares several pathologic and clinical characteristics with PD. Dementia with Lewy bodies (DLB) accounts for 15% to 20% of all dementia syndromes in old age, which makes it second only to Alzheimer's disease in prevalence. The relationship between dementia in PD and DLB has not been fully resolved but may be considered useful in terms of neuropathologic substrate, clinical features, and response to treatment.

McKeith, I. G. (2000). "Clinical Lewy body syndromes." Ann N Y Acad Sci 920: 1-8.
Lewy bodies are spherical, intracytoplasmic, eosinophilic, neuronal inclusions comprising abnormally truncated and phosphorylated intermediate neurofilament proteins, alpha-synuclein, ubiquitin, and associated enzymes. The clinical presentation of LB disease varies according to the site of LB formation and associated neuronal loss. Three main clinicopathological syndromes have been described--movement disorder, autonomic failure, and dementia. Parkinsonism is the most common presentation of LB disease developing in middle life. In older patients, a mixture of cognitive, autonomic, and motor dysfunction is more common. Dementia with LB (DLB) is a relatively recently described clinicopathological syndrome that accounts for up to 20% of all cases of dementia in old age. Patients, typically in their seventh and eighth decades, have LB pathology in cortical neurons as well as in the brain stem. LB disease should be considered in the differential diagnosis of a wide range of clinical presentations including episodic disturbances of consciousness, syncope, sleep disorders, and unexplained delirium.

Mattila, P. M., J. O. Rinne, et al. (2000). "Alpha-synuclein-immunoreactive cortical Lewy bodies are associated with cognitive impairment in Parkinson's disease." Acta Neuropathol (Berl) 100(3): 285-90.
Amygdala, hippocampus and six cortical gyri were examined for the Lewy body (LB) degeneration and Alzheimer's disease (AD) type changes in 45 patients with Parkinson's disease (PD). For detection of LBs, the brain areas were stained with an antibody against alpha-synuclein. The extent of neuropathological lesions was investigated in relation to cognitive dysfunction and apolipoprotein E (apoE) epsilon4 allele dosage. At least one cortical LB was found in 95% of cases (43/45). Furthermore, 40% of cases (18/45) had histological findings of definite AD (CERAD class C). Those PD cases with the apoE epsilon4 allele had a significantly greater number of cortical LBs than those without the apoE epsilon4 allele, but this was statistically significant only in precentral, angular and temporal gyri. The LB density correlated better with the number of plaques than with the density of tangles. The number of LBs in several cortical areas correlated significantly with the cognitive impairment. In stepwise linear regression analysis, the number of LBs in the cingulate gyrus and the amount of tangles in the temporal cortex remained statistically significant. When the CERAD class C was excluded, the correlation between cognitive decline and the number of LBs in cortical areas became even more pronounced. A stepwise linear regression analysis in these cases found the number of LBs in the frontal gyrus to be the statistically most significant predictor of cognitive impairment. This study shows, for the first time, that in PD, alpha-synuclein-positive cortical LBs are associated with cognitive impairment independent of AD-type pathology.

Masliah, E., E. Rockenstein, et al. (2000). "Dopaminergic loss and inclusion body formation in alpha-synuclein mice: implications for neurodegenerative disorders." Science 287(5456): 1265-9.
To elucidate the role of the synaptic protein alpha-synuclein in neurodegenerative disorders, transgenic mice expressing wild-type human alpha-synuclein were generated. Neuronal expression of human alpha-synuclein resulted in progressive accumulation of alpha-synuclein-and ubiquitin-immunoreactive inclusions in neurons in the neocortex, hippocampus, and substantia nigra. Ultrastructural analysis revealed both electron-dense intranuclear deposits and cytoplasmic inclusions. These alterations were associated with loss of dopaminergic terminals in the basal ganglia and with motor impairments. These results suggest that accumulation of wild-type alpha-synuclein may play a causal role in Parkinson's disease and related conditions.

Martin, G. M. (2000). "Molecular mechanisms of late life dementias." Exp Gerontol 35(4): 439-43.
A brief overview of the molecular pathology of dementia of the Alzheimer type (DAT), frontotemporal dementias (FTD), and Lewy body dementias (LBD) is preceded by a discussion of the evolutionary biological basis for the types of gene action responsible for the emergence of late life dementias. The beta amyloid cascade theory of the pathogenesis of DAT still predominates, but possible upstream events are being explored. Some familial forms of FTD have been shown to result from dominant mutations in the microtubular associated protein tau. A key element in pathogenesis is a shift in the ratios of various isoforms. Rare forms of Parkinson disease have been associated with dominant mutations in alpha synuclein, a protein of probable importance for synaptic plasticity. Aberrations in the metabolism of this protein (which is found in Lewy body fibrillar material) may therefore be of importance to the genesis of some LBD cases.

Libelius, R. and F. Johansson (2000). "Quantitative electromyography of the external anal sphincter in Parkinson's disease and multiple system atrophy." Muscle Nerve 23(8): 1250-6.
The distinction of multiple system atrophy (MSA) from Parkinson's disease (PD) can be difficult, especially early in the disease. In MSA degeneration of sacral anterior horn cells (Onuf's nucleus) results in denervation-reinnervation of anal and urethral sphincter muscles, which can be recognized as neurogenic electromyographic (EMG) changes of motor unit potentials. Sphincter EMG has therefore been recommended as a test for distinguishing MSA from PD. Our results confirm the presence of marked neurogenic EMG changes of the external anal sphincter muscle in patients with probable MSA compared to healthy controls. However, in patients with probable PD, our quantitative EMG data show a scatter from normal to marked neurogenic changes and the degree of EMG abnormality is correlated to the duration of the disease. Thus an abnormal sphincter EMG cannot be taken as a strong indicator of MSA rather than PD in the individual patient, especially in long-standing cases.

Leopold, N. A. (2000). "Risperidone treatment of drug-related psychosis in patients with parkinsonism." Mov Disord 15(2): 301-4.
Risperidone, a novel neuroleptic with approximately equal D2 and 5HT2A receptor blocking properties, has been used to treat drug-related hallucinations in patients with Parkinson's disease. However, the results of only small numbers of patients have been reported with the drug demonstrating limited usefulness. We report our experience with this drug in 39 patients (25 women and 19 men) with parkinsonism. Monitored clinical data included duration of disease, Hoehn and Yahr score, Mini-Mental State Score, Unified Parkinson's Disease Rating Scale (UPDRS) prior to drug administration and after 3 and 6 months of treatment, and response to treatment. Twenty-three patients with Parkinson's disease had either complete or near-complete resolution of hallucinations whereas an unsatisfactory response (N = 6) or worsening of parkinsonism (N = 6) was noted in 12 patients, only six of whom had Parkinson's disease. Excluding patients with diffuse Lewy body disease, there was no significant worsening of the UPDRS scores after either 3 or 6 months of treatment. The presence of dementia did not predict response to treatment. Our results suggest that risperidone is a useful treatment for hallucinations in patients with parkinsonism.

Kondo, K., K. Miyashita, et al. (2000). "[An autopsy case of dementia with Lewy bodies who showed the typical parkinsonism in the initial five years]." Nippon Ronen Igakkai Zasshi 37(12): 999-1003.
A 76-year-old man with parkinsonism and dementia was reported. He developed resting tremor at age 69 followed by hypokinesia, rigidity and small step gait. L-dopa ameliorated his symptoms with no hallucinations for the initial 5 years. His mental level did not decrease during that period. He was admitted to our hospital because of dehydration and fever at age 74. Subsequently, his cognitive function deteriorated, with visual hallucination. Serial brain CT studies displayed a progressive cerebral cortical atrophy without focal lesions. He died of respiratory distress syndrome and disseminated coagulopathy resulting from pneumonia, dehydration and syndrome malin. Postmortem examination revealed a marked bilateral loss of melanin-containing neurons with Lewy bodies in the substantia nigra and locus ceruleus. Lewy bodies were also in the basal nucleus of Meynert, with moderate neuronal cell loss. The distribution of Lewy bodies was widespread in the cerebral cortical areas, corresponding to the neocortical subtype according to the consensus guideline for the pathologic diagnosis of dementia with Lewy bodies. According to the criteria of the Consortium to Establish a Registry for Alzheimer's Disease, the age-related plaque score in the present case suggested Alzheimer's disease, although cortical neurofibrillary changes corresponded to stage II by the criteria of Braak and Braak. These pathological findings established the diagnosis of dementia with Lewy bodies from the quantitative and distributional viewpoints. Based on recent neuropathological evidence, a spectral theory, which presents idiopathic Alzheimer's disease and Parkinson's disease as the two extremes of a spectrum of neurodegeneration, has been proposed. Dementia with Lewy bodies is located in the middle of this spectrum. Pathological evaluation based on quantitative consensus guidelines is important to establish the diagnosis in patients with parkinsonism and dementia, since neuropathological changes of Alzheimer's disease, Parkinson's disease and dementia with Lewy bodies are often observed in a mixed manner in these patients.

Kahle, P. J., M. Jakowec, et al. (2000). "Combined assessment of tau and neuronal thread protein in Alzheimer's disease CSF." Neurology 54(7): 1498-504.
OBJECTIVE: Comparative study of CSF levels of tau and AD7C-neuronal thread protein (NTP) in patients with AD and control subjects. BACKGROUND: AD is characterized by neurofibrillary tangles composed of the abnormally hyperphosphorylated microtubule-associated protein tau. AD7C-NTP is a proposed AD marker expressed at early stages of neurofibrillary degeneration. METHODS: Enzyme-linked immunosorbent assays specific for tau and AD7C-NTP. CSF samples were obtained from 35 demented patients (25 with antemortem clinical diagnosis of probable AD, 5 with neuropathologic diagnosis of definite AD, 5 with Lewy body pathology), 29 nondemented patients with PD, and 16 elderly healthy control subjects. Receiver operating characteristics (ROC) and multivariate discriminant analysis for AD versus controls. Correlational analysis of CSF tau and AD7C-NTP and of each marker with Mini-Mental State Examination (MMSE) scores was performed. RESULTS: Levels of both tau and AD7C-NTP were significantly elevated in the AD patients compared with control subjects. ROC analysis showed that CSF tau distinguished between patients with AD and nondemented control subjects with 63% sensitivity and 89% specificity, AD7C-NTP with 70% sensitivity and 87% specificity. Combined evaluation of both markers with discriminant analysis raised the specificity to 93% at a 63% sensitivity level. Both markers positively correlated with each other within the AD group, but not among control subjects. CSF levels of AD7C-NTP, but not of tau, showed a small but significant inverse correlation (r = -0.43) with MMSE scores of AD patients. CONCLUSIONS: CSF levels of tau and AD7C-NTP may be useful biomarkers for AD.

Johnson, W. G. (2000). "Late-onset neurodegenerative diseases--the role of protein insolubility." J Anat 196 ( Pt 4): 609-16.
Recently, mutations of the alpha-synuclein gene were found to cause dominantly inherited Lewy-body Parkinson's disease (PD) and alpha-synuclein was identified as a major component of the Lewy body. However, the cause of the common form of PD, with a multifactorial rather than autosomal dominant inheritance pattern, remains unknown. Alpha-synuclein precipitates slowly and apparently spontaneously at high concentration in solution and the mutations that cause PD accelerate precipitation. Other dominantly inherited late-onset or adult-onset dominantly inherited neurodegenerative diseases are associated with precipitation of proteins. In Alzheimer disease, beta-amyloid and tau abnormalities are present and in prion disorders, prion proteins are found. In Huntington disease, a disorder with expanded CAG repeats, huntingtin precipitates occur. In dominantly inherited spinocerebellar ataxias, also expanded CAG repeat disorders, the corresponding ataxin protein precipitates are found. In multiple system atrophy, alpha-synuclein precipitates are encountered and in progressive supranuclear palsy, tau precipitates occur. In familial amyotrophic lateral sclerosis, a group of dominantly inherited disorders, SOD1 precipitates are found. Most of these disorders can involve the basal ganglia in some way. Since similar processes seem to affect neurons of adults or older individuals and since a relatively limited group of proteins seems to be involved, each producing a form of neurodegeneration, it is possible that certain common features are present that affect this group of proteins. Candidates include a conformational shift, as in prions, an abnormality of the ubiquitin-proteosome pathway, as seen in PD, an abnormality of a pathway preventing precipitation (e.g. chaperonins), or potentiation of a pathway promoting precipitation (e.g. gamma-glutamyl-transpeptidase) or apoptosis. Elucidation of the pathways causing this protein insolubilisation is the first step towards approaching prevention and reversal in these late-onset neurodegenerative diseases.

Jin, K., N. Sato, et al. (2000). "[Diffuse Lewy body disease searched out from 114 patients with parkinsonism]." Rinsho Shinkeigaku 40(4): 329-33.
From 114 patients who had been previously diagnosed as Parkinson's disease, we diagnosed six cases as clinically definite "diffuse Lewy body disease (DLBD)" according to McKeith's criteria with more strict modifications. Besides a central feature, dementia, and core features including parkinsonism, fluctuating cognition, and recurrent visual hallucinations, the patients presented some of supportive features, that is, repeated falls (4 cases), syncope (5 cases), and transient loss of consciousness (all cases). Autopsy, which was performed in 2 of the cases, revealed Lewy bodies in various nervous tissues including autonomic nervous systems in both cases. 7 cases of probable DLBD and 8 cases of possible DLBD, which lacked fluctuating cognition and/or visual hallucinations, demonstrated neither of repeated falls, syncope, nor transient loss of consciousness. Episodes of these supportive features, which seem to be associated with autonomic dysfunctions and/or fluctuating cognition, should be important in the differential diagnosis of DLBD.

Jensen, P. H., K. Islam, et al. (2000). "Microtubule-associated protein 1B is a component of cortical Lewy bodies and binds alpha-synuclein filaments." J Biol Chem 275(28): 21500-7.
Lewy bodies, neuropathological hallmarks of Parkinson's disease and dementia with Lewy bodies, comprise alpha-synuclein filaments and other less defined proteins. Characterization of Lewy body proteins that interact with alpha-synuclein may provide insight into the mechanism of Lewy body formation. Double immunofluorescence labeling and confocal microscopy revealed approximately 80% of cortical Lewy bodies contained microtubule-associated protein 1B (MAP-1B) that overlapped with alpha-synuclein. Lewy bodies were isolated using an immunomagnetic technique from brain tissue of patients dying with dementia with Lewy bodies. Lewy body proteins were resolved by polyacrylamide gel electrophoresis. Immunoblotting confirmed the presence of MAP-1B and alpha-synuclein in purified Lewy bodies. Direct binding studies revealed a high affinity interaction (IC(50) approximately 20 nm) between MAP-1B and alpha-synuclein. The MAP-1B-binding sites were mapped to the last 45 amino acids of the alpha-synuclein C terminus. MAP-1B also bound in vitro assembled alpha-synuclein fibrils. Thus, MAP-1B may be involved in the pathogenesis of Lewy bodies via its interaction with monomeric and fibrillar alpha-synuclein.

Jellinger, K. A. (2000). "Morphological substrates of mental dysfunction in Lewy body disease: an update." J Neural Transm Suppl 59: 185-212.
Mental dysfunction including cognitive, behavioural changes, mood disorders, and psychosis are increasingly recognized in patients with Parkinson's disease (PD) and related disorders. Their morphological correlates are complex due to multiple system degeneration. CNS changes contributing to cognitive changes in PD include 1. Dysfunction of subcorticocortical networks with neuron losses in a) the dopaminergic nigrostriatal loop, causing striato-(pre)frontal deafferentation and mesocortico-limbic system (medial substantia nigra, ventral tegmentum); b) noradrenergic (locus coeruleus), and serotonergic systems (dorsal raphe nuclei), c) cholinergic forebrain system (nucleus basalis of Meynert, etc), and d) specific nuclei of amygdala and limbic system (thalamic nuclei, hippocampus); 2. Limbic and/or cortical Lewy body and Alzheimer type pathologies with loss of neurons and synapses, 3. Combination of subcortical, cortical, and other pathologies. In general, degeneration of subcortical and striato-frontal networks causes cognitive, executive, behavioural, and mood disorders but less severe dementia than cortical changes which, when present in sufficient numbers, are important factors for overt dementia. In PD, cortical tau pathology with similar or differential patterns than in Alzheimer disease (AD) shows significant linear correlation with cognitive decline. In dementia with Lewy bodies (DLB), the second most frequent cause of dementia in the elderly, cortical Lewy bodies (LB) may or may not be associated with amyloid plaques and neuritic AD lesions. They predominantly affect the limbic system with less frequent isocortical Braak stages, whereas the cholinergic forebrain system is more severely affected than in AD. Both neuritic degeneration in limbic system in PD and DLB and the density of cortical synapse markers correlate with neuritic AD pathology and less with cortical LB counts. Apolipoprotein E epsilon4 allele frequency may represent a common genetic background for both AD and LB pathologies but there are different proportions of plaques between DLB (less Abeta1-40) and AD (more frequent Abeta1-40). Familial parkinsonism with dementia, linked to chromosome 17 (frontotemporal dementia with Parkinsonism (FTDP-17), and other tauopathies pathologically resembling PD plus AD, are often related to mutations of the tau gene, whereas familial PD with alpha-synuclein and Parkin mutations usually show no cognitive impairment. Mood disorders, in particular depression, and psychotic complications in both PD and DLB are related to complex involvement of noradrenergic and serotonergic systems, not confirmed in AD with depression, and both the prefrontal and limbic dopaminergic systems. The specific contributions of cortical and subcortical pathologies to mental dysfunction in PD and related disorders, their relationship to AD, and their genetic and aetiological backgrounds await further elucidation.

Hellstrom-Lindahl, E. and J. A. Court (2000). "Nicotinic acetylcholine receptors during prenatal development and brain pathology in human aging." Behav Brain Res 113(1-2): 159-68.
Nicotinic acetylcholine receptor (nAChRs) proteins and gene transcripts are already present in human prenatal brain and spinal cord at 4-6 weeks gestation, and a clear age-related increase in number of nAChRs was apparent during first trimester. In pons, there was also a parallel increase in the alpha7 mRNA level with age. The highest specific binding of [3H]epibatidine and [3H]cytisine was detected in spinal cord, pons and medulla oblongata, and binding of [125I]alpha-bungarotoxin was highest in spinal cord, medulla oblongata and mesencephalon. From the late fetal stage brain nAChRs have been shown to fall with increasing age. During aging (between 40 and 100 years) high affinity nicotine binding in the frontal cortex decreases in parallel with glutamate NMDA receptor binding ([3H]MK801). In the hippocampal formation and entorhinal cortex nicotine binding also declines with age, in common with [125I]alpha-bungarotoxin in the entorhinal cortex, but NMDA receptor binding remains unchanged. These reductions in nicotine binding with age may predispose the neo- and archicortex to the loss of nAChRs observed in age-associated neurodegenerative conditions. By contrast no loss in nAChR binding with aging is observed in the thalamus and only after the 70th decade in the striatum, although in Alzheimer's disease, Parkinson's disease and Lewy body dementia deficits in nAChRs are observed in these areas and may be associated with specific disease-related processes.

Hattori, N., H. Shimura, et al. (2000). "Importance of familial Parkinson's disease and parkinsonism to the understanding of nigral degeneration in sporadic Parkinson's disease." J Neural Transm Suppl(60): 101-16.
We review here familial Parkinson's disease (PD) from clinical as well as molecular genetic aspects. The contribution of genetic factors to the pathogenesis of PD is supported by the demonstration of the high concordance in twins, increased risk among relatives of PD patients in case control and family studies, and the existence of familial PD and parkinsonism based on single gene defects. Recently, several genes have been mapped and/or identified in patients with familial PD. Alpha-synuclein is involved in a rare dominant form of familial PD with dopa responsive parkinsonian features and Lewy body positive pathology. In contrast, parkin is responsible for autosomal recessive form of early-onset PD with Lewy body-negative pathology. This form is identified world-wide among patients with young-onset PD. Furthermore, ubiquitin carboxy terminal hydrolase L1 gene is responsible for an autosomal dominant form of typical PD, although only a single family has so far been identified with a mutation of this gene, and tau has been identified as a causative gene for frontotemporal dementia and parkinsonism. In addition, five other chromosome loci have been identified to be linked to familial PD or dystonia-parkinsonism. The presence of different loci or different causative genes indicates that PD is not a single entity but a highly heterogeneous. Identification and elucidation of the causative genes should enhance our understanding of the pathogenesis of sporadic PD.

Haroutunian, V., M. Serby, et al. (2000). "Contribution of Lewy body inclusions to dementia in patients with and without Alzheimer disease neuropathological conditions." Arch Neurol 57(8): 1145-50.
CONTEXT: Lewy bodies (LBs) are intraneuronal inclusions in the brain that have been increasingly recognized as neuropathological lesions with relevance not only to Parkinson disease but also to Alzheimer disease. However, the degree to which the density of LBs in the brain contributes to the severity of dementia has not been clear. OBJECTIVE: To determine the degree to which LB "burden" contributes to dementia. DESIGN: Brain specimens were examined from 273 consecutive autopsies of elderly subjects residing in a nursing home. The numbers and densities of LBs were determined in multiple brain regions, and their correlation with a measure of cognition and functional status (Clinical Dementia Rating) during the 6 months preceding death was determined. SETTING AND PATIENTS: Postmortem study of nursing home residents. RESULTS: The severity of dementia correlated significantly and positively with the density of LBs. These correlations were independent of other neuropathological disorders commonly associated with dementia, including Alzheimer disease. The density of LBs correlated significantly with dementia severity whether or not the diagnostic criteria for Alzheimer disease were met and after the contribution of classical Alzheimer disease lesions, neuritic plaques, and neurofibrillary tangles had been accounted for by partial correlation analysis. CONCLUSION: Lewy body inclusions appear to contribute significantly to cognitive deficits in the elderly in a manner that is independent of other neuropathological disorders. Arch Neurol. 2000;57:1145-1150

Harding, A. J., J. J. Kril, et al. (2000). "Practical measures to simplify the Braak tangle staging method for routine pathological screening." Acta Neuropathol (Berl) 99(2): 199-208.
The examination of neurofibrillary tangles is now recommended for the diagnosis of Alzheimer's disease as their location and density can distinguish early, intermediate and late disease stages. While the Braak tangle staging protocol can identify these stages, it uses an uncommon silver stain and hippocampal sample. The present study evaluates the Braak protocol using commonly used methods and cases fulfilling either CERAD criteria for Alzheimer's disease, criteria for dementia with Lewy bodies or without neurological disease. Temporal and occipital cortices from 72 cases were stained using tau immunohistochemistry and the Gallyas and modified Bielschowsky silver stains. The modified Bielschowsky silver stain was equivalent to the Gallyas silver stain for tangle staging. Semiquantitative evaluation of neurofibrillary tangles in the hippocampus and the inferior temporal cortex provided equivalent information to that obtained using the original Braak tangle staging protocol (kappa statistic of 0.97). Comparison of this modification with the CERAD criteria provided moderate agreement (0.51) between diagnostic categories when cases with dementia with Lewy bodies were included, but substantially increased agreement (0.74) when they were excluded. This simplification of the Braak tangle staging protocol is easy to apply, can be readily incorporated into existing CERAD procedures, and helps to distinguish cases with neurofibrillary tangles from those with Lewy bodies.

Gwinn-Hardy, K., N. D. Mehta, et al. (2000). "Distinctive neuropathology revealed by alpha-synuclein antibodies in hereditary parkinsonism and dementia linked to chromosome 4p." Acta Neuropathol (Berl) 99(6): 663-72.
The identification of the alpha-synuclein gene on chromosome 4q as a locus for familial Lewy-body parkinsonism and of alpha-synuclein as a component of Lewy bodies has heralded a new era in the study of Parkinson's disease. We have identified a large family with Lewy body parkinsonism linked to a novel locus on chromosome 4p15 that does not have a mutation in the alpha-synuclein gene. Here we report the clinical and neuropathological findings in an individual from this family and describe unusual high molecular weight alpha-synuclein-immunoreactive proteins in brain homogenates from brain regions with the most marked neuropathology. Distinctive histopathology was revealed with alpha-synuclein immunostaining, including pleomorphic Lewy bodies, synuclein-positive glial inclusions and widespread, severe neuritic dystrophy. We also discuss the relationship of this familial disorder to a Lewy body disease clinical spectrum, ranging from Parkinson's disease to dementia with psychosis.

Giasson, B. I., J. E. Duda, et al. (2000). "Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions." Science 290(5493): 985-9.
Aggregated alpha-synuclein proteins form brain lesions that are hallmarks of neurodegenerative synucleinopathies, and oxidative stress has been implicated in the pathogenesis of some of these disorders. Using antibodies to specific nitrated tyrosine residues in alpha-synuclein, we demonstrate extensive and widespread accumulations of nitrated alpha-synuclein in the signature inclusions of Parkinson's disease, dementia with Lewy bodies, the Lewy body variant of Alzheimer's disease, and multiple system atrophy brains. We also show that nitrated alpha-synuclein is present in the major filamentous building blocks of these inclusions, as well as in the insoluble fractions of affected brain regions of synucleinopathies. The selective and specific nitration of alpha-synuclein in these disorders provides evidence to directly link oxidative and nitrative damage to the onset and progression of neurodegenerative synucleinopathies.

Gasser, T. (2000). "Autosomal-dominantly inherited forms of Parkinson's disease." J Neural Transm Suppl(58): 31-40.
Today, a genetic contribution to the etiology of Parkinson's disease (PD) is generally accepted, based on the demonstration of a familial aggregation of the disease, as demonstrated by several case-control and twin-studies. However, most cases of PD appear to be sporadic, and in the majority of those with a positive family history, no clear mendelian mode of inheritance can be established. Therefore, a polygenic mode of inheritance or a multifactorial etiology is likely in these cases. On the other hand, a number of families have been identified, in whom parkinsonism is inherited as an apparently monogenic mendelian trait with high penetrance. In several of these families, the disease genes have been mapped and mutations have been identified in some of them. The first gene locus has been mapped to the long arm of chromosome 4 in a small number of families with autosomal-dominant inheritance and typical Lewy-body pathology (PARK 1), and mutations have been identified in the gene for alpha-synuclein in these kindreds. Two other loci in families with dominant inheritance have been mapped, to chromosome 2p13 (PARK 3) and to chromosome 4p, respectively. A gene causing autosomal recessive parkinsonism of juvenile onset has been mapped to chromosome 6 (PARK 2), and the causative gene has been identified and named parkin. Each of these genetically defined familial disorders share clinical characteristics that fulfill the criteria accepted for idiopathic Parkinson's disease but, as in sporadic PD, also show a variability of clinical expressions, both within and between families. At present, there is no direct evidence that any of these genes for familial Parkinsonian syndromes have a direct role in the etiology of the common sporadic form of PD. However, the elucidation of the molecular sequence of events leading to nigral degeneration in these inherited cases is likely to shed light also on the molecular pathogenesis of the common sporadic form of this disorder.

Galasko, D., D. Salmon, et al. (2000). "The clinical spectrum of Guam ALS and Parkinson-dementia complex: 1997-1999." Ann N Y Acad Sci 920: 120-5.

Gai, W. P., H. X. Yuan, et al. (2000). "In situ and in vitro study of colocalization and segregation of alpha-synuclein, ubiquitin, and lipids in Lewy bodies." Exp Neurol 166(2): 324-33.
alpha-Synuclein and ubiquitin are two Lewy body protein components that may play antagonistic roles in the pathogenesis of Lewy bodies. We examined the relationship between alpha-synuclein, ubiquitin, and lipids in Lewy bodies of fixed brain sections or isolated from cortical tissues of dementia with Lewy bodies. Lewy bodies exhibited a range of labeling patterns for alpha-synuclein and ubiquitin, from a homogeneous pattern in which alpha-synuclein and ubiquitin were evenly distributed and overlapped across the inclusion body to a concentric pattern in which alpha-synuclein and ubiquitin were partially segregated, with alpha-synuclein labeling concentrated in the peripheral domain and ubiquitin in the central domain of the Lewy body. Lipids represented a significant component in both homogeneous and concentric Lewy bodies. These results suggest that Lewy bodies are heterogeneous in their subregional composition. The segregation of alpha-synuclein to Lewy body peripheral domain is consistent with the hypothesis that alpha-synuclein is continually deposited onto Lewy bodies.

Ferrer, I. and R. Blanco (2000). "N-myc and c-myc expression in Alzheimer disease, Huntington disease and Parkinson disease." Brain Res Mol Brain Res 77(2): 270-6.
The present study examines N-myc and c-myc protein expression with Western blotting and single and double-labeling immunohistochemistry in the hippocampus in Alzheimer disease (AD), the striatum in Huntington disease (HD) and the substantia nigra in Parkinson disease (PD). No modifications in the N-myc and c-myc expression are found in hippocampal neurons in AD, striatal neurons in HD, and pigmented neurons of the substantia nigra in PD. Yet punctate synaptic-like N-myc immunoreactivity, matching enhanced synaptophysin expression, occurs in diffuse plaques, but not in dystrophic neurites of neuritic plaques. In contrast, c-myc immunoreactivity is found in dystrophic neurites, but not in aberrant sproutings of neuritic plaques, as shown by double-labeling immunohistochemistry to c-myc and phosphorylated tau or phosphorylated neurofilament epitopes, and to c-myc and GAP-43, respectively. Strong N-myc and c-myc are observed in reactive astrocytes in AD, HD and PD, as revealed by double-labeling with N-myc or c-myc and GFAP. Finally, no relationship is found between nuclear DNA fragmentation and increased N-myc or c-myc expression in individual cells. These results demonstrate that neuron death in AD, HD and PD is not associated with modifications in the steady-state expression of N-myc and c-myc in individual neurons, and that neurofibrillary degeneration and Lewy body formation are not accompanied by increased immunoreactivity to these transcription factors. Increased N-myc and c-myc expression in reactive astrocytes probably plays a role in reactive astrocytosis in human neurodegenerative disorders.

Del Ser, T., I. McKeith, et al. (2000). "Dementia with lewy bodies: findings from an international multicentre study." Int J Geriatr Psychiatry 15(11): 1034-45.
OBJECTIVES: To describe the baseline demographic, neuropsychiatric and neurological data of a large selected clinical sample of patients with dementia with Lewy Bodies (DLB) from an international multicentre trial with rivastigmine. To examine the usefulness of the Consensus Criteria for the diagnosis of DLB in different countries. METHODS: Seventeen centres from Spain, the UK and Italy recruited patients diagnosed clinically as probable DLB according to recent Consensus Criteria (McKeith et al., 1996). A standard clinical protocol including inclusion/exclusion criteria, collection of demographic and medical data, cognitive (Mini Mental State Examination: MMSE), motor (Unified Parkinson's Disease Rating Scale: UPDRS) and neuropsychiatric (Neuropsychiatric Inventory: NPI) examinations, was applied after obtaining informed consent. Data were summarised and compared across countries with uni- and multivariate analyses. RESULTS: One hundred and twenty patients were recruited: 56.7% males, mean (SD) age 73.9 (6.4) years, range 57 - 87 years. Sixty percent fulfilled all three core diagnostic features of DLB, and 40% only two ('parkinsonism' 92.4%, 'cognitive fluctuations' 89.1%, 'visual hallucinations' 77.3%). 'Systematised delusions' (46%) and 'repeated falls' (42%) were the most frequent supportive diagnostic features. There were no differences across countries in demographic, diagnostic or clinical features. Patients showed a wide range of psychopathology which was weakly correlated with cognitive impairment. Some mild extrapyramidal signs (EPS) were observed in most patients. CONCLUSIONS: The Consensus Criteria for DLB can be consistently applied across many different sites for multicentre studies. 'Parkinsonism' and 'cognitive fluctuations' as core features and 'systematised delusions' and 'repeated falls' as supportive features are the most frequent diagnostic clues. Neuropsychiatric disturbances, in particular apathy, delusions, hallucinations and anxiety, and mild symmetric EPS are frequent in DLB and are only related weakly to cognitive impairment.

Crowther, R. A., S. E. Daniel, et al. (2000). "Characterisation of isolated alpha-synuclein filaments from substantia nigra of Parkinson's disease brain." Neurosci Lett 292(2): 128-30.
The defining neuropathological deposits of Parkinson's disease, dementia with Lewy bodies and multiple system atrophy are strongly immunoreactive for alpha-synuclein. We have shown previously that isolated filaments from dementia with Lewy bodies and multiple system atrophy brains are labelled in a characteristic fashion by a number of alpha-synuclein antibodies. Here we have extracted filaments from substantia nigra of patients with idiopathic Parkinson's disease. Antibodies directed against the carboxy-terminal region of alpha-synuclein labelled isolated filaments along their entire lengths. By contrast, an antibody directed against the amino-terminal region of alpha-synuclein only labelled one filament end. These characteristics were identical to those of filaments extracted from brains of patients with dementia with Lewy bodies and multiple system atrophy.

Court, J. A., M. A. Piggott, et al. (2000). "Nicotine binding in human striatum: elevation in schizophrenia and reductions in dementia with Lewy bodies, Parkinson's disease and Alzheimer's disease and in relation to neuroleptic medication." Neuroscience 98(1): 79-87.
Striatal nicotinic acetylcholine receptors with high affinity for nicotinic agonists are involved with the release of a number of neurotransmitters, including dopamine. Previous findings as to whether these receptors are changed in Parkinson's disease and Alzheimer's disease are inconsistent and no previous investigations have focused on these receptors in dementia with Lewy bodies and schizophrenia, which are also associated with disorders of movement. The present autoradiographic study of striatal [3H]nicotine binding in Alzheimer's and Parkinson's diseases, dementia with Lewy bodies and schizophrenia was conducted with particular reference to the potentially confounding variables of tobacco use and neuroleptic medication. [3H]Nicotine binding in both dorsal and ventral caudate and putamen was significantly reduced in Parkinson's disease (43-67%, n=13), Alzheimer's disease (29-37%, n=13) and dementia with Lewy bodies (50-61%, n=20) compared to age-matched controls (n=42). Although tobacco use in the control group was associated with increased [3H]nicotine binding (21-38%), and neuroleptic treatment in dementia with Lewy bodies and Alzheimer's disease was associated with reduced [3H]nicotine binding (up to 29%), differences between neurodegenerative disease groups and controls persisted in subgroups of Alzheimer's disease cases (26-33%, n=6, in the ventral striatum) and dementia with Lewy body cases (30-49%, n=7, in both dorsal and ventral striatum) who had received no neuroleptic medication compared to controls who had not smoked (n=10). In contrast, striatal [3H]nicotine binding in a group of elderly (56-85 years) chronically medicated individuals with schizophrenia (n=6) was elevated compared with the entire control group (48-78%, n=42) and with a subgroup that had smoked (24-49%, n=8).The changes observed in [3H]nicotine binding are likely to reflect the presence of these receptors on multiple sites within the striatum, which may be differentially modulated in the different diseases. Further study is warranted to explore which nicotinic receptor subunits and which neuronal compartments are involved in the changes in [3H]nicotine binding reported, to aid development of potential nicotinic receptor therapy.

Court, J. A., C. Martin-Ruiz, et al. (2000). "Nicotinic receptors in human brain: topography and pathology." J Chem Neuroanat 20(3-4): 281-98.
Brain nicotinic acetylcholine receptors (nAChR) are a class of ligand-gated channels composed of alpha and beta subunits with specific structural, functional and pharmacological properties. They participate in the physiological and behavioural effects of acetylcholine and mediate responses to nicotine. They are associated with numerous transmitter systems and their expression is altered during development and ageing as well as in diseases such as autism, schizophrenia, Alzheimer's disease, Parkinson's disease and Lewy body dementia. Nicotinic receptors containing a number of different subunits are highly expressed during early human development. Disorders believed to be associated with abnormal brain maturation involve deficits in both alpha4beta2, in the case of autism, and alpha7 possibly in addition to alpha4beta2 nAChRs in the case of schizophrenia. In ageing and age-related neurodegenerative disorders nAChR deficits are predominantly associated with alpha4-containing receptors, although some studies also indicate the involvement of alpha3 and alpha7 subunits. Whilst ageing appears to be associated with reductions in subunit mRNA as well as protein expression, in Alzheimer's disease only protein loss is apparent. Nicotinic therapy may be of benefit in a number of neurological conditions, however studies evaluating further both the distribution of specific subunit involvement and the correlation of nAChR deficits with clinical symptoms are required to inform therapeutic strategy.

Corrigan, F. M., C. L. Wienburg, et al. (2000). "Organochlorine insecticides in substantia nigra in Parkinson's disease." J Toxicol Environ Health A 59(4): 229-34.
The concentrations of organochlorine (OC) compounds in the substantia nigra (SN) were compared in Parkinson's disease (PD) with concentrations in brain from cortical Lewy body dementia (CLBD), Alzheimer's disease (AD), and nondemented nonparkinsonian controls (CON). The levels of the gamma isomer of hexachlorocyclohexane (gammaHCH, lindane) were significantly higher in PD tissues (mean +/- SD: 0.56 +/- 0.434 microg/g lipid) than in the other three groups (CLBD 0.052 +/- 0.101 microg/g lipid; AD none detected; CON 0.125 +/- 0.195; all differences from PD significant at p < .05, Mann-Whitney U-test). Dieldrin (HEOD) was higher in PD brain than in AD or control brain, while 1,1'-(2,2-dichloroethenyl diene)-bis(4-chlorobenzene) (p,p-DDE) and total Aroclor-matched polychlorinated biphenyls (matched PCBs) were only higher in PD substantia nigra when these concentrations were compared with those of CLBD. These findings are not inconsistent with the hypothesis derived from epidemiological work and animal studies that organochlorine insecticides produce a direct toxic action on the dopaminergic tracts of the substantia nigra and may contribute to the development of PD in those rendered susceptible by virtue of cytochrome P-450 polymorphism, excessive exposure, or other factors.

Cordato, N. J., G. M. Halliday, et al. (2000). "Regional brain atrophy in progressive supranuclear palsy and Lewy body disease." Ann Neurol 47(6): 718-28.
There have been no previous three-dimensional volumetric studies of regional brain atrophy in patients with pathologically confirmed progressive supranuclear palsy (PSP). Postmortem cortical and subcortical volumes were compared with neuropathology in 9 patients with PSP, 15 patients with Parkinson's disease, 10 patients with dementia with Lewy bodies, and 23 controls. Cases with the neuritic pathology of Alzheimer's disease were excluded. The topography of brain atrophy differed according to clinicopathological phenotype. Patients with Parkinson's disease had atrophy confined to the amygdala. Atrophy of the frontal lobe was found in both PSP and dementia with Lewy bodies and correlated with increasing neurofibrillary tangle or Lewy body densities, respectively. Patients with PSP could be differentiated by their marked atrophy of the internal globus pallidus. Further analysis of variance revealed that trends for greater frontal lobe atrophy correlated with clinical dementia in PSP, whereas both greater frontal and hippocampal atrophy and higher densities of Lewy bodies and Lewy neurites correlated with clinical dementia in cases with Lewy bodies. The present study provides evidence for selective regional atrophy that correlates with the underlying pathology of PSP and Lewy body disease.

Conway, K. A., S. J. Lee, et al. (2000). "Accelerated oligomerization by Parkinson's disease linked alpha-synuclein mutants." Ann N Y Acad Sci 920: 42-5.

Chu, C. T., J. L. Caruso, et al. (2000). "Ubiquitin immunochemistry as a diagnostic aid for community pathologists evaluating patients who have dementia." Mod Pathol 13(4): 420-6.
Alzheimer's disease is the most common cause of dementia It is associated with genetic risk factors and at least three autosomal dominant mutations. Community pathologists are frequently asked by families to evaluate autopsy material for Alzheimer's disease. Neuropathologic diagnosis is based on technically difficult silver impregnation stains that may not be readily available to community-based pathologists. Because immunohistochemical techniques are more widely accessible, we evaluated the practical utility of using a single immunohistochemical stain for diagnosing Alzheimer's disease. The ubiquitin antigen was selected because of its presence in morphologically distinct deposits characteristic of several neurodegenerative diseases. Paraffin blocks were obtained from the Bryan Alzheimer's Disease Research Center Brain Bank, a repository of approximately 900 brains. Tissues from 16 individuals who exhibited the entire range of Alzheimer's-type neuropathology were selected. Ubiquitin immunostains, evaluated blindly and independently by four pathologists ranging from first-year resident trainee to experienced neuropathologist, reliably stained both neuritic plaques and neurofibrillary tangles essential for diagnosing and staging Alzheimer's disease. Nondemented controls with early Alzheimer's-type changes were easily distinguished from cases of definitive Alzheimer's disease. The stains also highlighted characteristic inclusions of Parkinson's disease or Lewy body dementia Ubiquitin immunohistochemistry is a reliable, reproducible, and readily available diagnostic aid for distinguishing Alzheimer's disease from other causes of dementia.

Chaudhuri, K. R., M. T. Hu, et al. (2000). "Atypical parkinsonism in Afro-Caribbean and Indian origin immigrants to the UK." Mov Disord 15(1): 18-23.
This article reviews evidence for the occurrence of atypical parkinsonism in Afro-Caribbean and Indian ethnic minority subjects living in western countries, particularly the UK. Current information on the frequency, pattern, and prevalence of Parkinson's disease and parkinsonism in these communities is unclear and controversial. While several workers have suggested that there is a low prevalence of Parkinson's disease in populations of African origin, other workers have suggested a higher prevalence of Parkinson's disease in African Americans. Furthermore, little information is available in relation to the pattern of parkinsonism in these subjects. A recent phenomenologic study of parkinsonism in the French West Indies by Caparros-Lefebvre and colleagues has indicated a significantly increased frequency of atypical parkinsonism in local non-white subjects. Since 1995, we have been studying the pattern and frequency of parkinsonism in Afro-Caribbean and Indian (originating from the Indian subcontinent) patients living in the UK, with London serving as the coordinating center. Our results indicate that there is a three- to fourfold increase in the frequency of occurrence of sporadic atypical parkinsonism characterized by levodopa hyporesponsiveness, bradykinesia-dominant disease, and early cognitive dysfunction in these patients even after exclusion of patients with clinically probable multiple system atrophy, progressive supranuclear palsy, and Lewy body dementia. These findings are similar to observations made in the French West Indies. Ongoing studies in India suggest that atypical parkinsonism also affects local patients, and the pattern of parkinsonism tends to differ from Afro-Caribbean subjects in the UK. Studies are currently underway to unravel the mechanism of increased frequency of atypical parkinsonism in these ethnic groups and include genetic studies addressing polymorphisms of enzymes metabolizing levodopa, dietary neurotoxin screen and functional imaging studies of the striatum using positron emission tomography. Furthermore, the contribution of diabetes mellitus and hypertension, commonly seen in these ethnic groups, is also being examined.

Caviness, J. N., K. Gwinn-Hardy, et al. (2000). "Electrophysiological observations in hereditary parkinsonism-dementia with Lewy body pathology." Mov Disord 15(1): 140-5.
We studied the only two living affected individuals who are part of a previously reported kindred that expresses a hereditary parkinsonism-dementia syndrome with Lewy body pathology. The electrophysiological characteristics of the hyperkinetic movement disorders in these patients were examined to provide physiological insights into the clinical phenotype of this syndrome. Evaluation of both patients showed 7-9 Hz electromyographic discharges in upper extremity muscles during postural activation, and one patient showed a 4-5 Hz discharge pattern correlating to a rest tremor. Brief (<50 ms) myoclonic electromyographic discharges were seen in both patients, and a time-locked relationship to a focal cortical premovement electroencephalographic potential was elicited in one patient. Somatosensory evoked potentials were not enlarged and long latency reflexes were not enhanced. Electroencephalography was normal in one patient but showed pathologic slow frequencies in the other. The electrophysiological findings show evolution which correlates with an apparent characteristic evolution of hyperkinetic movement disorders that accompanies the severe progression of parkinsonism-dementia in this kindred. These results have implications for the future study of this and similar syndromes.

Castellani, R. J., S. L. Siedlak, et al. (2000). "Sequestration of iron by Lewy bodies in Parkinson's disease." Acta Neuropathol (Berl) 100(2): 111-4.
Central to the oxidative stress hypothesis of Parkinson's disease (PD) pathogenesis is the ability of iron to generate hydroxyl radicals via the Fenton reaction, and the consistent demonstration of iron elevation in the pars compacta region of the substantia nigra. However, uncertainty exists as to whether the excess iron exists in a state suitable for redox chemistry. Here, using a method we developed that detects redox-active iron in situ, we were able to demonstrate strong labeling of Lewy bodies in substantia nigra pars compacta neurons in PD. In contrast, cortical Lewy bodies in cases of Lewy body variant of Alzheimer's disease were unstained. While the presence of elevated iron in PD substantiates the oxidative stress hypothesis, one must remember that these are viable neurons, indicating that Lewy bodies may act to sequester iron in PD brains in a protective, rather than degenerative, mechanism. The absence of redox-active iron in neocortical Lewy bodies highlights a fundamental difference between cortical and brain stem Lewy bodies.

Campbell, B. C., Q. X. Li, et al. (2000). "Accumulation of insoluble alpha-synuclein in dementia with Lewy bodies." Neurobiol Dis 7(3): 192-200.
The alpha-synuclein (alpha SN) protein is thought to play a central role in the pathogenesis of neurodegenerative diseases where it aggregates to form intracellular inclusions. We have used Western blotting to examine the expression levels and solubility of alpha SN in brain homogenates from dementia with Lewy bodies (DLB), Parkinson's disease (PD), Alzheimer's disease (AD), and normal controls using samples from the parahippocampus/transentorhinal cortex. Compared to controls, DLB brains accumulate significantly greater amounts of sodium dodecyl sulfate (SDS)-soluble and SDS-insoluble alpha SN but levels of TBS-soluble alpha SN did not change. Levels of synaptophysin, a marker of synaptic integrity, were significantly lower in DLB cases than in normal aged controls regardless of whether concurrent changes of AD were present. This limbic synaptic dysfunction may contribute to cognitive impairment in DLB. Whether aggregated alpha SN is a cause or effect of the disease process in DLB and PD remains to be determined, but the presence of aggregated alpha SN is consistent with a pathogenesis similar to that associated with aggregates of Abeta amyloid in AD.

Ballard, C., J. O'Brien, et al. (2000). "One year follow-up of parkinsonism in dementia with Lewy bodies." Dement Geriatr Cogn Disord 11(4): 219-22.
The progression of parkinsonism over 1 year was evaluated in a prospective cohort of patients (n = 338), suffering from dementia with Lewy bodies (DLB), Alzheimer's disease (AD) or vascular dementia (VaD). Parkinsonism was assessed using the modified Unified Parkinson's Disease Rating Scale. Significant parkinsonism was significantly commoner in DLB sufferers (71%) than amongst patients with AD (7%) or VaD (10%). DLB patients with established parkinsonism had an annual increase in severity of 9%, but progression was more rapid (49% in 1 year) in patients with early parkinsonism. Parkinsonism was frequent at all severities in DLB patients, but usually only present in other dementias when MMSE <10.

Arai, K., N. Kato, et al. (2000). "Pure autonomic failure in association with human alpha-synucleinopathy." Neurosci Lett 296(2-3): 171-3.
We studied an autopsy case with pure autonomic failure, using anti-alpha-synuclein antibody. Until now there has been no report about the immunohistochemical properties of alpha-synuclein in pure autonomic failure. In conventional stainings, both pre- and post-ganglionic lesions of the sympathetic and parasympathetic nervous systems were found. Lewy bodies and Lewy neurites were abundant especially in the sympathetic nervous system. These inclusions were immunoreactive to anti-alpha-synuclein antibody. The intensity of alpha-synuclein immunoreactivity was stronger in the halos than in the cores of the Lewy bodies. The edges of the swollen neurites had strong immunoreactivity. The substantia nigra was well preserved, and no cortical Lewy bodies were seen. These findings indicate that pure autonomic failure is one of the Lewy body type alpha-synucleinopathies, such as Parkinson's disease and dementia with Lewy bodies, targeting the peripheral autonomic nervous system.

Alam, Z. I., B. Halliwell, et al. (2000). "No evidence for increased oxidative damage to lipids, proteins, or DNA in Huntington's disease." J Neurochem 75(2): 840-6.
It has been proposed that mitochondrial dysfunction and excitotoxic mechanisms lead to oxidative damage in the brain of Huntington;s disease patients. We sought evidence that increased oxidative damage occurs by examining postmortem brain material from patients who had died with clinically and pathologically diagnosed Huntington's disease. Oxidative damage was measured using methods that have already demonstrated the presence of increased oxidative damage in Parkinson's disease, Alzheimer's disease, and senile dementia of the Lewy body type. No alterations in the levels of lipid peroxidation (as measured by lipid peroxides and thiobarbituric acid-malondialdehyde adducts) were found in the caudate nucleus, putamen, or frontal cortex of patients with Huntington's disease compared with normal controls. Similarly, there were no elevations in the levels of 8-hydroxyguanine or of a wide range of other markers of oxidative DNA damage. Levels of protein carbonyls in these tissues were also unaltered. Our data suggest that oxidative stress is not a major component of the degenerative processes occurring in Huntington's disease, or at least not to the extent that occurs in other neurodegenerative disorders.

Wenning, G. K., G. Ebersbach, et al. (1999). "Progression of falls in postmortem-confirmed parkinsonian disorders." Mov Disord 14(6): 947-50.
Although falls are known to occur in several parkinsonian disorders, such as Parkinson's disease (PD), multiple system atrophy (MSA), dementia with Lewy bodies (DLB), corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP), differences in the evolution of this feature have not been studied systematically in pathologically confirmed cases. Seventy-seven cases with pathologically confirmed parkinsonian disorders (PD: n = 11, MSA: n = 15, DLB: n = 14, CBD: n = 13, PSP: n = 24), collected up to 1994, formed the basis for a multicenter clinicopathologic study organized by the National Institute of Neurological Disorders and Stroke to improve differential diagnosis of parkinsonian disorders. In the present study, we determined the time course, that is, the duration from first symptom to onset (latency) and duration from onset to death, of recurrent falls. Furthermore, we analyzed the diagnostic validity of a predefined latency to onset of recurrent falls within 1 year of symptom onset. Significant group differences for latency, but not duration, of recurrent falls were observed. Latencies to onset of falls were short in PSP patients, intermediate in MSA, DLB, and CBD, and long in PD. Recurrent falls occurring within the first year after disease onset predicted PSP in 68% of the patients. Our study demonstrates for the first time that latency to onset, but not duration, of recurrent falls differentiates PD from other parkinsonian disorders. Whereas early falls are important for the diagnosis of PSP, the addition of other features increases its diagnostic predictive value.

Vieregge, P., J. Hagenah, et al. (1999). "Parkinson's disease in twins: a follow-up study." Neurology 53(3): 566-72.
OBJECTIVE: To reevaluate concordance rates in 9 monozygotic (MZ) and 12 dizygotic (DZ) twin pairs with PD 8 years after the initial study. BACKGROUND: Longitudinal investigations increase accuracy in clinical diagnosis of PD. METHODS: Follow-up by personal interview and clinical examination. RESULTS: Concordance rates were not different between MZ (3/9) and DZ (5/12) twin pairs at follow-up, even when PD-associated dementia and isolated postural tremor were considered diagnostic of familial Lewy body parkinsonism. Evaluation of medical history, personality traits, and blink rate did not reveal putative early or premorbid parkinsonism in 9 co-twins who were motor-asymptomatic during the follow-up interval. However, these co-twins had reduced semantic fluency in comparison with a healthy control group of similar age. None of 7 co-twins without motor signs who underwent PET investigation 6 years previously showed signs of extrapyramidal disease at follow-up, but verbal memory continued to be reduced in 5 of these co-twins. CONCLUSION: Based on concordance rates only, the findings in our twin sample do not support a major genetic impact for the motor expression of PD.

Takanashi, M., T. Urabe, et al. (1999). "[A 73-year-old woman with familial Parkinson's disease]." No To Shinkei 51(12): 1087-96.
We report a 73-year-old Japanese woman with familial Parkinson's disease. The patient was well until her 67 years of the age, when she noted rest tremor in her right hand. Soon after her gait became short stepped. She visited our clinic on October 6, 1992 when she was 68 years old. She was alert and well oriented without dementia. She showed masked face, small voice, small stepped gait, retropulsion, resting tremor in her right hand, rigidity in the neck, and bradykinesia. She was treated with 400 mg/day of levodopa-carbidopa, which improved her symptoms, however, she developed wearing off phenomenon 3 years after the initiation of levodopa treatment. On August 26, 1998, she developed abdominal pain, diarrhea, and vomiting. She was admitted to another hospital, where abdominal plain x-ray revealed an evidence of intestinal obstruction (ileus). She was treated with nasogastric suction and intravenous fluid. Her condition did not improve and she was transferred to our hospital on August 29, 1998. Her family history revealed no consanguineous marriage. She had two elder brothers and three elder sisters. One of her brothers had been diagnosed as Parkinson's disease. Her husband also suffered from Parkinson's disease, however, her parents apparently did not have Parkinson's disease. On admission, she appeared to be drowsy. Her blood pressure was 102/70 mmHg, body temperature 36.2 degrees C. The lungs were clear and no cardiac murmur was present. Abdomen was flat and bowel sound was audible. No abnormal mass was palpable. Neurologic examination revealed mild consciousness disturbance, masked face, and small voice. No motor paralysis was noted. Muscle tone was hypotonic. No abnormal involuntary movement was noted. Abnormal laboratory findings on admission were as follows; WBC 11,300/microliter, amylase 1,373 IU/l, CK 446 IU/l, BUN 50 mg/dl, creatinine 1.17 mg/dl, CRP 22.7 mg/ dl, Na 134 mEq/l, K 3.1 mEq/l, and Cl 81 mEq/l. A chest x-ray film revealed pneumonic shadows in both lower lung fields. She was treated by nasointestinal suction, intravenous fluids, and chemotherapy for her infection. Her BP started to drop on September 2 and she developed cardiac arrest on the same day. She was discussed in a neurological CPC. The chief discussant arrived at the conclusion that the patient had a form of autosomal dominant familial Parkinson's disease. As parents did not have Parkinson's disease, some of the participants raised the possibility of autosomal recessive inheritance. But the age of onset was too late for autosomal recessive inheritance. Majority thought that the mode of inheritance was autosomal dominant with low penetrance. alpha-Synuclein mutation causes an autosomal dominant familial Parkinson's disease, but this type is very rare in non-Greek populations and the penetrance is high. Chromosome 2-linked autosomal dominant familial Parkinson's disease shows low penetrance. There are many other autosomal dominant forms of familial Parkinson's disease linked to yet unknown chromosome loci. Majority thought that this patient also had a form of Lewy-body positive autosomal dominant familial Parkinson's disease of unknown chromosome locus. Post mortem examination revealed ischemic intestinal lesion with strangulation. This was thought to be the cause of her death. In the central nervous system, the brain appeared to be normal by inspection. In the coronal sections, the substantia nigra and the locus coeruleus showed marked depigmentation. Histologic examination revealed marked neuronal loss and Lewy body formation in the remaining neurons. Pathologic examination was consistent with Parkinson's disease. Mutational analysis for the parkin gene was negative.

Stoppe, G., C. A. Brandt, et al. (1999). "Behavioural problems associated with dementia: the role of newer antipsychotics." Drugs Aging 14(1): 41-54.
Behavioural disorders are a common feature in dementia, especially in the later stages of the disease. The most frequent disorders are agitation, aggression, paranoid delusions, hallucinations, sleep disorders, including nocturnal wandering, incontinence and (stereotyped) vocalisations or screaming. Behavioural disorders, rather than cognitive disorders, are the main reason why caregivers place patients with dementia in a nursing home. However, although behavioural disorders are important, there is still no international agreement with respect to the description and definition of symptoms and syndromes. This also holds true for the wide variety of scales for quantification and measurement of behavioural disorders. Drug therapy should be considered after possible underlying causes such as physical illness, drug adverse effects and environmental stressors have been ruled out, or specifically addressed, and a behavioural approach has also failed. This article briefly reviews the evidence for non-antipsychotic drug therapies, which include a variety of substances. However, antipsychotics are the group of drugs which have been most frequently studied for the treatment of behavioural syndromes in dementia. Drug responsive symptoms include anxiety, verbal and physical agitation, hallucinations, delusions, uncooperativeness and hostility, whereas wandering, hoarding, unsociability, poor self-care, screaming and other stereotyped behaviour seem to be unresponsive to all drugs. Although the use of classical antipsychotics is limited by extrapyramidal symptoms, anticholinergic adverse effects, sedation and postural hypotension, the newer antipsychotics offer the chance of a better risk:benefit ratio. This article reviews the small amount of data published on the use of the newer antipsychotics, and concludes that risperidone at low dosages (0.5 to 2 mg/day) seems to be especially useful for the treatment of behavioural symptoms in dementia because of its negligible anticholinergic adverse effects. The use of clozapine is limited by its anticholinergic activity, at least in dementia of the Alzheimer and Lewy body types. However, in patients with psychosis arising from Parkinson's disease it seems to be the drug of choice, and similar activity is likely for olanzapine. There are no published data on other newer drugs, such as sertindole, quetiapine or ziprasidone. Future studies should also address questions of dementia heterogeneity and should compare different drug treatments and treatment combinations.

Sohn, Y. K., N. Ganju, et al. (1999). "Neuritic sprouting with aberrant expression of the nitric oxide synthase III gene in neurodegenerative diseases." J Neurol Sci 162(2): 133-51.
Neuronal loss, synaptic disconnection and neuritic sprouting correlate with dementia in Alzheimer's disease (AD). Nitric oxide (NO) is an important synaptic plasticity molecule generated by nitric oxide synthase (NOS) oxidation of a guanidino nitrogen of L-arginine. Experimentally, the NOS III gene is modulated with neuritic sprouting. In a previous study, NOS III expression was found to be abnormal in cortical neurons, white matter glial cells, and dystrophic neurites in AD and Down syndrome brains. The present study demonstrates the same abnormalities in neuronal and glial NOS III expression with massive proliferation of NOS III-immunoreactive neurites and glial cell processes in other neurodegenerative diseases including: diffuse Lewy body disease, Pick's disease, progressive supranuclear palsy, amyotrophic lateral sclerosis, multiple system atrophy, and Parkinson's disease. However, each disease, including AD, was distinguished by the selective alterations in NOS III expression and sprouting in structures marred by neurodegeneration. Double label immunohistochemical staining studies demonstrated nitrotyrosine and NOS III co-localized in only rare neurons and neuritic sprouts, suggesting that peroxynitrite formation and nitration of growth cone proteins may not be important consequences of NOS III enzyme accumulation. The results suggest that aberrant NOS III expression and NOS III-associated neuritic sprouting in the CNS are major abnormalities common to several important neurodegenerative diseases.

Shiozaki, K., E. Iseki, et al. (1999). "Alterations of muscarinic acetylcholine receptor subtypes in diffuse lewy body disease: relation to Alzheimer's disease." J Neurol Neurosurg Psychiatry 67(2): 209-13.
OBJECTIVES: Dementia associated with Lewy bodies in cortical and subcortical areas is classified as dementia of the non-Alzheimer type and termed diffuse Lewy body disease (DLBD). The generic term "dementia with Lewy bodies (DLB)" was proposed in the international workshop on Lewy body dementia to include the similar disorders presenting Lewy bodies. In DLB, a lower level of choline acetyltransferase (ChAT) activity in the neocortex was found compared with that in Alzheimer's disease. The purpose of the present study was to determine the total amount of muscarinic acetylcholine receptors (mAChRs) and relative proportion of each subtype (m1-m4) of mAChRs in the frontal and temporal cortex of seven DLBD and 11 Alzheimer's disease necropsied brains. METHODS: A [(3)H]quinuclidinyl benzilate (QNB) binding assay and an immunoprecipitation assay using subtype-specific antibodies were performed. Each antibody was raised against fusion proteins containing peptides corresponding to the third intracellular (i3) loops of the respective mAChR subtype. RESULTS: The total amounts of mAChRs were significantly lower in the preparations of temporal cortices from DLBD and Alzheimer's disease than in those from dead controls (seven cases). In both diseases, the proportion of the m3 receptor in the frontal cortex was significantly increased and that of the m4 receptor in the temporal cortex was significantly decreased compared with the control specimens. The proportions of the m1 and m2 subtypes were significantly different in the temporal cortex. The proportion of the m1 receptor was significantly greater in the DLBD brains, whereas that of the m2 receptor was significantly greater in the Alzheimer's disease brains than in the controls. CONCLUSIONS: The m1 receptor is the major subtype in the cerebral cortex, and m2 is known to be present at presynaptic terminals. The higher proportions of m1 in DLBD and m2 in Alzheimer's disease suggest that the manner of degeneration in the cholinergic system is different between the diseases. It is hypothesised that a severe depletion of presynaptic cholinergic projective neurons causes the upregulation of m1 receptor in the temporal cortex in DLBD.

Shinotoh, H. (1999). "[Dementia with Lewy bodies and Parkinson's disease with dementia]." Rinsho Shinkeigaku 39(11): 1171-2.

Scott, L. (1999). "Parkinson's disease and dementia with Lewy bodies." Elder Care 11(4): 37-9.

Primavera, J., B. X. Lu, et al. (1999). "Brain Accumulation of Amyloid-beta in Non-Alzheimer Neurodegeneration." J Alzheimers Dis 1(3): 183-193.
We report an unusual case of amyotrophic lateral sclerosis (ALS) marked by extensive cerebral amyloid-beta deposition in small and medium-size vessels, capillaries, and perivascular plaques in the cerebral cortex, and in most leptomeningeal vessels. Despite considerable cerebral amyloidosis, the patient remained cognitively intact until death. For comparison with other neuro-degenerative diseases and normal aging, we assessed the densities of amyloid-beta-immunoreactive cortical vessels and plaques in matched frontal and temporal lobe sections from archival uncomplicated cases of Alzheimer's disease (N=10), Pick's disease (PkD; N=4), Parkinson's disease (PD; N=6), Diffuse Lewy body disease (DLBD; N=7), progressive supranuclear palsy (PSP; N=5), multiple systems atrophy (MSA; N=4), ALS (N=7), or normal aging (N=10) by semi-quantitative grading (0 to 3+). Moderate (2+) or abundant (3+) cerebrovascular amyloid-beta immunoreactivity was detected in 8/10 AD, 3/7 DLBD, 3/6 PD, 1 each with PSP or PkD, and 2/10 controls. Moderate or abundant densities of amyloid-beta-immunoreactive diffuse plaques were detected in all cases of AD or DLBD, 4/6 with PD, 3/5 with PSP, and 2/10 controls. Moderate or abundant amyloid-beta-immunoreactive mature (dense core) plaques were present in all cases of AD or DLBD, and 3 each with PD or PSP. Importantly, amyloid-beta-immunoreactivity was not observed in the 4 MSA or 7 archival ALS cases. This study demonstrates that prominent amyloid-beta accumulation in cerebral vessels and plaques occurs frequently in AD, DLBD, PSP, and PD, but not in ALS or MSA, indicating that the case described is unique. The lack of cognitive impairment in the case presented argues against the idea that extensive amyloid-beta deposition in the brain causes dementia.

Mizutani, T. (1999). "[Familial parkinsonism and dementia with ballooned neurons, argyrophilic neuronal inclusions, atypical neurofibrillary tangles, tau-negative astrocytic fibrillary tangles, and Lewy bodies]." Rinsho Shinkeigaku 39(12): 1262-3.
We reported a new type of familial Parkinson's disease (familial PD) previously. After that, we examined this family by both the immunohistochemical staining using anti-alpha-synuclein antibody and the analysis of alpha-synuclein gene. We reported these results, and briefly reviewed both familial PD and "familial frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17)". Immunohistochemical staining with anti-alpha-synuclein antibody revealed that the argyrophilic neuronal inclusions and atypical barely tau-positive neurofibrillary tangles were strongly immunoreactive, whereas the ballooned neurons and astrocytic fibrillary tangles were unreactive. DNA analysis of the leukocytes obtained from one live patient of our family did not show any mutations in the entire exons of alpha-synuclein gene. Our results indicated that our family had familial diffuse Lewy body disease with atypical features and without alpha-synuclein gene abnormalities. Features of familial PD included 1) autosomal dominant inheritance, 2) not uncommon atypical clinical features, 3) variable symptomatology and dopa-responsiveness, and 4) low incidence of alpha-synuclein gene abnormalities. Our familial PD showed similar features, and neuropathological findings of our patients also resembled FTPD-17 in the presence of frequent ballooned neurons and neurofibrillary tangles in the cerebral cortex, but were different in the presence of Lewy bodies and paucity of tau pathology.

Mattila, P. M., J. O. Rinne, et al. (1999). "Neuritic degeneration in the hippocampus and amygdala in Parkinson's disease in relation to Alzheimer pathology." Acta Neuropathol (Berl) 98(2): 157-64.
It has been suggested that dystrophic neurites in the hippocampal CA2-3 sector are characteristic of diffuse Lewy body disease (DLBD) but not of Parkinson's disease (PD). We investigated the severity of neuritic change in the CA2-3 sector of the hippocampus and in the periamygdaloid cortex (PAC) in 45 patients with clinically diagnosed and neuropathologically verified PD. Samples from amygdala, hippocampus, entorhinal cortex (ERC) and cortical gyri were examined for Alzheimer-type (AD) changes and Lewy bodies (LBs) using antibodies against ubiquitin and tau. Ubiquitin-positive but polyclonal tau-negative neurites were detected in the CA2-3 region of the hippocampus in 88% of patients and in the PAC in 91% of patients. The CA2-3 sector neurites correlated significantly only with LBs in all other brain areas, except in the amygdala. The neurites in the PAC correlated significantly with neuropathological variables in all other brain areas examined, except with tangles in the pre-central and frontal gyrus and with LBs in the amygdala and in the ERC. Unlike in the CA2-3 sector, the neuritic change in the PAC was more prominent in those PD patients with more severe cognitive impairment (P = 0.03). There was no significant correlation between the apoE4 allele load and the neuritic change in the PAC or in the CA2-3 sector. Our study revealed that cortical LBs and neuritic change in the amygdala and hippocampal CA2-3 sector co-exist in PD. Unlike hippocampal neurites, the PAC neurites are related to AD pathology. There seems to be a relationship between the PAC neurites and cognitive impairment in PD, but its significance needs further elucidation.

Luis, C. A., W. W. Barker, et al. (1999). "Sensitivity and specificity of three clinical criteria for dementia with Lewy bodies in an autopsy-verified sample." Int J Geriatr Psychiatry 14(7): 526-33.
OBJECTIVE: To evaluate the sensitivity and specificity of the clinical features of three published diagnostic criteria for diffuse Lewy body disease (DLBD) using autopsy-confirmed Alzheimer's (AD), DLBD and AD+DLBD (mixed) dementia cases. DESIGN: Retrospective chart review of an autopsy series of 56 patients selected from the State of Florida Brain Bank on the basis of a pathological diagnosis of either pure AD, DLBD (pure and common forms) or AD+DLBD (mixed) dementia. Clinical features were assessed by three raters blind to the pathological diagnosis. RESULTS: The existing criteria for a clinical diagnosis of DLBD were highly specific (90-100%) but not very sensitive (49-63%) in the differential diagnosis of DLBD versus AD; sensitivity did improve (61-74%) when mixed AD+DLBD cases were eliminated. Clinical features that occur more frequently in DLBD than in AD were unspecified hallucinations, unspecified EPS, fluctuating course and rapid progression. Post-hoc analysis also indicated that hallucinations and EPS were more common early in the disease course of DLBD than in AD. Empirically derived criteria, formulated using the most prevalent clinical features, demonstrated sensitivity values of 57-96% for pure forms and 43-91% for mixed forms. CONCLUSIONS: This study demonstrated that additional improvements in the established criteria for DLBD are needed. Our empirically derived criteria enhanced the distinction of DLBD from AD while allowing the clinician the choice of maximizing sensitivity with acceptable specificity, and vice versa.

Luis, C. A., W. Mittenberg, et al. (1999). "Diffuse Lewy body disease: clinical, pathological, and neuropsychological review." Neuropsychol Rev 9(3): 137-50.
The pathophysiological etiologies and clinical presentations of neurodegenerative dementias have been found to be complex and heterogeneous. Recently, Lewy body inclusions have been identified as an etiological factor in 20-34% of autopsied dementia cases. The term diffuse Lewy body disease (DLBD) is generally accepted as the diagnostic term representative of this currently under-reported and under-recognized disease. This article reviews the literature on the clinical, pathological, and neuropsychological features of this disorder. Differential diagnostic issues are discussed as well as current pharmacological treatment. Nine confirmed cases of DLBD are presented to demonstrate the various features of this disorder. The diagnostic implications of neuropsychological examination results are discussed in relation to other common dementing neurologic diseases.

Iwatsubo, T. (1999). "[Parkinson's disease, dementia with Lewy bodies, multiple system atrophy and alpha-synuclein]." Rinsho Shinkeigaku 39(12): 1285-6.
Lewy bodies (LBs) are hallmark lesions of degenerating neurons in the brains of patients with Parkinson's disease (PD) and dementia with Lewy bodies (DLB). DLB is the second most common neurodegenerative dementia after Alzheimer's disease, which is characterized clinically by fluctuating cognitive impairments, visual hallucinations and parkinsonism, and pathologically by the appearance of cortical LBs. To characterize the components of LBs, we have developed a purification procedure for LBs from cortices of patients with DLB using sucrose density separation followed by fluorescence-activated particle sorting. We then raised monoclonal antibodies (mAbs) to purified LBs, and obtained a mAb (LB509) that intensely immunolabeled LBs and specifically reacted with a approximately 18kDa brain protein, which was identified as alpha-synuclein. LB509 as well as other antibodies to alpha-synuclein, but not to beta-synuclein, immunostained brainstem and cortical LBs in sporadic PD and DLB brains. Recently, a point mutation in alpha-synuclein gene was identified in some autosomal-deminantly inherited familial PD pedigrees. Moreover, glial cytoplasmic inclusions in the brains of patients with multiple system atrophy (MSA) were shown to be alpha-synuclein positive. Taken together, our data strongly implicate alpha-synuclein in the formation of LBs and the selective neuronal degeneration in PD, DLB and MSA.

Hattori, N., S. Sumino, et al. (1999). "[An 80-year-old woman with parkinsonism and progressive dementia]." No To Shinkei 51(6): 541-50.
We report an 80-year-old Japanese woman who presented levodopa-responsible parkinsonism followed by progressive dementia. She was well until her 61 years of age (in 1978) when she noted onset of resting tremor in her right hand followed by tremor in her right leg. She was treated with levodopa and trihexyphenidyl with good response, however, later on, she suffered from gait disturbance. In 1985, she had an episode of cardio-pulmonary arrest from which she was resuscitated, however, she started to show hypermetamorphosis, memory defect, and aggressive behaviors. She also developed motor fluctuations and dyskinesias from levodopa. She was admitted to our service in 1986; she showed rather typical parkinsonism and mild dementia. She received left Vim thalamotomy in the same year. Her dyskinesias improved, however, her gait disturbance became progressively worse. In 1995, she was admitted to our service again; she showed marked dementia and advanced parkinsonism; she was unable to walk unsupported. She became bedridden in 1996 and gastrostomy was placed. She was transferred to Zushi Aoki Hospital. Her dementia became progressively worse, and she was in the akinetic and mute state. She expired on April 22, 1998. She was discussed in a neurological CPC. The chief discussant arrived at a conclusion that the patient had Parkinson's disease with complication by Alzheimer's disease in her later clinical course. The diagnoses of participants were divided among Parkinson's disease with dementia, Parkinson's disease and Alzheimer's disease, and diffuse Lewy body disease. Postmortem examination revealed marked neuronal loss in the substantia nigra and the locus coeruleus. Lewy bodies were found in the substantia nigra. In addition, rather many Lewy bodies of cortical type were seen in the cingulate gylus, inferior temporal gylus, and in the amygdaloid nucleus. These Lewy bodies were positive for alpha-synuclein. Also, tau-positive intra-neuronal tangles were seen in the hippocampus and in the substantia nigra. The Meynert nucleus showed marked neuronal loss. Pathologic findings were consistent with the diagnosis of diffuse Lewy body disease.

Hashimoto, M., A. Takeda, et al. (1999). "Role of cytochrome c as a stimulator of alpha-synuclein aggregation in Lewy body disease." J Biol Chem 274(41): 28849-52.
alpha-Synuclein is a major component of aggregates forming amyloid-like fibrils in diseases with Lewy bodies and other neurodegenerative disorders, yet the mechanism by which alpha-synuclein is intracellularly aggregated during neurodegeneration is poorly understood. Recent studies suggest that oxidative stress reactions might contribute to abnormal aggregation of this molecule. In this context, the main objective of the present study was to determine the potential role of the heme protein cytochrome c in alpha-synuclein aggregation. When recombinant alpha-synuclein was coincubated with cytochrome c/hydrogen peroxide, alpha-synuclein was concomitantly induced to be aggregated. This process was blocked by antioxidant agents such as N-acetyl-L-cysteine. Hemin/hydrogen peroxide similarly induced aggregation of alpha-synuclein, and both cytochrome c/hydrogen peroxide- and hemin/hydrogen peroxide-induced aggregation of alpha-synuclein was partially inhibited by treatment with iron chelator deferoxisamine. This indicates that iron-catalyzed oxidative reaction mediated by cytochrome c/hydrogen peroxide might be critically involved in promoting alpha-synuclein aggregation. Furthermore, double labeling studies for cytochrome c/alpha-synuclein showed that they were colocalized in Lewy bodies of patients with Parkinson's disease. Taken together, these results suggest that cytochrome c, a well known electron transfer, and mediator of apoptotic cell death may be involved in the oxidative stress-induced aggregation of alpha-synuclein in Parkinson's disease and related disorders.

Hashimoto, M. and E. Masliah (1999). "Alpha-synuclein in Lewy body disease and Alzheimer's disease." Brain Pathol 9(4): 707-20.
Alzheimer's disease (AD) and Lewy body disease (LBD) are the most common causes of dementia in the elderly population. Previous studies have shown that cognitive alterations in these disorders are associated with synaptic loss. Injury and loss of synapses might be associated with altered function of synaptic proteins. Among them, recent studies have shown that abnormal aggregation and accumulation of synaptic proteins, such as alpha-synuclein, might be associated with plaque formation in AD and Lewy body formation in LBD. Further reinforcing the hypothesis that alpha-synuclein plays a major role in the pathogenesis of these disorders, recent work has shown that mutations that alter the conformation of this molecule are associated with familial forms of Parkinson's disease. The mechanisms by which altered function or aggregation of alpha-synuclein might lead to neurodegeneration are not completely clear; however, new evidence points to a potential role for this molecule in synaptic damage and neurotoxicity via amyloid-like fibril formation and mitochondrial dysfunction. In this manuscript we review the data linking alpha-synuclein to the pathogenesis of AD and LBD.

Hanyu, H., T. Asano, et al. (1999). "[Is hippocampal atrophy a specific change for Alzheimer's disease?]." No To Shinkei 51(11): 947-51.
Although detection of hippocampal atrophy has been proposed for the diagnosis of Alzheimer's disease (AD), atrophic changes in MRI can be found in other dementia diseases. This study was undertaken to determine whether hippocampal atrophy was a specific change for AD. Coronal T 1-weighted images were performed in 36 patients with AD, 40 patients with non-AD including vascular dementia, frontemporal dementia, Parkinson's disease with dementia, dementia with Lewy bodies, progressive supranuclear palsy, and normal pressure hydrocephalus, 9 patients with age-associated memory impairment (AAMI), and 24 control subjects. Hippocampal atrophy was graded subjectively on a 5-point scale. Scores of hippocampal atrophy for AD (2.11 +/- 0.95) and non-AD (1.80 +/- 0.91) were significantly higher than those for controls (0.79 +/- 0.72). Scores for AD were also significantly higher than those for AAMI (1.11 +/- 0.160), but no difference was found between AD and non-AD. These results suggest that hippocampal atrophy is not a specific marker for AD and appears to be a common phenomenon in dementia syndromes.

Galvin, J. E., K. Uryu, et al. (1999). "Axon pathology in Parkinson's disease and Lewy body dementia hippocampus contains alpha-, beta-, and gamma-synuclein." Proc Natl Acad Sci U S A 96(23): 13450-5.
Pathogenic alpha-synuclein (alphaS) gene mutations occur in rare familial Parkinson's disease (PD) kindreds, and wild-type alphaS is a major component of Lewy bodies (LBs) in sporadic PD, dementia with LBs (DLB), and the LB variant of Alzheimer's disease, but beta-synuclein (betaS) and gamma-synuclein (gammaS) have not yet been implicated in neurological disorders. Here we show that in PD and DLB, but not normal brains, antibodies to alphaS and betaS reveal novel presynaptic axon terminal pathology in the hippocampal dentate, hilar, and CA2/3 regions, whereas antibodies to gammaS detect previously unrecognized axonal spheroid-like lesions in the hippocampal dentate molecular layer. The aggregation of other synaptic proteins and synaptic vesicle-like structures in the alphaS- and betaS-labeled hilar dystrophic neurites suggests that synaptic dysfunction may result from these lesions. Our findings broaden the concept of neurodegenerative "synucleinopathies" by implicating betaS and gammaS, in addition to alphaS, in the onset/progression of PD and DLB.

Forstl, H. (1999). "The Lewy body variant of Alzheimer's disease: clinical, pathophysiological and conceptual issues." Eur Arch Psychiatry Clin Neurosci 249 Suppl 3: 64-7.
In 1923, Friedrich H. Lewy described dementia with Lewy bodies in a large proportion of his patients with paralysis agitans which had co-incident plaques and neurofibrillary tangles. The potential contribution of Lewy bodies to a dementia syndrome with fluctuating course, visual hallucinations, Parkinsonian features and neuroleptic hypersensitivity was rediscovered many decades later. The comorbidity of Alzheimer's and Parkinson's disease is not uncommon as both diseases show an exponential increase with advancing age and their coincidence is of great clinical importance. The combination of a cholinergic deficit--which is particularly severe due to the double pathology targeting the basal nucleus of Meynert--and a dopaminergic deficit requires cholinergic and cautious dopaminergic treatment. Excessive dopamine (L-dopa), antidopaminergic (neuroleptic) or anticholinergic treatment (anti-Parkinson or neuroleptic medication) may further complicate the condition, worsen extrapyramidal, psychotic or cognitive disturbances and even lead to a neuroleptic malignant syndrome.

Farrer, M., K. Gwinn-Hardy, et al. (1999). "The genetics of disorders with synuclein pathology and parkinsonism." Hum Mol Genet 8(10): 1901-5.
Despite being considered the archetypal non-genetic neurological disorder, genetic analysis of Parkinson's disease has shown that there are at least three genetic loci. Furthermore, these analyses have suggested that the phenotype of the pathogenic loci is wider than simple Parkinson's disease and may include Lewy body dementia and some forms of essential tremor. Identification of alpha-synuclein as the first of the loci involved in Parkinson's disease and the identification of this protein in pathological deposits in other disorders has led to the suggestion that it may share pathogenic mechanisms with multiple system atrophy, Alzheimer's disease and prion disease and that these mechanisms are related to a synuclein pathway to cell death. Finally, genetic analysis of the synuclein diseases and the tau diseases may indicate that this synuclein pathway is an alternative to the tau pathway to cell death.

Cervilla, J. A., C. Russ, et al. (1999). "CYP2D6 polymorphisms in Alzheimer's disease, with and without extrapyramidal signs, showing no apolipoprotein E epsilon 4 effect modification." Biol Psychiatry 45(4): 426-9.
BACKGROUND: Allelic variation at the CYP2D6 gene has been reported to be associated with Parkinsons' disease (PD) and Lewy body dementia (LBD), but not with Alzheimer's disease (AD). AD has been associated with apolipoprotein E (apoE) epsilon 4 allele loading. METHODS: We examined CYP2D6 and apoE polimorphisms in a sample of 259 patients with dementia, 210 of whom had a diagnosis of AD, and 107 healthy controls. RESULTS: We found that the allelic frequency in our AD sample did not vary from that in the controls. The debrisoquine hydroxylase poor metabolize phenotype was not more prevalent among AD cases than among controls in contrast to that reported for PD and LBD. We also found that CYP2D6 status does not modify the risk effect for AD conferred by apoE epsilon 4 alleles. CONCLUSIONS: These findings provide some support to the notion that, at a genetic level, at least at this locus, AD could be distinct from PD and LBD.

Brown, D. F. (1999). "Lewy body dementia." Ann Med 31(3): 188-96.
Although Lewy body dementia (LBD) has received a considerable amount of interest in the last decade, there still exists a certain level of confusion concerning the clinical and neuropathological features associated with this disorder. According to many researchers, LBD represents a distinct dementing illness with specific clinical features. The neuropathological hallmark for this disorder is the Lewy body, a spherical intraneuronal cytoplasmic inclusion originally described in brainstem nuclei in Parkinson's disease. In LBD, Lewy bodies are found in subcortical nuclei, such as the substantia nigra, as well as diffusely in the neocortex. Recently, a consortium on dementia with Lewy bodies was held that established consensus guidelines for the clinical and pathological diagnosis of LBD. This review will focus on the newest developments in LBD, addressing specifically clinical and neuropathological features, diagnostic classification, genetics and potential pharmacotherapy.

Bayer, T. A., P. Jakala, et al. (1999). "Alpha-synuclein accumulates in Lewy bodies in Parkinson's disease and dementia with Lewy bodies but not in Alzheimer's disease beta-amyloid plaque cores." Neurosci Lett 266(3): 213-6.
A growing body of evidence suggests that the non-Abeta component of Alzheimer's disease amyloid precursor protein (NACP) or alpha-synuclein contributes to the neurodegenerative processes in Alzheimer's disease (AD), Parkinson's disease (PD) and dementia with Lewy bodies (DLB). In the present study antisera to the N terminus and the NAC domain of the alpha-synuclein protein were employed to elucidate the expression pattern in brains of patients with AD, PD, DLB and control specimen. Alpha-synuclein exhibited an overall punctuate expression profile compatible with a synaptic function. Interestingly, while Lewy bodies were strongly immunoreactive, none of the alpha-synuclein antisera revealed staining in mature beta-amyloid plaques in AD. These observations suggest that alpha-synuclein does not contribute to late neurodegenerative processes in AD brains.

Arima, K., S. Hirai, et al. (1999). "Cellular co-localization of phosphorylated tau- and NACP/alpha-synuclein-epitopes in lewy bodies in sporadic Parkinson's disease and in dementia with Lewy bodies." Brain Res 843(1-2): 53-61.
The precursor of the non-Abeta-component of Alzheimer's disease (AD) amyloid (NACP, alpha-synuclein) aggregates into insoluble filaments of Lewy bodies (LBs) in Parkinson's disease (PD) and dementia with LBs (DLB). The microtubule-associated protein tau is an integral component of filaments of neurofibrillary tangles (NFTs). NFTs are occasionally found in brains of PD and DLB; however, the presence of NFTs or tau-epitopes within LB-containing neurons is rare. Double-immunofluorescence study and peroxidase-immunohistochemical study in serial sections, performed to examine the co-localization of tau- and NACP-epitopes in the brainstem of PD and DLB, demonstrated that four different epitopes of tau including phosphorylation-dependent and independent ones were present in a minority of LBs, but more often than previously considered. A tau (tau2)-epitope was localized to filaments in the outer layers of brainstem-type LBs by immunoelectron microscopy. Therefore, we conclude that tau is incorporated into filaments in certain LBs. Extensive investigation has enabled us to classify this co-localization into four types: type 1, LBs with ring-shaped tau-immunoreactivity; type 2, LBs surrounded by NFTs; type 3, NACP- and tau-immunoreactive filamentous and granular masses; and type 4, NACP- and tau-immunoreactive dystrophic neurites. This study raises a new question whether aggregation and hyperphosphorylation of tau in PD and DLB are triggered by the collapse of intraneuronal organization of microtubules due to NACP-filament aggregation in neuronal perikarya and axons.

Arai, T., H. Akiyama, et al. (1999). "Immunohistochemical localization of amyloid beta-protein with amino-terminal aspartate in the cerebral cortex of patients with Alzheimer's disease." Brain Res 823(1-2): 202-6.
We investigated immunohistochemically the localization of amyloid beta-protein (Abeta) with amino-terminal aspartate (N1[D]) in brains of patients with Alzheimer's disease, diffuse Lewy body disease and Down's syndrome. A monoclonal antibody, 4G8, which recognizes the middle portion of Abeta, was used as a reference antibody to label the total Abeta deposits. Double staining with anti-Abeta(N1[D]) and 4G8 revealed that Abeta deposits in the subiculum and the neocortical deep layers often lacked N1[D] immunoreactivity, indicating N-terminal truncation of Abeta in these deposits. Abeta deposits in the neocortical superficial layers and the presubicular parvopyramidal layer always contained Abeta with N1[D]. Such regional as well as laminar differences in the distribution of Abeta beginning at N1[D] suggest that some local factors influence N-terminal processing of Abeta deposited in the brain.

Aksenova, M. V., M. Y. Aksenov, et al. (1999). "Oxidation of cytosolic proteins and expression of creatine kinase BB in frontal lobe in different neurodegenerative disorders." Dement Geriatr Cogn Disord 10(2): 158-65.
The presence of the biomarkers of oxidative damage, protein carbonyl formation and the inactivation of oxidatively sensitive brain creatine kinase (CK BB, cytosolic isoform), were studied in frontal lobe autopsy specimens obtained from patients with different age-related neurodegenerative diseases: Alzheimer's disease (AD), Pick's disease (PkD), diffuse Lewy body disease (DLBD), Parkinson's disease (PD), and age-matched control subjects. The CK activity was significantly reduced in the frontal lobe of AD, PkD and DLBD subjects, and CK BB-specific mRNA was significantly reduced in AD and DLBD. Protein carbonyl content was significantly increased in AD, PkD and DLBD. The results of this study confirm that the presence of biomarkers of oxidative damage is related to the presence of histopathological markers of neurodegeneration. Our data suggest that oxidative damage contributes to the development of the symptoms of frontal dysfunction in AD, PkD and DLBD. The development of frontal dysfunction in idiopathic PD might be secondary to oxidative damage and neuronal loss primarily located in the nigrostriatal system. The results of CK BB expression analysis demonstrate that the loss of the isoenzyme in different neurodegenerative diseases is likely the consequence of its posttranslational modification, possibly oxidative damage. Changes in CK BB expression may be an early indicator of oxidative stress in neurons.

Yamada, H., M. L. Dahl, et al. (1998). "No association between familial Alzheimer disease and cytochrome P450 polymorphisms." Alzheimer Dis Assoc Disord 12(3): 204-7.
Four different loci have been found to be involved in the development of familial Alzheimer disease (AD). The epsilon4 allele of the apolipoprotein E gene on chromosome 19 is a susceptibility factor for AD, and in a small number of AD families, dominant mutations with high penetrance are operating in genes on chromosomes 1, 14 and 21. However, the disease in many familial AD cases cannot be explained by these genes; thus, other genetic factors involved in the etiology of AD should exist. Recently, an association between the cytochrome P450 2D6B (CYP2D6B) allele and the Lewy body variant of AD was reported. In the present study, 54 unrelated Swedish familial AD patients and 56 age- and sex-matched healthy controls were studied with respect to the two genetic polymorphisms of oxidative drug metabolism, CYP2D6 and CYP2C19. No significant association was found between the defect CYP2D6A and -B or CYP2C19ml and -m2 alleles and familial AD patients, with the exception of a lower frequency of CYP2D6B in the male AD cases.

Wakabayashi, K., A. Kakita, et al. (1998). "Apolipoprotein E epsilon4 allele and progression of cortical Lewy body pathology in Parkinson's disease." Acta Neuropathol (Berl) 95(5): 450-4.
To elucidate whether the apolipoprotein E epsilon4 allele (APOE4) affects cortical neuropathology in Parkinson's disease (PD), we determined APOE genotypes and quantified the densities of cortical Lewy bodies (LBs), amyloid plaques and neurofibrillary tangles in 22 autopsy-proven PD cases (12 with dementia; 10 without dementia) that were not accompanied by Alzheimer's disease. The APOE4 frequency in the demented patient group was 0.21, which was significantly higher than that in Japanese controls (P < 0.04). LB densities in demented PD patients were significantly higher than those in non-demented PD patients, despite the shorter disease duration in the former. Moreover, plaque density in the temporal cortex and LB density in the cingulate cortex were significantly higher in the group with APOE4 than in that without the allele. There was no difference in tangle density between these two groups. These results suggest that APOE4 may influence the increase in the number of cortical LBs and amyloid plaques in PD. It is possible that when PD occurs in individuals with APOE4, concomitantly evolving cortical LB pathology in a proportion of cases results in limbic (transitional) or neocortical-type LB disease.

Wakabayashi, K., S. Hayashi, et al. (1998). "Autosomal dominant diffuse Lewy body disease." Acta Neuropathol (Berl) 96(2): 207-10.
We describe a Japanese family with parkinsonism and later-onset dementia. The proband developed parkinsonism at the age of 61 years, followed by dementia starting when she was 67. Her uncle, who was also her husband, died at the age of 78 years after 7- and 5-year histories of parkinsonism and dementia, respectively. Pathological examination of these two patients showed marked neuronal loss with Lewy bodies (LBs) in the brain stem pigmented nuclei and numerous cortical LBs and ubiquitin-positive hippocampal CA2/3 neurites were observed. The proband also had many amyloid plaques. Their two sons developed similar parkinsonism at the ages of 39 and 28 years and also suffered later-on-set dementia. The apolipoprotein E genotype of the proband, her uncle and one of their sons was epsilon3/4 and that of the other son was epsilon4/4. These findings strongly suggest that this family has autosomal dominant diffuse LB disease.

Verny, M. and C. Duyckaerts (1998). "Dementia with Lewy bodies." Ann Med Interne (Paris) 149(4): 209-15.
The presence of a high number of Lewy bodies--the morphological marker of Parkinson's disease--in the cerebral cortex of some cases of dementia has been frequently observed in association to Alzheimer type lesions (mainly senile plaques) and changes in the substantia nigra, that may be held responsible for the frequently associated symptoms of parkinsonism. The term "dementia with Lewy body" (DLB) has recently been suggested by a consensus conference and indicates that the pathogenetic mechanism of the dementia remains poorly understood. Marked fluctuations of alertness and of the cognitive performances, moderate parkinsonism and episodes of visual hallucinations may lead to suspect this diagnosis in cases of dementia. Unexplained falls, syncopes, delirium or alterations of consciousness may also be observed, and the patients may then be admitted in departments of internal medicine or geriatrics. The Lewy body is an intraneuronal spherical inclusion, present in Parkinson's disease. It is observed in the brainstem (substantia nigra, locus coeruleus, dorsal nucleus of the Xth nerve) and in the nucleus basalis of Meynert. The cortical Lewy bodies have a different aspect, but retain their antigenic characteristics: they are, in particular, stained by the antiubiquitin antibodies. Recently, they were found to be also labeled by antisynuclein antibodies. A mutation of the synuclein gene was recently identified in cases of familial Parkinson's disease. Clinically as well as pathologically, DLB may thus be difficult to distinguish from Alzheimer's disease on the one hand, and from Parkinson's disease, on the other. That diagnosis, however, is associated with a poor prognosis and should lead to specific therapeutic measures.

Trojanowski, J. Q. and V. M. Lee (1998). "Aggregation of neurofilament and alpha-synuclein proteins in Lewy bodies: implications for the pathogenesis of Parkinson disease and Lewy body dementia." Arch Neurol 55(2): 151-2.

Trojanowski, J. Q., M. Goedert, et al. (1998). "Fatal attractions: abnormal protein aggregation and neuron death in Parkinson's disease and Lewy body dementia." Cell Death Differ 5(10): 832-7.
The abnormal aggregation of proteins into fibrillar lesions is a neuropathological hallmark of several sporadic and hereditary neurodegenerative diseases. For example, Lewy bodies (LBs) are intracytoplasmic filamentous inclusions that accumulate primarily in subcortical neurons of patients with Parkinson's disease (PD), or predominantly in neocortical neurons in a subtype of Alzheimer's disease (AD) known as the LB variant of AD (LBVAD) and in dementia with LBs (DLB). Aggregated neurofilament subunits and alpha-synuclein are major protein components of LBs, and these inclusions may contribute mechanistically to the degeneration of neurons in PD, DLB and LBVAD. Here we review recent studies of the protein building blocks of LBs, as well as the role LBs play in the onset and progression of PD, DLB and LBVAD. Increased understanding of the protein composition and pathological significance of LBs may provide insight into mechanisms of neuron dysfunction and death in other neurodegenerative disorders characterized by brain lesions containing massive deposits of proteinacious fibrils.

Tanaka, S., X. Chen, et al. (1998). "Association of CYP2D microsatellite polymorphism with Lewy body variant of Alzheimer's disease." Neurology 50(6): 1556-62.
OBJECTIVE: To examine the genetic association of CYP2D6 locus with Lewy body variant (LBV) and Parkinson's disease (PD). METHODS: Allelic association was studied in patients with pure AD, LBV, and PD by using the CYP2D microsatellite, the (dG-dT)n dinucleotide repeat (n=16 to 27) located between CYP2D8P and CYP2D7 genes, and the CYP2D6 B and D mutations. RESULTS: We found overrepresentation of the alleles longer than 21 repeat (the long-type alleles) in LBV (allele frequency, 0.313) (odds ratio=1.99, p=0.019 by chi2 test) and in PD (0.298) (odds ratio=1.86, p=0.037), but not in pure AD (0.196), compared with the age-matched control (0.186). Strong association was noted of the long-type alleles with the CYP2D6 B mutation (odds ratio=88.50, p < 0.001 by Fisher's exact test), but not with the D mutation or the deletion of CYP2D6 gene. CONCLUSIONS: The CYP2D locus is closely associated with LBV and PD. The CYP2D6 B mutation may be involved in pathogenesis of LBV and PD in a dominant-negative manner, or in the linkage disequilibrium of the CYP2D microsatellite to another pathogenic gene locus.

Talbot, P. R., J. J. Lloyd, et al. (1998). "A clinical role for 99mTc-HMPAO SPECT in the investigation of dementia?" J Neurol Neurosurg Psychiatry 64(3): 306-13.
OBJECTIVES: To provide the clinician with a guide to the clinical utility of 99mTc-HMPAO single photon emission computed tomography (SPECT) and to the interpretation of specific test results in the differential diagnosis of dementia. METHODS: Three hundred and sixty three patients with dementia were studied prospectively for a median three (range 1-6) years and classified into disease groups on the basis of established clinical criteria. The degree to which different patterns of cerebral blood flow (CBF) abnormality found on 99mTc-HMPAO SPECT imaging at the time of initial patient presentation modified clinical diagnoses was determined by calculating the likelihood ratios for pairwise disease group comparisons. The optimal clinical usage of 99mTc-HMPAO SPECT was determined by calculating the percentage of significant test results for each pairwise disease group comparison. RESULTS: Bilateral posterior CBF abnormality was found to significantly increase the odds of a patient having Alzheimer's disease as opposed to vascular dementia or frontotemporal dementia. Bilateral anterior CBF abnormality significantly increased the odds of a patient having frontotemporal dementia as opposed to Alzheimer's disease, vascular dementia, or Lewy body disease. "Patchy" CBF changes significantly increased the odds of a patient having vascular dementia as opposed to Alzheimer's disease. Unilateral anterior, unilateral anterior plus unilateral posterior, and generalised CBF abnormality failed to contribute to the differentiation of any of these forms of dementia. CONCLUSIONS: 99mTc-HMPAO SPECT was found to be most useful in distinguishing Alzheimer's disease from vascular dementia and fronto temporal dementia, and least useful in differentiating between Alzheimer's disease and Lewy body disease, and between vascular dementia, frontotemporal dementia, and progressive aphasia. It is suggested that CBF SPECT should be used selectively and as an adjunct to clinical evaluation and CT.

Spillantini, M. G., R. A. Crowther, et al. (1998). "alpha-Synuclein in filamentous inclusions of Lewy bodies from Parkinson's disease and dementia with lewy bodies." Proc Natl Acad Sci U S A 95(11): 6469-73.
Lewy bodies and Lewy neurites are the defining neuropathological characteristics of Parkinson's disease and dementia with Lewy bodies. They are made of abnormal filamentous assemblies of unknown composition. We show here that Lewy bodies and Lewy neurites from Parkinson's disease and dementia with Lewy bodies are stained strongly by antibodies directed against amino-terminal and carboxyl-terminal sequences of alpha-synuclein, showing the presence of full-length or close to full-length alpha-synuclein. The number of alpha-synuclein-stained structures exceeded that immunoreactive for ubiquitin, which is currently the most sensitive marker of Lewy bodies and Lewy neurites. Staining for alpha-synuclein thus will replace staining for ubiquitin as the preferred method for detecting Lewy bodies and Lewy neurites. We have isolated Lewy body filaments by a method used for the extraction of paired helical filaments from Alzheimer's disease brain. By immunoelectron microscopy, extracted filaments were labeled strongly by anti-alpha-synuclein antibodies. The morphologies of the 5- to 10-nm filaments and their staining characteristics suggest that extended alpha-synuclein molecules run parallel to the filament axis and that the filaments are polar structures. These findings indicate that alpha-synuclein forms the major filamentous component of Lewy bodies and Lewy neurites.

Spillantini, M. G., R. A. Crowther, et al. (1998). "Filamentous alpha-synuclein inclusions link multiple system atrophy with Parkinson's disease and dementia with Lewy bodies." Neurosci Lett 251(3): 205-8.
Alpha-synuclein forms the major component of Lewy bodies and Lewy neurites, the defining neuropathological characteristics of Parkinson's disease and dementia with Lewy bodies. Here we show that alpha-synuclein is also the major component of the filamentous inclusions of multiple system atrophy which comprises several neurodegenerative diseases with a shared filamentous pathology in nerve cells and glial cells. These findings provide an unexpected link between multiple system atrophy and Lewy body disorders and establish that alpha-synucleinopathies constitute a major class of human neurodegenerative disorder.

Sparks, D. L., T. G. Beach, et al. (1998). "Immunohistochemical localization of nicotinic beta2 and alpha4 receptor subunits in normal human brain and individuals with Lewy body and Alzheimer's disease: preliminary observations." Neurosci Lett 256(3): 151-4.
Optimum immunohistochemical methods were established to immuno-localize nicotinic acetylcholine receptor alpha4 and beta2 subunits in temporal cortex and substantia nigra of normal aged and diseased human brain. In normal aged brain, fibers were immunoreactive for both the alpha4 and beta2 subunits of the nicotinic receptor in the temporal cortex and the substantia nigra. In the cortex of normal aged brain, rare neurofibrillary tangles occurring could be identified with either anti-alpha4 or anti-beta2 antibodies, but existing senile plaques were demonstrable with neither. In Alzheimer's disease temporal cortex, there were diminished numbers of nicotinic receptor subunit immunoreactive fibers, and there were appreciable numbers of neuropil threads, neurofibrillary tangles and senile plaques immunoreactive with both the alpha4 and beta2 antibodies.

Shiwach, R. S. and S. Woods (1998). "Risperidol and withdrawal bruxism in Lewy body dementia." Int J Geriatr Psychiatry 13(1): 65-6.

Scarbrough, T. J. (1998). "Diffuse Lewy body disease: a common yet misdiagnosed dementia in which neuroleptics may be contraindicated." Tenn Med 91(2): 58-60.

Sarter, M. and J. P. Bruno (1998). "Cortical acetylcholine, reality distortion, schizophrenia, and Lewy Body Dementia: too much or too little cortical acetylcholine?" Brain Cogn 38(3): 297-316.
Aberrations in cortical cholinergic transmission have been hypothesized to mediate the development and manifestation of psychotic cognition. Based primarily on hypotheses about mesolimbic dopaminergic hyperactivity in schizophrenia, the actions of antipsychotic drugs, the trans-synaptic regulation of the excitability of basal forebrain corticopetal cholinergic neurons, and the role of cortical cholinergic inputs in attentional functions, we hypothesized that persistent disinhibition of cortical cholinergic inputs mediates the fundamental cognitive dysfunctions which form the basis for the development of positive symptoms in schizophrenia. In contrast to this hypothesis, Perry and Perry (1995), based on evidence from hallucinating patients with Lewy Body Dementia (LBD), concluded that the extensive loss of cortical acetylcholine allows irrelevant information to enter "conscious awareness" and thus hallucinations to emerge. The discussion of these contrasting hypotheses highlights the need for more dynamic and precise theories describing the cognitive variables and neuronal processes which contribute to the development and manifestation of psychotic cognition. While the hypothesis that a disinhibited cholinergic system mediates the evolution of psychotic symptoms corresponds more convincingly with current theories about the cognitive functions of cortical cholinergic inputs, both hypotheses stress the critical role of cortical acetylcholine in the highest levels of cognitive functioning.

Rosenstein, L. D. (1998). "Differential diagnosis of the major progressive dementias and depression in middle and late adulthood: a summary of the literature of the early 1990s." Neuropsychol Rev 8(3): 109-67.
There is a preponderance of research on the neuropsychology of the various dementias. There are also direct comparisons between two or more dementias available in the literature. This paper sought to summarize the most recent literature, primarily from 1990 through mid-1996, including recent reviews of the literature from previous decades. The purpose was to provide, in one location, a summary of neuropsychological (i.e., cognitive, motor, and psychiatric) characteristics of major noninfectious, progressive dementias and depression of middle and late adulthood. It is hoped that this review, particularly a summary table provided, will serve as a guide in the differential diagnosis of the dementias by clinicians. In addition to Alzheimer's disease, vascular dementias, Parkinson's disease, Lewy body dementia, Huntington's disease, and frontal lobe dementia, the impact of depression on cognitive functioning is covered given the frequency with which neuropsychologists are asked to differentiate depression from primary dementia.

Pirim, I. (1998). "Production of anti-polyubiquitin and anti-ubiquitin carboxyl terminal hydrolase antibodies and immunohistochemically assessment of them on brain sections of Alzheimer's disease and Lewy body disease." Int J Neurosci 95(1-2): 33-42.
Several ubiquitin (ub) moieties are lined up head to tail by function of class III genes which code for polyubiquitin proteins. Ubiquitin carboxyl terminal hydrolyses (UCTH) disassemble the polyubiquitin chains. In our study we synthetically produced polyubiquitin (last six amino acids of ub is linked with first five amino acids of ub, UBI(71-76 + 1-5)) and purified anti-UCTH from human brain to produce antibodies against them. These antibodies were used on Alzheimer's and Lewy body disease brains. Anti-UBI(71-76 + 1-5) antibody stained plaque neurites of both disease brains. Anti-UCTH antibody showed reactivity with cortical Lewy bodies within the neurons and bulbous neurites of Alzheimer's disease and Lewy body disease brains.

Petit, H., F. Lebert, et al. (1998). "[Lewy body dementia]." Rev Neurol (Paris) 154 Suppl 2: S99-105.
Dementia with Lewy Bodies (DLB) is an entity which now fulfils clinical and neuropathological criteria according to international consensus guidelines (McKeith et al., 1996). It is now possible, in clinical practice, to consider the diagnosis of DLB from the beginning of the management of a demented patient. The clinical, diagnostic and therapeutic aspects of DLB are investigated in a prospective manner. Visual hallucinations, fluctuations and extrapyramidal symptoms seem to have, in association with the progressive cognitive decline, some particularities. However their specificity should be correlated with neuropathological data. Other symptoms, such as repeated falls or syncope, neuroleptic sensitivity, systematized delusions or other modalities of hallucinations, are probably additional arguments giving more predictive value to the association of the major symptoms. The role of neuropsychological patterns at the beginning of the cognitive decline is shown. There are some recent concordant results of functional imaging in DLB. The neuropathological aspects of DLB and the links with Parkinson pathology and especially Alzheimer pathology are emphasized.

Petersen, R. C. (1998). "Clinical subtypes of Alzheimer's disease." Dement Geriatr Cogn Disord 9 Suppl 3: 16-24.
Alzheimer's disease (AD) can present as a variety of clinical profiles. Although the most common presentation is that of a progressive amnestic disorder with subsequent involvement of other cognitive functions and personality alterations, there are numerous other clinical profiles. AD can present as a focal cortical degenerative syndrome with the clinical features dependent on the regions of the brain involved. Some of these syndromes include disturbances of language, visuospatial skills, attentional functions, executive processes and praxis. The neuropathological substrate of these disorders is variable and can include AD. Recently, the Lewy body variant of AD has been described. Finally, other modifying features that affect the progression of AD, such as extrapyramidal symptoms and myoclonus, are also discussed. Although the progressive amnestic form of AD is the most common presentation, other variations on the clinical syndrome can be important to identify because they may have implications for prognosis and treatment.

Perl, D. P., C. W. Olanow, et al. (1998). "Alzheimer's disease and Parkinson's disease: distinct entities or extremes of a spectrum of neurodegeneration?" Ann Neurol 44(3 Suppl 1): S19-31.
Alzheimer's disease (AD) and Parkinson's disease (PD) are generally considered to be separate and distinct disease entities. However, a considerable amount of evidence demonstrates that these disorders share common clinical and neuropathologic features and that overlap between the two conditions is extensive. For example, a significant percentage of AD patients exhibit extrapyramidal features, and many PD patients develop dementia. Similarly, at autopsy many AD patients not only exhibit the neuropathologic features of that disorder but also exhibit nigral pathology, including Lewy bodies. The vast majority of demented PD patients show widespread neurofibrillary tangles and senile plaques as well as Lewy body formation and nigral degeneration. The extent of such overlap is far greater than one would anticipate by chance alone. We argue that such overlap reflects a common pathogenic mechanism for the neurodegeneration encountered within specific vulnerable neuronal populations. Furthermore, we suggest that the current nosologic approach, which attempts to separate AD from PD, fails to properly deal with the issue of overlap and that a new classification of the neurodegenerative disorders should be considered.

Papka, M., A. Rubio, et al. (1998). "A review of Lewy body disease, an emerging concept of cortical dementia." J Neuropsychiatry Clin Neurosci 10(3): 267-79.
Dementia associated with cortical Lewy bodies on neuropathologic examination may comprise the second largest category of age-related cognitive impairment, after Alzheimer's disease. Despite its prevalence, a consensus has not yet been reached regarding the terminology, neuropathologic criteria, or clinical symptomatology of this postulated nosologic entity. Lewy body disease (LBD) is beginning to be diagnosed clinically in neuropsychiatric clinics, but universally accepted diagnostic criteria for LBD remain to be validated. In this article the authors review the literature on LBD, including both neuropathologic and clinical findings.

Papka, M., A. Rubio, et al. (1998). "Lewy body disease: can we diagnose it?" J Neuropsychiatry Clin Neurosci 10(4): 405-12.
The authors assessed the accuracy of published clinical criteria and their own modifications of those criteria in diagnosing Lewy body disease (LBD). Clinical diagnoses were made by two clinicians, blinded to neuropathologic diagnoses, using the Rochester Alzheimer's Disease Center database and traditional medical records. Neuropathologic diagnoses were made according to published guidelines. Results from 21 Alzheimer's disease and 18 LBD patients indicated that no set of clinical criteria was accurate in diagnosing LBD. The only significant predictor of LBD in this population was depression, which was more common in LBD than in Alzheimer's disease. The authors conclude that clinical identification of LBD is an important but unresolved neurological problem.

Olichney, J. M., D. Galasko, et al. (1998). "Cognitive decline is faster in Lewy body variant than in Alzheimer's disease." Neurology 51(2): 351-7.
OBJECTIVES: To quantify the rate of cognitive decline on the Mini-Mental State Examination (MMSE) in autopsy-diagnosed Lewy body variant (LBV) of Alzheimer's disease (AD) cases. We hypothesized that LBV patients would have a faster cognitive decline and shorter survival compared with patients with pure AD. BACKGROUND: Prior reports have shown extrapyramidal signs to be associated with a poorer prognosis in AD. It has been suggested that LBV is often characterized by a rapidly progressive course. Few data are available regarding the rate of cognitive decline in autopsy-confirmed LBV dementia cases. METHODS: We searched the databases of the University of California-San Diego Alzheimer's Disease Research Center and the Consortium to Establish a Registry in Alzheimer's Disease (CERAD) for dementia cases with 1) an autopsy diagnosis of definite or probable AD (CERAD criteria) with concomitant Lewy bodies and 2) longitudinal MMSE assessments. This resulted in a series of 40 LBV cases and 148 AD cases without Lewy bodies, with comparable baseline MMSE scores, age, and education. The rate of cognitive decline was calculated as the baseline MMSE -- final MMSE. Methods were devised to reduce floor effects on the MMSE. RESULTS: The average rate of cognitive decline was -5.8 +/- 4.5 points/y in LBV and -4.1 +/- 3.0 points/y in AD (t-test, p < 0.01). The LBV group declined a similar amount on the MMSE (means, -10.0 versus -9.6 points) over a significantly shorter time interval (1.9 versus 2.7 years; p = 0.005) than did AD patients. At baseline, the mean MMSE scores were nearly identical (18.2 in LBV; 17.8 in AD), but on follow-up examinations approximately 1, 2, and 3 years later, there were intergroup mean differences of 1.8 points (two-tailed p = 0.19), 4.2 points (p = 0.04), and 5.6 points (p = 0.03), respectively. The LBV cases had shorter survival time from the onset of cognitive symptoms (7.7 +/- 3.0 years versus 9.3 +/- 3.5 years; p = 0.007) and a shorter mean survival after entry/baseline, which was of marginal significance (3.6 versus 4.1 years; p = 0.11). CONCLUSIONS: This study demonstrates that LBV is characterized by a faster cognitive decline and accelerated mortality compared with AD.

Okuma, Y., N. Hattori, et al. (1998). "[A 74-year-old woman with parkinsonism and dementia who died four years after the onset]." No To Shinkei 50(7): 671-82.
We report a 74-year-old woman with parkinsonism and dementia, who died 4 years after the onset of the disease. She was well until 70 years of the age (1993) when she noted slowness in the movement in her left hand. She also developed gait disturbance and the similar symptoms spread to the right upper and lower extremities. Two years after the onset, she had difficulty in walk, and was admitted to our hospital on March 9, 1995. Her daughter had the onset of hand tremor at 50 years of the age and gait disturbance at 52. Her gait improved after levodopa treatment, but her MRI revealed a liner T2-high signal lesion along the outer surface of each putamen. On admission, the patient was alert but slighted demented. Higher cerebral functions were normal. She had a masked face and small voice. Her gait was of small step without arm swing. Retropulsion was present. Rigidity was noted in the neck but not in the limbs. She was bradykinetic but tremor was absent. She was treated with levodopa/carbidopa, dops, and bromocriptine with considerable improvement and was discharged on March 30, 1995. On January 19, 1996, she developed fever and hallucination; she became more akinetic and admitted again. She showed marked dementia and stage IV parkinsonism. She was treated by supportive measures with improvement in the general condition, but she was found to have a gastric cancer for which a subtotal gastrectomy was performed on March 11, 1996. Post-operative course was uneventful, but her parkinsonism progressed to stage V. She was transferred to another hospital on May 13, 1996. In July 21, 1996, she developed dyspnea and fever and was admitted to our hospital again. She was somnolent. Rigidity was moderate to marked and she was unable to stand or walk. By supportive cares, her general condition improved and was discharged to home on November 4, 1996. She developed fever on June 13, 1997 and admitted to our service again. Her BP was 150/90 mmHg. She was alert but markedly demented. Laboratory examination revealed increases in liver enzymes (GOT 75 IU/l, GPT 101 IU/l) and renal dysfunction (BUN 68 mg/dl, creatinine 3.27 mg/dl). Subsequent hospital course was complicated by renal failure and thrombocytopenia (33,000/ml). She expired on July 1, 1997. The patient was discussed in a neurologic CPC, and a chief discussant arrived at the conclusion that the patient had diffuse Lewy body disease and her daughter striatonigral degeneration. Some participants thought both the patient and her daughter had diffuse Lewy body disease. Post-mortem examination revealed marked degeneration of the substania nigra and the locus coeruleus. The medial part of the nigra also showed marked cell loss. Lewy bodies were found in the remaining nigral and coeruleus neurons. Cortical Lewy bodies were very few and the striatum was intact. Pathologic diagnosis was Parkinson's disease. Dementia was in part attributed to the marked degeneration of the medial part of the substantia nigra.

Ohara, K. and N. Kondo (1998). "Changes of monoamines in post-mortem brains from patients with diffuse Lewy body disease." Prog Neuropsychopharmacol Biol Psychiatry 22(2): 311-7.
1. In the present study, we measured the concentrations of 5-hydroxytryptamine (5-HT), norepinephrine and dopamine in post-mortem brains from five patients with diffuse Lewy body disease (DLBD), in comparison with five brains from patients with Alzheimertype dementia (ATD), and five brains from normal controls. 2. They were measured by means of high-performance liquid chromatography fluorometric detection. 3. Compared with the ATD and normal control brains, the DLBD ones showed decreased concentrations of 5-HT, norepinephrine and dopamine in the putamen, and lower 5-HT and norepinephrine concentrations, and almost equal dopamine ones in the neocortex.

McKeith, I. G., P. Ince, et al. (1998). "What are the relations between Lewy body disease and AD?" J Neural Transm Suppl 54: 107-16.
Several hospital based autopsy series indicate dementia with Lewy bodies (DLB) to be the second most common pathological subtype of degenerative dementia in elderly subjects. The majority of DLB cases have high densities of beta amyloid senile plaques, whereas neocortical neurofibrillary tangle density is only slightly increased above age-matched normal control values and over tenfold lower than the average in Alzheimer's disease. The interpretation of this Alzheimer type pathology is problematic, reflecting in part changing views about the neuropathological diagnosis of AD itself. AD is characterised by hyperphosphorylation of the microtubular associated protein tau, and DLB by neurofilament abnormalities including phosphorylation, ubiquitination, proteolysis, and cross-linking of constituent proteins. The two diseases appear therefore to be distinct at an ultrastructural and molecular level, a conclusion which is consistent with the fact that the clinical syndromes associated with DLB and AD are sufficiently differentiated to allow for accurate antemortem diagnosis.

Manford, M. and F. Andermann (1998). "Complex visual hallucinations. Clinical and neurobiological insights." Brain 121 ( Pt 10): 1819-40.
Complex visual hallucinations may affect some normal individuals on going to sleep and are also seen in pathological states, often in association with a sleep disturbance. The content of these hallucinations is striking and relatively stereotyped, often involving animals and human figures in bright colours and dramatic settings. Conditions causing these hallucinations include narcolepsy-cataplexy syndrome, peduncular hallucinosis, treated idiopathic Parkinson's disease, Lewy body dementia without treatment, migraine coma, Charles Bonnet syndrome (visual hallucinations of the blind), schizophrenia, hallucinogen-induced states and epilepsy. We describe cases of hallucinosis due to several of these causes and expand on previous hypotheses to suggest three mechanisms underlying complex visual hallucinations. (i) Epileptic hallucinations are probably due to a direct irritative process acting on cortical centres integrating complex visual information. (ii) Visual pathway lesions cause defective visual input and may result in hallucinations from defective visual processing or an abnormal cortical release phenomenon. (iii) Brainstem lesions appear to affect ascending cholinergic and serotonergic pathways, and may also be implicated in Parkinson's disease. These brainstem abnormalities are often associated with disturbances of sleep. We discuss how these lesions, outside the primary visual system, may cause defective modulation of thalamocortical relationships leading to a release phenomenon. We suggest that perturbation of a distributed matrix may explain the production of similar, complex mental phenomena by relatively blunt insults at disparate sites.

Litvan, I., A. MacIntyre, et al. (1998). "Accuracy of the clinical diagnoses of Lewy body disease, Parkinson disease, and dementia with Lewy bodies: a clinicopathologic study." Arch Neurol 55(7): 969-78.
BACKGROUND: Whether Parkinson disease (PD) and dementia with Lewy bodies (DLB) represent 2 distinct nosologic entities or are diverse phenotypes of Lewy body disease is subject to debate. OBJECTIVES: To determine the accuracy of the diagnoses of Lewy body disease, PD, and DLB by validating the clinical diagnoses of 6 neurologists with the neuropathologic findings and to identify early predictors of the diagnoses. METHODS: Six raters who were unaware of the neuropathologic diagnoses analyzed 105 clinical vignettes corresponding to 29 cases of Lewy body disease (post hoc analysis of 15 patients with PD and 14 with DLB) and 76 patients without PD or DLB whose cases were confirmed through autopsy findings. MAIN OUTCOME MEASURES: Sensitivity and positive predictive value (PPV) were chosen as validity measures and the K statistic as a reliability measure. RESULTS: Interrater reliability for the diagnoses of Lewy body disease and PD was moderate for the first visit and substantial for the last, whereas agreement for diagnosis of DLB was fair for the first visit and slight for the last. Median sensitivity for diagnosis of Lewy body disease was 56.9% for the first visit and 67.2% for the last; median PPV was 60.0% and 77.4%, respectively. Median sensitivity for the diagnosis of PD was 73.3% for the first visit and 80.0% for the last; median PPV was 45.9% and 64.1%, respectively. Median sensitivity for the diagnosis of DLB was 17.8% for the first visit and 28.6% for the last; median PPV was 75.0% for the first visit and 55.8% for the last. The raters' results were similar to those of the primary neurologists. Several features differentiated PD from DLB, predicted each disorder, and could be used as clinical pointers. CONCLUSIONS: The low PPV with relatively high sensitivity for the diagnosis of PD suggests overdiagnosis. Conversely, the extremely low sensitivity for the diagnosis of DLB suggests underdiagnosis. Although the case mix included in the study may not reflect the frequency of these disorders in practice, limiting the clinical applicability of the validity measures, the raters' results were similar to those of the primary neurologists who were not exposed to such limitations. Overall, our study confirms features suggested to predict these disorders, except for the early presence of postural imbalance, which is not indicative of either disorder.

Lindboe, C. F. and H. B. Hansen (1998). "The frequency of Lewy bodies in a consecutive autopsy series." Clin Neuropathol 17(4): 204-9.
In a consecutive autopsy series comprising 284 subjects > or = 50 years, 22 cases (7.7%) revealed Lewy bodies (LBs) of whom 21 had LBs in substantia nigra and/or locus ceruleus and 9 (3.2%) in the cerebral cortex. Only one case had cortical LBs without concomitant inclusions in the brain stem. The mean age of subjects with LBs was significantly higher than in those without (78.0 vs. 72.3 years). Cortical LBs had not been demonstrated in routine HE stains in any case and their identification necessitated the use of staining for ubiquitin. Although great care was taken not to interpret globose neurofibrillary tangles (NFTs) as LBs, anti-tau staining revealed that many of the suspected LBs were in fact NFTs. Thus, we recommend to apply both anti-ubiquitin and anti-tau staining for the demonstration of cortical LBs. In this material 21 of the 22 cases with LBs (95.5%) also revealed Alzheimer type of pathology as compared with 187 of 262 cases without LBs (71.4%). This difference may be explained by the higher age of subjects with LBs. Altogether 96 of the 284 cases (33.8%) had cerebrovascular lesions. None of the 9 cases with cortical LBs were clinically demented, and our results do not support the assertion that Lewy body-associated dementias should outnumber those of vascular origins.

Lapalio, L. R. and S. S. Sakla (1998). "Distinguishing Lewy body dementia." Hosp Pract (Off Ed) 33(2): 93-6, 99-102, 107-8.
The presence of the distinctive formations known as Lewy bodies within brain cells has been linked to senile dementia. A pattern of clinical features helps distinguish Lewy body dementia from Alzheimer's and Parkinson's diseases. Differentiation can be important, because many patients with Lewy body dementia have a hypersensitivity to neuroleptic medications.

Kosaka, K. (1998). "Diffuse Lewy body disease." Intern Med 37(1): 6-10.
Diffuse Lewy body disease (DLBD) has been studied from various viewpoints, and although clinical diagnostic criteria for DLBD have been proposed, the diagnosis remains difficult. It has been reported that DLBD is the second most frequent degenerative dementia among the elderly, following Alzheimer-type dementia. Many DLBD cases, however, are clinically misdiagnosed. Therefore, the search for diagnostic markers for DLBD must continue. Very recently, "dementia with Lewy bodies" (DLB) was proposed as a generic term including DLBD and similar disorders. Cortical Lewy bodies are the most important pathological marker for diagnosis of DLB. At this time, however, the mechanism of cortical Lewy body formation is yet to be disclosed.

Kosaka, K. and E. Iseki (1998). "Recent advances in dementia research in Japan: non-Alzheimer-type degenerative dementias." Psychiatry Clin Neurosci 52(4): 367-73.
In this article, we review recent reports by Japanese researchers on non-Alzheimer-type degenerative dementias. These dementias can be classified into the following subtypes: dementias with Lewy bodies, including diffuse Lewy body disease, dementias with neurofibrillary tangles, dementias with glial tangles, including progressive supranuclear palsy and corticobasal degeneration, argyrophilic grain dementia, frontotemporal dementias including Pick's disease; dementias with degeneration of subcortical nuclei, including Huntington's disease and, last, unclassified dementias. Recently, these various forms of dementia have received much attention in Japan, as elsewhere.

Jensen, P. H., M. S. Nielsen, et al. (1998). "Binding of alpha-synuclein to brain vesicles is abolished by familial Parkinson's disease mutation." J Biol Chem 273(41): 26292-4.
The presynaptic protein alpha-synuclein has been implicated in the pathogenesis of Parkinson's disease. First, two missense mutations A30P and A53T cause inheritable early onset Parkinson's disease in some families. Secondly, alpha-synuclein is present in Lewy bodies of affected nerve cells in the predominant sporadic type of Parkinson's disease as well as in dementia with Lewy bodies. We demonstrate in the rat optic system that a portion of alpha-synuclein is carried by the vesicle-moving fast component of axonal transport and that it binds to rat brain vesicles through its amino-terminal repeat region. We find alpha-synuclein with the A30P mutation of familial Parkinson's disease devoid of vesicle-binding activity and propose that mutant alpha-synuclein may accumulate, leading to assembly into Lewy body filaments.

Jellinger, K. A. (1998). "Neuropathology of movement disorders." Neurosurg Clin N Am 9(2): 237-62.
This article reviews the cytoskeletal abnormalities, morphologic lesion patterns, and resulting pathophysiology of the most frequent neurodegenerative movement disorders caused by dysfunction of the basal ganglia and related neuronal loops. The following topics are discussed: Among the akinetic-rigid Lewy body disorders is idiopathic Parkinson's disease, which reveals specific lesion patterns of pathophysiologic and therapeutic relevance. Dementia with Lewy bodies characterized by cortical Lewy bodies appears intermediate between Parkinson's and Alzheimer's diseases. Tau pathologic disorders may show some clinical and morphologic overlap. Multiple system atrophy has ubiquitous oligodendroglial inclusions as a cytopathologic hallmark. Secondary parkinsonism includes drug-related, toxic, and other symptomatic disorders. Hyperkinetic disorders include CAG-related inherited diseases, showing specific genetic defects and morphologic lesions. Dystonia syndromes show inconsistent pathologic findings, and myoclonus may be related to a variety of disorders. Consensus data on clinical and neuropathologic criteria already existing for some disorders, together with molecular genetic and biochemical data will provide further insight into the complex pathophysiology and pathogenesis of movement disorders.

Jellinger, K. A. (1998). "Commentary on "Neuropathologic evidence that the Lewy body variant of Alzheimer disease represents coexistence of Alzheimer disease and idiopathic Parkinson's disease (1998;57:39-46)"." J Neuropathol Exp Neurol 57(5): 467-8.

Iseki, E. and K. Kosaka (1998). "[Hippocampal pathology in diffuse Lewy body disease]." No To Shinkei 50(10): 907-12.

Irizarry, M. C., W. Growdon, et al. (1998). "Nigral and cortical Lewy bodies and dystrophic nigral neurites in Parkinson's disease and cortical Lewy body disease contain alpha-synuclein immunoreactivity." J Neuropathol Exp Neurol 57(4): 334-7.
A mutation in the alpha-synuclein gene has recently been linked to some cases of familial Parkinson's disease (PD). We characterized the expression of this presynaptic protein in the midbrain, striatum, and temporal cortex of control, PD, and dementia with Lewy bodies (DLB) brain. Control brain showed punctate pericellular immunostaining. PD brain demonstrated alpha-synuclein immunoreactivity in nigral Lewy bodies, pale bodies and abnormal neurites. Rare neuronal soma in PD brain were immunoreactive for alpha-synuclein. DLB cases demonstrated these findings as well as alpha-synuclein immunoreactivity in cortical Lewy bodies and CA2-3 neurites. These results suggest that, even in sporadic cases, there is an early and direct role for alpha-synuclein in the pathogenesis of PD and the neuropathologically related disorder DLB.

Ince, P. G., E. K. Perry, et al. (1998). "Dementia with Lewy bodies. A distinct non-Alzheimer dementia syndrome?" Brain Pathol 8(2): 299-324.
Lewy body formation is central to the pathological phenotype of a spectrum of disorders. The most familiar of these is the extrapyramidal syndrome of idiopathic Lewy-body Parkinson's disease (PD). Studies of dementia in the elderly suggest that another manifestation of Lewy body pathology is equally or more common than Parkinson's disease. This syndrome of Dementia with Lewy bodies (DLB) has been given a number of diagnostic labels and is characterised by dementia, relatively mild parkinsonism, visual hallucinations, and fluctuations in conscious level. Although many of these features can arise in Parkinson's disease, the patients with DLB tend to have early neuropsychiatric features which predominate the clinical picture, and the diagnosis of the syndrome in practice is more concerned with the differential diagnosis of Alzheimer's disease (AD). Distinction from AD has clinical importance because of potentially differing therapeutic implications. Diagnostic guidelines for the clinical diagnosis and pathological evaluation of DLB are reviewed. Research into the disorder has centered around characterising the clinical, neuropsychological, pathological, neurochemical and genetic relationships with Alzheimer's disease on the one hand, and Parkinson's disease on the other. Many cases of DLB have prominent pathological features of AD and there are some shared genetic risk factors. Differences from the pathology of PD are predominantly quantitative rather than qualitative and evidence is discussed which suggests that DLB represents a clinicopathological syndrome within the spectrum of Lewy body disorders. The possibility that the syndrome represents a chance association of PD and AD is not supported by published studies.

Hardy, J., J. Perez-Tur, et al. (1998). "Exclusion of genetic linkage to 4q21-23 and 17q21 in a family with Lewy body parkinsonism." Am J Med Genet 81(2): 166-71.
Genetic analysis of markers from chromosomes 4q21-23 and 17q21 in a family with apparently autosomal dominant Lewy body parkinsonism is presented. This analysis shows that the locus leading to this disease is not allelic with that previously shown to lead to Lewy body parkinsonism on chromosome 4 or to the locus on chromosome 17 leading to frontotemporal dementia with parkinsonism. A brief clinical comparison of this family with families showing linkage to these loci is presented. The data suggest that at least one other major genetic determinant for Lewy body parkinsonism remains to be identified.

Harding, A. J. and G. M. Halliday (1998). "Simplified neuropathological diagnosis of dementia with Lewy bodies." Neuropathol Appl Neurobiol 24(3): 195-201.
Pathological criteria have recently been developed to differentiate those cases where Lewy bodies contribute to the dementing process. We applied consensus criteria to 20 cases with a pathological diagnosis of Alzheimer's disease (all demented) and/or Parkinson's disease (three without dementia) and eight controls. In addition, we applied the criteria to the different cortical layers to determine whether the site of the semiquantification affected the diagnosis. In the parietal lobe, few Lewy bodies were observed, and this region could be excluded. Rare Lewy bodies present in the frontal association cortex in a number of Parkinson's disease cases resulted in their classification as limbic or transitional cases with Lewy bodies. Exclusion of this non-limbic association cortex resulted in many of these cases with rare cortical Lewy bodies being re-classified as having brain stem predominant Lewy bodies, thus improving the diagnostic accuracy of the criteria. Most of these cases were non-demented. No other case was re-classified by excluding these cortical regions from the analysis. Few Lewy bodies were present in cortical layers I and II, and these layers could be excluded from the semiquantitative procedure without change to the overall classification of cases. The occasional presence of possible Lewy bodies in cases with Alzheimer's disease and controls incorrectly classified these cases as having brain stem predominant Lewy body disease, although these cases had no brain stem Lewy bodies. These modifications to the consensus criteria for assessing Lewy body disease (i.e. exclude parietal and frontal lobe, cortical layers I and II, and cases without brain stem Lewy bodies), provide significant time and cost savings for neuropathologists and researchers using this criteria to diagnose and study dementia with Lewy bodies.

Hansen, L. A., S. E. Daniel, et al. (1998). "Frontal cortical synaptophysin in Lewy body diseases: relation to Alzheimer's disease and dementia." J Neurol Neurosurg Psychiatry 64(5): 653-6.
OBJECTIVES: Dementia in Alzheimer's disease correlates closely with loss of neocortical synapses. Similar synaptic loss has been shown in patients whose Alzheimer's disease is also associated with neocortical and brain stem Lewy bodies. The aim was to determine if dementia in Lewy body disease was associated with diminished concentrations of midfrontal cortex synaptophysin. METHODS: An immunobinding assay was used to measure synaptophysin in postmortem samples of midfrontal cortex from 89 patients with Alzheimer's disease (ages 59-100, mean 79), 22 with combined Lewy body disease and Alzheimer's disease (ages 69-103, mean 79), 15 demented patients with "pure" Lewy body disease (ages 57-80, mean 74), nine with neocortical and brain stem Lewy bodies who had Parkinson's disease but were not demented (ages 68-85, mean 79), and 20 neurologically normal controls (ages 58-89, mean 75). The diagnosis was confirmed in all cases by detailed neuropathological examination of the contralateral hemibrain. Seven of the patients in the pure Lewy body disease with dementia group had initially presented with parkinsonism and eight with dementia. RESULTS: Synaptophysin concentrations (arbitrary units (AU)/microg) in patients with Alzheimer's disease (mean 79 (SD 28)) or combined Lewy body disease and Alzheimer's disease (mean 83 (SD 33)) were significantly lower than in controls (mean 115 (SD 29)) (p=0.002). Synaptophysin concentrations in demented patients with pure Lewy body disease (mean 106 SD 39) and patients with Lewy body disease who were not demented (mean 101 (SD 18)) did not differ significantly from control values or from each other. CONCLUSION: Loss of midfrontal cortex synapses probably contributes to dementia in Lewy body disease when Alzheimer's disease is also present but not to the dementia of pure Lewy body disease.

Gu, M., A. D. Owen, et al. (1998). "Mitochondrial function, GSH and iron in neurodegeneration and Lewy body diseases." J Neurol Sci 158(1): 24-9.
The cause of neuronal loss in patients with idiopathic Parkinson's disease is unknown. Oxidative stress and complex I deficiency have both been identified in the substantia nigra in Parkinson's disease but their place in the sequence of events resulting in dopaminergic cell death is uncertain. We have analysed respiratory chain activity, iron and reduced glutathione concentrations in Parkinson's disease substantia innominata and in the cingulate cortex of patients with Parkinson's disease, Alzheimer's disease and dementia with Lewy bodies to investigate their association with neuronal death and Lewy body formation. No abnormalities of mitochondrial function, iron or reduced glutathione levels were identified in Parkinson's disease substantia innominata or cingulate cortex. Mitochondrial function also appeared to be unchanged in cingulate cortex from patients with Alzheimer's disease and from patients with dementia with Lewy bodies, however, iron concentrations were mildly increased in both, and reduced glutathione decreased only in Alzheimer's disease. These results confirm the anatomic specificity of the complex I deficiency and decreased levels of reduced glutathione within the Parkinson's disease brain and suggest that these parameters are not associated with cholinergic cell loss in Parkinson's disease nor with Lewy body formation in this or other diseases. We propose that our data support a 'two-hit' hypothesis for the cause of neuronal death in Parkinson's disease.

Ginsberg, S. D., J. E. Galvin, et al. (1998). "RNA sequestration to pathological lesions of neurodegenerative diseases." Acta Neuropathol (Berl) 96(5): 487-94.
Cytoplasmic RNA species have been identified recently within neurofibrillary tangles and senile plaques of Alzheimer's disease brain. To determine whether RNA sequestration is a common feature of other lesions found in progressive neurodegenerative disorders, acridine orange histofluorescence was employed, alone or in combination with immunohistochemistry and thioflavine-S staining to identify RNA species in paraffin-embedded brain tissue sections. Postmortem samples came from 39 subjects with the following diagnoses: Alzheimer's disease, amyotrophic lateral sclerosis/parkinsonism-dementia complex of Guam, corticobasal degeneration, diffuse Lewy body disease, normal controls, multiple system atrophy, Parkinson's disease, Pick's disease, progressive supranuclear palsy, and Shy-Drager syndrome. RNAs were detected in neurofibrillary tangles and neuritic senile plaques as well as in Pick bodies. However, Lewy bodies, Hirano bodies, and cytoplasmic glial inclusions did not contain abundant cytoplasmic RNA species. These observations demonstrate the selective localization of RNA species to distinct pathological lesions of neurodegenerative disease brains.

Geizer, M. and R. J. Ancill (1998). "Combination of risperidone and donepezil in Lewy body dementia." Can J Psychiatry 43(4): 421-2.

Farrer, M., F. Wavrant-De Vrieze, et al. (1998). "Low frequency of alpha-synuclein mutations in familial Parkinson's disease." Ann Neurol 43(3): 394-7.
A mutation in exon 4 of the alpha-synuclein (NACP) gene has been reported to explain the chromosome 4 linkage to autosomal dominant Parkinson's disease. We developed primers and methods for exonic sequencing of this gene and sequenced the entire coding region of the gene in 6 families with autosomal dominant disease and in 2 cases of lytico and bodig from Guam. In addition, we have sequenced exon 4 of this gene in 5 cases of familial disease and have screened for the specific mutation (A53T) in a 40 cases of idiopathic Parkinson's disease, 3 cases of multisystem atrophy, and 15 cases of Lewy body dementia. We have found no genetic variation in the gene. We discuss these findings with respect to both the epidemiology of Parkinson's disease and the possibility that NACP is not the chromosome 4 locus for disease.

Cullen, K. M. and G. M. Halliday (1998). "Neurofibrillary degeneration and cell loss in the nucleus basalis in comparison to cortical Alzheimer pathology." Neurobiol Aging 19(4): 297-306.
Neurofibrillary tangle staging was compared in the nucleus basalis and cerebral cortex of Alzheimer's disease patients with and without Lewy body disease. In pure Alzheimer's disease, cholinergic nucleus basalis cell number, as determined from counts in serial forebrain sections, was 22-60% of control mean, with the majority of residual cells containing tangles. A comparison between control cell number and the combined number of tangles plus tangle-free neurons in pure Alzheimer's disease suggests that the majority of nucleus basalis neurons were lost through neurofibrillary degeneration. The staging of neurofibrillary degeneration in the nucleus basalis was discordant with cortical changes as some controls had more extensive tangle formation in the nucleus basalis than in the cerebral cortex. Patients having both Alzheimer's disease and Lewy body pathology had few or no tangles in the nucleus basalis despite greater loss of neurons than purely demented patients. The presence of concomitant pathology had a greater effect on nucleus basalis tangle burden than did cortical disease stage, suggesting dichotomous disease processes in the cerebral cortex and forebrain.

Cras, P. (1998). "Differential diagnosis in dementia." Acta Neurol Belg 98(2): 186-9.
Dementia is characterised by progressive memory loss, associated with agnosia, aphasia, dyscalculia, apraxia, and deficits in executive functioning. Alzheimer disease is the most frequent cause of dementia, with vascular dementia, diffuse Lewy body disease, and other etiologies being important differential diagnoses. A strategy and diagnostic hierarchy for diagnosis in dementia is proposed. Diagnostic criteria for Alzheimer disease, diffuse Lewy body disease, and vascular dementia are discussed.

Connor, D. J., D. P. Salmon, et al. (1998). "Cognitive profiles of autopsy-confirmed Lewy body variant vs pure Alzheimer disease." Arch Neurol 55(7): 994-1000.
OBJECTIVE: To compare the cognitive profiles of patients with autopsy-confirmed Alzheimer disease (AD), with or without concomitant Lewy bodies, on 2 dementia screening measures. METHODS: Profiles on subtests of the Mattis Dementia Rating Scale (range, 105-125) and of component items of the Mini-Mental State Examination were compared between 23 patients with uncomplicated AD and 23 patients with concomitant AD and Lewy body pathology (Lewy body variant [LBV]). RESULTS: Although the groups did not differ significantly regarding age, years of education, total Mini-Mental State Examination score, or total Mattis Dementia Rating Scale score, the AD group performed significantly worse than the LBV group on the Mattis Dementia Rating Scale Memory subscale (P < .005). In contrast, the LBV group demonstrated poorer performance than the pure AD group on the Initiation/Perseveration subscale (P < .02). The groups did not differ significantly on the Attention, Construction, or Conceptualization subscales. The same overall pattern of results was obtained when subgroups with mild to moderate and moderate to severe dementia were examined separately, with the additional finding that in the mild-to-moderate range patients with dementia and LBV performed worse than patients with pure AD on the Construction subscale. CONCLUSIONS: The difference in pattern of cognitive deficits among patients with pure AD vs those with AD and LBV is similar to that seen between AD and more subcortical/frontal dementias (eg, Huntington disease) This suggests that the concomitant Lewy body pathology significantly contributes to the presentation of the cognitive dysfunction in individuals with LBV.

Browne, S. E., A. C. Bowling, et al. (1998). "Metabolic dysfunction in familial, but not sporadic, amyotrophic lateral sclerosis." J Neurochem 71(1): 281-7.
Autosomal dominant familial amyotrophic lateral sclerosis (FALS) is associated with mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1). Previous studies have implicated the involvement of metabolic dysfunction in ALS pathogenesis. To further investigate the biochemical features of FALS and sporadic ALS (SALS), we examined SOD activity and mitochondrial oxidative phosphorylation enzyme activities in motor cortex (Brodmann area 4), parietal cortex (Brodmann area 40), and cerebellum from control subjects, FALS patients with and without known SOD mutations, SALS patients, and disease controls (Pick's disease, progressive supranuclear palsy, diffuse Lewy body disease). Cytosolic SOD activity, predominantly Cu/Zn SOD, was decreased approximately 50% in all regions in FALS patients with SOD mutations but was not significantly altered in other patient groups. Marked increases in complex I and II-III activities were seen in FALS patients with SOD mutations but not in SALS patients. We also measured electron transport chain enzyme activities in a transgenic mouse model of FALS. Complex I activity was significantly increased in the forebrain of 60-day-old G93A transgenic mice overexpressing human mutant SOD1, relative to levels in transgenic wild-type animals, supporting the hypothesis that the motor neuron disorder associated with SOD1 mutations involves a defect in mitochondrial energy metabolism.

Brown, D. F., M. A. Dababo, et al. (1998). "Neuropathologic evidence that the Lewy body variant of Alzheimer disease represents coexistence of Alzheimer disease and idiopathic Parkinson disease." J Neuropathol Exp Neurol 57(1): 39-46.
We undertook this study to investigate the neuropathologic relationships among Alzheimer disease (AD), idiopathic Parkinson disease (PD), and the Lewy body variant of AD (AD/LBV). We retrieved 30 autopsy cases in which Lewy bodies (LB) had been identified in the substantia nigra (SN) in routine hematoxylin-eosin-stained sections. Twenty-two of the cases had a primary clinical diagnosis of dementia and neuropathologic changes of AD; 12 of these demented patients also had clinical parkinsonism. Eight cases had clinical and neuropathologic evidence of PD with minimal or no AD neuropathology, though 6 had clinical dementia. Controls consisted of 6 cases of AD without SN LB by hematoxylin-eosin, and 5 neurologically normal aged controls. Paraffin sections of SN, superior temporal gyrus, and cingulate gyrus from each case were immunostained with rabbit anti-ubiquitin antiserum, randomized, and analyzed individually by light microscopy, and the density of LB-like profiles in each section were graded. None of 5 nondemented aged controls showed any neocortical LB, even though 2 had significant numbers of incidental SN LB by ubiquitin immunostaining. Of 6 AD cases without SN LB by hematoxylin-eosin, 3 had rare SN LB on ubiquitin stain, 1 of which showed rare neocortical Lewy-like profiles. Seven of 8 PD cases showed neocortical LB, including the 6 with dementia. Twenty-one of 22 AD cases with SN LB showed ubiquitin-immunoreactive Lewy-like bodies in the neocortex that were statistically significantly greater in number than in either pure PD or pure AD cases. The frequent occurrence of LB in the neocortex in PD alone suggests that AD/LBV likely represents mixed AD/PD. However, AD neuropathology may favor or promote the formation of neocortical LB in patients who go on to develop mixed AD/PD pathology.

Boeve, B. F., M. H. Silber, et al. (1998). "REM sleep behavior disorder and degenerative dementia: an association likely reflecting Lewy body disease." Neurology 51(2): 363-70.
BACKGROUND: REM sleep behavior disorder (RBD) has been reported with various neurodegenerative disorders, most frequently in disorders with Lewy body pathology. RBD often precedes the onset of PD, and a recent prospective study showed that 38% of patients with RBD eventually developed PD. METHODS: We identified 37 patients with degenerative dementia and a history of bursts of vigorous movement of the arms and legs with vocalization during sleep and associated with dream recall. Patients with and without two or more signs of parkinsonism were compared. Clinical, laboratory, and neuropsychometric features were analyzed, and criteria for the clinical diagnosis of dementia with Lewy bodies (DLB) were applied to all patients. RESULTS: Thirty-four of the 37 patients were male with mean age at onset of 61.5 years for RBD and 68.1 years for cognitive decline. RBD commenced before or concurrently with dementia in all patients but two. Parkinsonism (two or more signs) occurred in 54% of the sample (20/37), with a mean age at onset of 69.1 years. Polysomnography (PSG) confirmed RBD in all patients studied. Neuropsychological testing demonstrated impaired perceptual-organizational skills, verbal fluency, and marked constructional dyspraxia in more than one-half the patients. There were no statistically significant differences in the frequency of clinical features or in neuropsychological performance between patients with and without parkinsonism. Thirty-four patients (92%) met criteria for clinically possible or probable DLB. Three patients were autopsied; all had limbic with or without neocortical Lewy bodies. CONCLUSIONS: We report a group of predominantly male patients with a characteristic association of RBD and degenerative dementia. The clinical and neuropsychometric features of the groups of patients with and without parkinsonism are similar. We hypothesize that the underlying pathology in these patients is DLB.

Ballard, C. and I. G. McKeith (1998). "Psychiatric features in diffuse Lewy body disease." Neurology 50(2): 573.

Yoshimura, M. (1997). "[Diffuse Lewy body disease]." Rinsho Shinkeigaku 37(12): 1134-6.
Lewy body disease (LBD) is a progressive neurological disorder with parkinsonism, having many Lewy bodies (LBs) and degenerative changes. LBD is classified into the three types according to the distribution of LBs: "brain-stem type", "transitional type" and "diffuse type". The brain-stem type is identical to classical Parkinson's disease (PD). The diffuse type is nominated as "diffuse Lewy body disease" (DLBD). DLBD is a neuropathological entity, characterized by abundant LBs not only in the basal ganglia and brain-stem but in the cerebral cortex, combined with senile changes. Juvenile onset DLBD is called "pure form" of DLBD because of no or few senile changes. The LBs are present in the amygdala, nucleus basalis of Meynert, hypothalamic nuclei, substantia nigra, nucleus paranigralis, locus caeruleus, dorsal vagal nucleus and reticular nuclei. The cerebral LBs are numerous in the parahippocampal gyrus, cingular gyrus, and insular, frontal and temporal cortices. The LBs show immunoreactivity to ubiquitin and the ubiquitin-immunoreactive neurites in the CA2-3 region appear to be specific for DLBD. The clinical features of DLBD in the senium are progressive dementia, psychotic state, parkinsonism and autonomic signs. In general, progressive dementia is an initial symptom, followed by parkinsonism in the later stage. Some show progressive autonomic failure. A few present respiratory failure or vocal cord palsy resulting in sudden death in DLBD. DLBD is characterized neurochemically by severe affection of multiple neurotransmitters networks. In DLBD an impairment of the innominato-cortical cholinergic and mesocortical dopaminergic system, differentiating from Alzheimer's disease and PD, may play an important role in developing disease process.

Turjanski, N. and D. J. Brooks (1997). "PET and the investigation of dementia in the parkinsonian patient." J Neural Transm Suppl 51: 37-48.
Parkinsonism and dementia are present in a number of neurodegenerative conditions. They may be a manifestation of isolated brain stem (Parkinson's disease) or diffuse Lewy body disease (DLBD), or be secondary to combined Lewy body and Alzheimer's disease (AD) pathologies. Positron emission tomography (PET) studies show a resting pattern of fronto-temporo-parietal hypometabolism in both, AD and in parkinsonism-dementia (PD-dementia) patients, even when only isolated brain stem Lewy body disease is found at pathology. We have studied three patients fulfilling clinical criteria for diagnosis of DLBD. Their 18F-fluorodeoxyglucose (FDG) PET results showed an AD pattern of fronto-temporo-parietal hypometabolism, though these patients had only mild cognitive dysfunction. Parkinsonism associated with apraxia is observed in corticobasal degeneration (CBD) while impairment of frontal functions, such as planning and sorting, is seen in patients with progressive supranuclear palsy (PSP). PET studies in CBD patients have shown an asymmetric hypometabolism of cortex and thalamus contralateral to the affected limbs, while in PSP patients there is a global metabolic reduction most pronounced in frontal areas and the basal ganglia. These results suggest that metabolic PET studies can help to distinguish PD-dementia, PSP and CBD, but are unable to distinguish PD-dementia from AD. Further studies with post-mortem confirmation are required to establish if DLBD is associated with a distinctive pattern of resting hypometabolism.

Tompkins, M. M. and W. D. Hill (1997). "Contribution of somal Lewy bodies to neuronal death." Brain Res 775(1-2): 24-9.
Neuronal degeneration occurs in the substantia nigra pars compacta (SNpc) of patients with Parkinson's disease and other Lewy body-associated disorders. Lewy bodies (LBs) are abnormal inclusions found in the SNpc and other neurons of these patients. It is not known what role LBs play in the disease process; they may be harmful to the neuron or simply an epiphenomenon of the disease process. We have previously shown that some of the neuronal death occurring in the SNpc of Lewy body-associated disorders resembles apoptosis. The present study was undertaken to determine whether apoptotic-like changes were more common in SNpc neurons with somal LBs compared to those without somal LBs. Substantia nigra from cases of Lewy body-associated disorders were labeled to colocalize apoptotic-like changes and LBs using in situ end-labeling and an anti-ubiquitin antibody. Three cases demonstrated that SNpc neurons with LBs in the perikarya had the same proportion of apoptotic-like changes as SNpc neurons without somal LBs. One case had no LB-containing SNpc neurons undergoing apoptotic-like cell death. The majority of SNpc neurons undergoing apoptotic-like cell death did not appear to contain somal LBs and thus may be dying before LB formation can occur. These results support the theory that the presence of a somal LB does not predispose a neuron to undergo apoptotic-like cell death.

St Clair, D. (1997). "Apolipoprotein E gene in Parkinson's disease, Lewy body dementia and Alzheimer's disease." J Neural Transm Suppl 51: 161-5.
Apolipoprotein E (Apo E) epsilon 4 allele is a risk factor for early and late onset Alzheimer's disease. This prompted us to examine other neurophyschiatric phenotypes. Epsilon 4 allele was significantly enriched in Lewy body dementia (n = 39) but not in Parkinson's disease (n = 50) or Schizophrenia (n = 175) compared to aged non-demented controls (n = 47) and the Scottish population (n = 400). We conclude that Lewy body disease should be regarded as a variant of Alzheimer's but not Parkinson's disease.

Perry, R., I. McKeith, et al. (1997). "Lewy body dementia--clinical, pathological and neurochemical interconnections." J Neural Transm Suppl 51: 95-109.
Senile dementia of Lewy body type or Lewy body dementia (SDLT or LBD) is defined as a Lewy body associated disease presenting in the elderly primarily with dementia with variable extrapyramidal disorder. Characteristic clinical symptoms include fluctuating cognitive impairment, psychotic features such as hallucinations and a particular sensitivity to neuroleptic medication. Although apolipoprotein e4 allele is increased 2-3 fold in SDLT (as in Alzheimer's disease) and beta-amyloidosis occurs in most cases, the most robust neurobiological correlate of the dementia so far identified appears to be extensive cholinergic deficits in the neocortex. This is consistent with previously reported correlations between cortical cholinergic activity and dementia in Parkinson's disease (PD) and Alzheimer's disease. There is also a significant interaction between the density of limbic cortical Lewy bodies and dementia in both SDLT and PD, although the cortical neuronal population affected remains to be identified. Cortical Lewy body density is positively correlated with the age of disease onset in PD and SDLT. This may account for the increased incidence of psychiatric syndromes, as opposed to extrapyramidal disorder in Lewy body disease with advancing age as may age-related loss of cholinergic activity in cortical areas such as the hippocampus.

Lennox, G. G. and J. S. Lowe (1997). "Dementia with Lewy bodies." Baillieres Clin Neurol 6(1): 147-66.
Dementia with Lewy bodies (DLB) is the recommended term for a common cause of dementia characterized by the histological presence of distinctive inclusions within neurons, Lewy bodies (McKeith et al, 1996). Following increasing pathological recognition, core clinical diagnostic features have been identified to allow diagnosis in life. Insights into the biology of this type of neurodegeneration suggest that the regional patterns of involvement might allow therapeutic intervention. Although Lewy bodies had long been recognized in the substantia nigra and other subcortical nuclei in patients with Parkinson's disease (PD), it was only in the 1970s that a significant number of reports began to be published from Japan describing patients with dementia and parkinsonism associated with the presence of Lewy bodies in cortical neurons (reviewed by Kosaka, 1990). Since these reports, different workers have used a variety of terms to describe this disease process, including diffuse Lewy body disease (Yoshimura, 1983), Lewy body dementia (Gibb et al, 1987), senile dementia of Lewy body type (Perry et al, 1990a) and the Lewy body variant of Alzheimer's disease (Hansen et al, 1990).

Jonker, C. (1997). "[Dementia. Outlook on current developments]." Tijdschr Gerontol Geriatr 28(4): 163-71.
The results of recent neuropathologic and genetic studies in Alzheimer's disease led to a renewed interest in differentiations within the dementia syndrome. New disease-entities can be distinguished (Lewy Body Dementia, Frontal Lobe Dementia) and other criteria have been put forward for vascular dementia. Hachinski's Ischemic Score, for many years the diagnostic criterium for vascular dementia, has been cancelled. Instead a CT- or MRI scan must demonstrate the vascular pathology in the brain. For clinical practice, the differentiation between cortical and subcortical dementia is still important. For reasons of management it appears useful to distinguish between early-onset and late-onset Alzheimer's disease. The amyloid cascade hypothesis for the pathogenesis of Alzheimer's disease is credible for the early-onset as well as the late-onset type, because results from epidemiological as well as from neurobiological studies might be fit in. Moreover, this hypothesis is promising from the point of view of developing specific therapies. Finally, the breakdown of the dementia syndrome in separate disease-entities stimulated interest in the psychiatric symptoms in these patients and activated the development of rational and symptomatic therapeutics.

Jendroska, K., M. Kashiwagi, et al. (1997). "Amyloid beta-peptide and its relationship with dementia in Lewy body disease." J Neural Transm Suppl 51: 137-44.
Cerebral cortical Lewy bodies occur in a spectrum of clinical syndromes including Parkinson's disease (PD) with and without dementia, and dementing conditions clinically resembling Alzheimer's disease with few or without parkinsonian features. It is unclear whether these conditions are variants of one disease process or represent pathogenetically distinct entities. Here we compared the cortical pathology in post mortem brains of three groups representing the predominant clinical phenotypes of Lewy body disease, including 27 non-demented cases of PD, 23 demented PD cases, and 11 cases of Lewy body disease who initially presented with dementia and showed only limited features of parkinsonism during the course of their illness. In addition to neuropathology, computer-assisted histoblot analysis was used to assess cortical amyloid beta-peptide deposition. There was wide overlap of the pathomorphometric features between the two groups of demented cases. It appears that substantial cortical Alzheimer-type pathology present in most demented cases contributes significantly to the development of dementia in Lewy body disease.

Jellinger, K. A. (1997). "Morphological substrates of dementia in parkinsonism. A critical update." J Neural Transm Suppl 51: 57-82.
Dementia in parkinsonism is caused by a variety of central nervous system (CNS) lesions, of which the molecular and pathogenic causes are poorly understood but probably include: 1. Degeneration of subcortical ascending systems with neuronal losses in dopaminergic, noradrenergic, serotonergic, cholinergic or multiple systems including the amygdyloid nucleus; 2. limbic and/or cortical Alzheimer and/or Lewy body pathologies, with loss of synapses and neurons, and 3. a combination of these lesions or additional CNS pathologies. In general, degeneration of subcortical neuronal networks appears insufficient to induce severe mental decline although, occasionally, cognitive impairment occurs without apparent cortical lesions. On the other hand, neuritic cortical Alzheimer change showing similar or differential distribution compared to Alzheimer's disease (AD) displays a significant linear correlation with dementia in Parkinsonism. Plaques can be associated with cortical Lewy bodies and, the contribution of each to dementing processes remains unresolved. In a consecutive autopsy series of 610 patients with parkinsonism, the total prevalence of retrospectively assessed dementia was 34.6%. In Parkinson's disease (PD) of the Lewy body type, it was 30.2%, mostly associated with other brain lesions, mainly AD, while only 3.5% of "pure" PD without additional brain pathologies were demented. There was no significant difference in age and duration of illness between demented and non-demented PD patients. Secondary parkinsonian syndromes showed a higher incidence of dementia (56.3%), again with predominant Alzheimer pathology which was present in 73% of the total of demented parkinsonian patients and in almost 82% of the demented PD cases in this series. The specific contribution of cortical and subcortical lesions to mental impairment in parkinsonism, their relationship to AD, and an etiology await further elucidation.

Hansen, L. A. (1997). "The Lewy body variant of Alzheimer disease." J Neural Transm Suppl 51: 83-93.
The Lewy body variant of Alzheimer disease (LBV) occupies a messy middle ground between Alzheimer disease (AD) on the one hand, and pure Lewy body diseases (Parkinson's disease or diffuse Lewy body disease), on the other. In addition to brainstem and neocortical Lewy bodies, LBV brains have enough neocortical neuritic plaques to meet diagnostic criteria for AD. However, neurofibrillary pathology in LBV is modest, since tangle densities in LBV are typically intermediate between AD and age-matched controls or pure Lewy body disease brains. Apolipoprotein E-4 is overrepresented in LBV, as it is in AD but is not in PD or diffuse Lewy body disease (DLBD). Neurologically, LBV patients often display sufficient parkinsonian signs to separate them from AD, but these findings are usually too subtle to warrant clinical diagnoses of Parkinson's disease (PD). Neuropsychological deficits in LBV include a subcortical dementia pattern similar to DLBD, and more severe global cognitive impairment reminiscent of AD.

Burns, A. (1997). "Psychiatric symptoms and behavioural disturbances in the dementias." J Neural Transm Suppl 51: 27-35.
This contribution will summarise the relationship between psychiatric symptoms and behavioural disturbances in dementia. The different types of symptoms will be discussed with particular relation to Alzheimer's and Parkinson's disease and results will be presented in relation to clinical symptomatology in the Lewy body variant of Alzheimer's disease.

Snow, R. E. and S. E. Arnold (1996). "Psychosis in Neurodegenerative Disease." Semin Clin Neuropsychiatry 1(4): 282-293.
Psychosis has been recognized as a common feature in neurodegenerative disease for many years. Hallucinations, delusions, and other psychotic phenomena occur in a wide range of degenerative disorders including Alzheimer disease, Huntington disease, Parkinson's disease, diffuse Lewy body disease, "Parkinson plus" syndromes, Pikc's disease, and other frontotemporal degenerations, amyotrophic lateral sclerosis, and prion associated diseases. It is also interesting that neurodegenerative disease-type dementia may be a feature in some psychotic illnesses such as schizophrenia. Clinical evaluation of psychosis in the setting of dementia presents a significant challenge for clinicians and researchers. Amnesia, language or speech impairments, and behavioral problems amy distort and obscure the presentation of symptoms. However, recognition and understanding of the psychotic manifestations may lead to the institution of more effective therapeutic or preventive options that can serve to delay long term care placement and improve patient and caregiver quality of life. In addition, a more comprehensive understanding of the pathophysiology, neuroanatomical substrates, and distinctive pathological features underlying the development of psychotic symptoms in neurodegenerative diseases may provide important insights into psychotic processes in general.