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 bodi