Diffuse Lewy Body Disease

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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.

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.

McLean, P. J. and B. T. Hyman (2002). "An alternatively spliced form of rodent alpha-synuclein forms intracellular inclusions in vitro: role of the carboxy-terminus in alpha-synuclein aggregation." Neurosci Lett 323(3): 219-23.
In the rat, the -synuclein gene is alternatively spliced and exists in three forms, rat synuclein 1 (rSYN1), synuclein 2 (rSYN2) and synuclein 3. rSYN2 cDNA encodes a 149 amino acid protein that is homologous to rSYN1 and human -synuclein for the first 100 amino acids, but is divergent for the 49 amino acid carboxy-terminal region. We demonstrate here that rSYN2 forms small aggregates throughout the cytoplasm when overexpressed in human H4 cells, whereas rSYN1 expression is diffuse. Inhibition of the proteasome promotes the formation of larger, cytoplasmic rSYN2 inclusions in transfected cells. Although a survey of the available databases suggests that there is no human splice form equivalent of rSYN2, thus arguing against a direct role in Lewy body formation and Parkinson's disease, these data nonetheless suggest that modifications of the carboxy-terminal region of -synuclein predispose it to inclusion formation.

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.

Kovacs, G., P. Zerbi, et al. (2002). "The prion protein in human neurodegenerative disorders." Neurosci Lett 329(3): 269.
We evaluate cellular prion protein (PrP(C)) immunoreactivity (IR) in Alzheimer's, Parkinson's, diffuse Lewy body, and motor neuron diseases (MND), progressive supranuclear palsy, and multiple system atrophy. We use immunohistochemistry for PrP, including five monoclonal antibodies against different epitopes and three different pretreatments, alpha-synuclein, phosphorylated tau, beta-amyloid, and ubiquitin. Disease-specific inclusions are devoid of PrP(C) IR. Using double immunofluorescence and confocal laser microscopy we observe focal overlapping of PrP(C) with tau and with alpha-synuclein in early, but not in fully developed inclusions. However, PrP(C) IR neurons may contain abnormal tau or alpha-synuclein aggregates. Additionally, we observe a loss of PrP(C) IR in anterior horn neurons in MND. Our results suggest that expression of PrP(C) reflects a general response to cellular stress rather than specific co-operation in aggregation of other proteins.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Iwata, A., M. Maruyama, et al. (2001). "alpha-Synuclein affects the MAPK pathway and accelerates cell death." J Biol Chem 276(48): 45320-9.
Insoluble alpha-synuclein accumulates in Parkinson's disease, diffuse Lewy body disease, and multiple system atrophy. However, the relationship between its accumulation and pathogenesis is still unclear. Recently, we reported that overexpression of alpha-synuclein affects Elk-1 phosphorylation in cultured cells, which is mainly performed by mitogen-activated protein kinases (MAPKs). We further examined the relationship between MAPK signaling and the effects of alpha-synuclein expression on ecdysone-inducible neuro2a cell lines and found that cells expressing alpha-synuclein had less phosphorylated MAPKs. Moreover, they showed significant cell death when the concentration of serum in the culture medium was reduced. Under normal serum conditions, the addition of the MAPK inhibitor U0126 also caused cell death in alpha-synuclein-expressing cells. Transfection of constitutively active MEK-1 resulted in MAPK phosphorylation in alpha-synuclein-expressing cells and improved cell viability even under reduced serum conditions. Thus, we conclude that alpha-synuclein regulates the MAPK pathway by reducing the amount of available active MAPK. Our findings suggest a mechanism for pathogenesis and thus offer therapeutic insight into synucleinopathies.

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.

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

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

Tiraboschi, P., L. A. Hansen, et al. (2000). "Cholinergic dysfunction in diseases with Lewy bodies." Neurology 54(2): 407-11.
OBJECTIVE: To evaluate cholinergic activity in diseases with Lewy bodies (LB; LB variant of AD [LBV], diffuse LB disease [DLBD], and Parkinson's disease [PD]) to determine if 1) AD changes are requisite to cholinergic dysfunction, 2) cholinergic activity declines to the same extent in neocortical and archicortical areas, and 3) cholinergic loss is influenced by APOE genotype. BACKGROUND: Like AD, diseases with LB are associated with decreased choline acetyltransferase (ChAT) activity. Increased APOE epsilon4 allele frequency has been reported in LBV. Whether APOE genotype affects cholinergic function in LBV remains unclear. METHODS: An autopsy series of 182 AD (National Institute on Aging and Consortium to Establish a Registry for Alzheimer's Disease criteria), 49 LBV, 11 PD, 6 DLBD, and 16 normal control (NC) subjects. APOE genotype and ChAT activity (nmol/h/100 mg) in the midfrontal and hippocampal cortices were determined. RESULTS: Mean midfrontal ChAT activity was markedly reduced in diseases with LB (LBV: 53.3 +/- 39.0; PD: 54.8 +/- 35.7; DLBD: 41.3 +/- 24.8) compared to NC (255.4 +/- 134.6; p < 0.001) and AD (122.6 +/- 78.9; p < 0.05). Among diseases with LB, midfrontal ChAT activity was decreased to a similar extent in patients with (LBV) and without (DLBD and PD) AD pathology. Although mean ChAT activity for LBV was less than half that for AD in the midfrontal cortex, it was similar to that for AD in the hippocampus (LBV: 243.5 +/- 189.7; AD: 322.8 +/- 265.6; p > 0.05). However, hippocampal ChAT activity for both AD and LBV was lower than that for NC (666.5 +/- 360.3; p < 0.001). The epsilon4 allele dosage did not influence midfrontal ChAT activity in LBV. CONCLUSION: Marked losses in midfrontal ChAT activity occur in diseases with LB, independent of coexistent AD changes. A greater midfrontal, as opposed to hippocampal, cholinergic deficit may differentiate LBV from AD. The lack of a relationship between epsilon4 allele dosage and midfrontal ChAT activity suggests that other factors may play a role in its decline in LBV.

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

Stocchi, F. and L. Brusa (2000). "Cognition and emotion in different stages and subtypes of Parkinson's disease." J Neurol 247 Suppl 2: II114-21.
This paper reviews the main neuropsychological features of movement disorders such as Parkinson's disease (PD), progressive supranuclear palsy (PSP), multiple system atrophy (MSA), Huntington's disease (HD), corticobasal degeneration (CBD), and diffuse Lewy body disease (DLBD). These neurodegenerative disorders all share a prominent frontal lobe-like syndrome which can be explained by damage to connections between the basal ganglia and the cortical areas involved in movement, and in behavioural and mood control. In this paper different types of cognitive and mood alteration are described in an attempt to identify additional reasons for the differential diagnosis of parkinsonism-like syndromes.

Shoji, M., Y. Harigaya, et al. (2000). "Accumulation of NACP/alpha-synuclein in lewy body disease and multiple system atrophy." J Neurol Neurosurg Psychiatry 68(5): 605-8.
OBJECTIVES: NACP/alpha-synuclein is an aetiological gene product in familial Parkinson's disease. To clarify the pathological role of NACP/alpha-synuclein in sporadic Parkinson's disease and other related disorders including diffuse Lewy body disease (DLBD) and multiple system atrophy (MSA), paraffin sections were examined immunocytochemically using anti-NACP/alpha-synuclein antibodies. METHODS: A total of 58 necropsied brains, from seven patients with Parkinson's disease, five with DLBD, six with MSA, 12 with Alzheimer's disease, one with Down's syndrome, one with amyotrophic lateral sclerosis (ALS), three with ALS and dementia, one with Huntington's disease, two with progressive supranuclear palsy (PSP), one with Pick's disease, one with myotonic dystrophy, and three with late cerebellar cortical atrophy (LCCA), and 15 elderly normal controls were examined. RESULTS: In addition to immunoreactive Lewy bodies, widespread accumulation of NACP/alpha-synuclein was found in neurons and astrocytes from the brainstem and basal ganglia to the cerebral cortices in Parkinson's disease/DLBD. NACP/alpha-synuclein accumulates in oligodendrocytes from the spinal cord, the brain stem to the cerebellar white matter, and inferior olivary neurons in MSA. These widespread accumulations were not seen in other types of dementia or spinocerebellar ataxia. CONCLUSION: Completely different types of NACP/alpha-synuclein accumulation in Parkinson's disease/DLBD and MSA suggest that accumulation is a major step in the pathological cascade of both diseases and provides novel strategies for the development of therapies.

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

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

McLean, P. J., H. Kawamata, et al. (2000). "Membrane association and protein conformation of alpha-synuclein in intact neurons. Effect of Parkinson's disease-linked mutations." J Biol Chem 275(12): 8812-6.
Two missense mutations (Ala-30 --> Pro and Ala-53 --> Thr) in the gene encoding alpha-synuclein are associated with rare autosomal dominant forms of familial Parkinson's disease. In addition, alpha-synuclein is an abundant component of Lewy bodies in sporadic Parkinson's disease and diffuse Lewy body disease. However, the normal conformation of alpha-synuclein, its cellular localization in neurons, and the effects of the mutations remain to be determined. In the present study, we examine these questions using sensitive fluorescence resonance energy transfer techniques. Transient transfection of alpha-synuclein expression constructs into primary cortical neurons and counterstaining with the lipophilic fluorescent marker, DiI, demonstrates a close association between alpha-synuclein and cellular membranes. Both the N- and C-terminal regions of alpha-synuclein are tightly associated with membranes. A weak interaction also occurs between the N and C termini themselves. The Parkinson's disease-associated mutations have no effect on membrane interaction; however, the Ala-30 --> Pro mutation alters the three-dimensional conformation of alpha-synuclein, as measured by significantly increased fluorescence resonance energy transfer between the N and C termini.

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

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

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

Engelender, S., T. Wanner, et al. (2000). "Organization of the human synphilin-1 gene, a candidate for Parkinson's disease." Mamm Genome 11(9): 763-6.
We have recently identified a protein we called synphilin-1, which interacts in vivo with alpha-synuclein. Mutations in alpha-synuclein cause familial Parkinson's disease (PD). Alpha-synuclein protein is present in the pathologic lesions of familial and sporadic PD, and diffuse Lewy body disease, indicating an important pathogenic role for alpha-synuclein. Here we describe the structure of the human synphilin-1 gene (SNCAIP). The open reading frame of this gene is contained within ten exons. We have designed primers to amplify each SNCAIP exon, so these primers can now be used to screen for mutations or polymorphisms in patients with Parkinson's disease or related diseases. We found a highly polymorphic GT repeat within intron 5 of SNCAIP, suitable for linkage analysis of families with PD. We have mapped SNCAIP locus to Chromosome (Chr) 5q23.1-23.3 near markers WI-4673 and AFMB352XH5. In addition, using immunohistochemistry in human postmortem brain tissue, we found that synphilin-1 protein is present in neuropil, similar to alpha-synuclein protein. Because of its association with alpha-synuclein, synphilin-1 may be a candidate for involvement in Parkinson's disease or other related disorders.

Stoessl, A. J. and J. Rivest (1999). "Differential diagnosis of parkinsonism." Can J Neurol Sci 26 Suppl 2: S1-4.
The diagnosis of Parkinson's disease is predominantly clinical, based on a combination of the cardinal features of tremor, bradykinesia and rigidity. The differential essentially lies between other conditions resulting in tremor, of which essential tremor is the commonest, and other akinetic-rigid syndromes. These include progressive supranuclear palsy, multiple system atrophy, toxins and other degenerative disorders, including diffuse Lewy body disease and corticobasal degeneration. The key clinical features of these disorders and a practical diagnostic approach are briefly reviewed in this article.

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

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

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

Pakiam, A. S., C. Bergeron, et al. (1999). "Diffuse Lewy body disease presenting as multiple system atrophy." Can J Neurol Sci 26(2): 127-31.
OBJECTIVES: The majority of patients with diffuse Lewy body disease have cognitive or psychiatric manifestations as part of their initial presentation. A sizable minority present with parkinsonian features alone. Autonomic features may also occur, typically after the development of cognitive changes. We aim to demonstrate that diffuse Lewy body disease may rarely also present with parkinsonism accompanied by marked autonomic dysfunction in the absence of significant cognitive or psychiatric abnormalities. METHODS: Case report based on a retrospective chart review and neuropathological examination. RESULTS: We report on a patient in whom a clinical diagnosis of multiple system atrophy was made based on a presentation of parkinsonism with prominent and early autonomic involvement. The former included postural tremor, rigidity and bradykinesia, while the latter consisted of repeated falls due to orthostasis and the subsequent development of urinary incontinence midway through the course of her illness. She was poorly tolerant of dopaminergic therapy due to accentuated orthostasis. Benefit from levodopa was limited and only evident when attempted withdrawal resulted in increased rigidity. There was no history of spontaneous or drug-induced hallucinations, delusions or fluctuating cognition, and in contrast to the prominence and progression of her parkinsonian and autonomic features over the first several years, cognitive impairment did not occur until the final stages of her illness, seven years after the onset of initial symptoms. Neuropathological examination revealed numerous Lewy bodies in both neocortical as well as subcortical structures consistent with a diagnosis of diffuse Lewy body disease. There was marked neuronal loss in the substantia nigra as well as the autonomic nuclei of the brainstem and spinal cord. CONCLUSIONS: In addition to cognitive, psychiatric, and parkinsonian presentations, diffuse Lewy body disease may present with parkinsonism and prominent autonomic dysfunction, fulfilling proposed criteria for the striatonigral form of MSA.

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

Mizukami, K., M. Sasaki, et al. (1999). "An autopsy case of myotonic dystrophy with mental disorders and various neuropathologic features." Psychiatry Clin Neurosci 53(1): 51-5.
An autopsy case of myotonic dystrophy (MD) is reported. The patient was a 58-year-old male. He presented with muscular weakness and muscular atrophy at the age of 33 and was diagnosed as having MD from myotonic symptoms (i.e. percussion and grip myotonia) at 49 years old. Mental disorders including a delusional hallucinatory state, mental slowness, indifference, and lack of spontaneity as well as visual cognitive impairments were noted at the age of 55. He showed Parkinsonism and died of septic shock. T2-weighted magnetic resonance imaging demonstrated diffuse cortical atrophy with a marked frontal atrophy and high-intensity signals in the white matter. Single photon emission computed tomography demonstrated hypoperfusion in the frontal cortex. Neuropathologic observation revealed neuronal loss in the superficial layer of the frontal and parietal cortices and extensive neuronal loss in the occipital cortex, intracytoplasmic inclusion body in the nerve cell of the medial thalamic nuclei, neuronal loss and presence of Lewy bodies in the substantia nigra and locus ceruleus corresponding to the pathologic features of Parkinson's disease, as well as abnormalities of myelin in the white matter. The present case suggests that in MD brain, various neuropathologic changes may occur and they contribute to the mental disorders.

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

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

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

Kosaka, K. (1999). "[Diffuse Lewy body disease]." Ryoikibetsu Shokogun Shirizu(27 Pt 2): 82-5.

Iseki, E., W. Marui, et al. (1999). "Frequent coexistence of Lewy bodies and neurofibrillary tangles in the same neurons of patients with diffuse Lewy body disease." Neurosci Lett 265(1): 9-12.
We examined the frequency of neurons with coexistent Lewy bodies (LB) and neurofibrillary tangles (NFT) in diffuse Lewy body disease brains, by a double-immunostaining method using MDV2 and Human tau. Double-positive neurons were frequently observed in the limbic areas. These neurons mostly revealed the feature of intermingled MDV2- and Human tau-positive substances. Immunoelectron microscopically, the MDV2-positive components were not in continuity with the MDV2-negative paired helical filaments (PHF). The MDV2-positive LB were surrounded by the small PHF bundles, frequently accompanied by the randomly oriented PHF within LB. In the intermingled neurons, MDV2-positive non-filamentous components without LB were found among the large PHF bundles. These non-filamentous components may represent the early stage of LB formation.

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

Arai, T., K. Ueda, et al. (1999). "Argyrophilic glial inclusions in the midbrain of patients with Parkinson's disease and diffuse Lewy body disease are immunopositive for NACP/alpha-synuclein." Neurosci Lett 259(2): 83-6.
Argyrophilic glial inclusions occur in the midbrain of patients with Parkinson's disease (PD) and diffuse Lewy body disease (DLBD). These inclusions are immunohistochemically positive for NACP/alpha-synuclein but negative for tau protein. The results of the present study suggest that a primary degenerative process involves NACP/alpha-synuclein in PD and DLBD and that the process takes place not only in neurons but also in glial cells. Argyrophilic cytoplasmic inclusions, both glial and neuronal, in a variety of degenerative diseases may be grouped into two major categories; one related to aggregates of abnormally phosphorylated tau protein and the other to unusual accumulations of NACP/alpha-synuclein.

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

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

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

Takeda, A., M. Mallory, et al. (1998). "Abnormal accumulation of NACP/alpha-synuclein in neurodegenerative disorders." Am J Pathol 152(2): 367-72.
The precursor of the non-Abeta component of Alzheimer's disease amyloid (NACP) (also known as a-synuclein) is a presynaptic terminal molecule that accumulates in the plaques of Alzheimer's disease. Recent studies have shown that a mutation in NACP is associated with familial Parkinson's disease, and that Lewy bodies are immunoreactive with antibodies against this molecule. To clarify the patterns of accumulation and differences in abnormal compartmentalization, we studied NACP immunoreactivity using double immunolabeling and laser scanning confocal microscopy in the cortex of patients with various neurodegenerative disorders. In Lewy body variant of Alzheimer's disease, diffuse Lewy body disease, and Parkinson's disease, NACP was found to immunolabel cortical Lewy bodies, abnormal neurites, and dystrophic neurites in the plaques. Double-labeling studies showed that all three of these neuropathological structures also contained ubiquitin, synaptophysin, and neurofilament (but not tau) immunoreactivity. In contrast, neurofibrillary tangles, neuropil threads, Pick bodies, ballooned neurons, and glial tangles (most of which were tau positive) were NACP negative. These results support the view that NACP specifically accumulates in diseases related to Lewy bodies such as Lewy body variant of Alzheimer's disease, diffuse Lewy body disease, and Parkinson's disease and suggests a role for this synaptic protein in the pathogenesis of neurodegeneration.

Takeda, A., M. Hashimoto, et al. (1998). "Abnormal distribution of the non-Abeta component of Alzheimer's disease amyloid precursor/alpha-synuclein in Lewy body disease as revealed by proteinase K and formic acid pretreatment." Lab Invest 78(9): 1169-77.
The precursor of the non-Abeta component of Alzheimer's disease amyloid (NACP) (also known as alpha-synuclein) is a presynaptic terminal molecule that abnormally accumulates in the plaques of Alzheimer's disease (AD) and in the Lewy bodies (LBs) of Lewy body variant of AD, diffuse Lewy body disease, and Parkinson's disease. To better understand the distribution of NACP/alpha-synuclein and its fragments in the LB-bearing neurons and neurites, as well as to clarify the patterns of NACP/alpha-synuclein compartmentalization, we studied NACP/alpha-synuclein immunoreactivity using antibodies against the C-terminal, N-terminal, and NAC regions after Proteinase K and formic acid treatment in the cortex of patients with LBs. Furthermore, studies of the subcellular localization of NACP/alpha-synuclein within LB-bearing neurons were performed by immunogold electron microscopy. These studies showed that the N-terminal antibody immunolabeled the LBs and dystrophic neurites with great intensity and, to a lesser extent, the synapses. In contrast, the C-terminal antibody strongly labeled the synapses and, to a lesser extent, the LBs and dystrophic neurites. Whereas Proteinase K treatment enhanced NACP/alpha-synuclein immunoreactivity with the C-terminal antibody, it diminished the N-terminal NACP/alpha-synuclein immunoreactivity. Furthermore, formic acid enhanced LB and dystrophic neurite labeling with both the C- and N-terminal antibodies. In addition, whereas without pretreatment only slight anti-NAC immunoreactivity was found in the LBs, formic acid pretreatment revealed an extensive anti-NAC immunostaining of LBs, plaques, and glial cells. Ultrastructural analysis revealed that NACP/alpha-synuclein immunoreactivity was diffusely distributed within the amorphous electrodense material in the LBs and as small clusters in the filaments of LBs and neurites. These results support the view that aggregated NACP/alpha-synuclein might play an important role in the pathogenesis of disorders associated with LBs.

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

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

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

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

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

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

Iseki, E., W. Marui, et al. (1998). "Degenerative terminals of the perforant pathway are human alpha-synuclein-immunoreactive in the hippocampus of patients with diffuse Lewy body disease." Neurosci Lett 258(2): 81-4.
We investigated the hippocampal pathology in diffuse Lewy body disease (DLBD) using alpha-synuclein immunohistochemistry. Ubiquitin-positive intrahippocampal structures caused by the degeneration of terminal axons of the perforant pathway were observed to be alpha-synuclein immunoreactive. These alpha-synuclein-positive degenerative terminals contained granulo-filamentous or vesiculo-tubular components similar to those of Lewy bodies (LB) immunoelectron microscopically, suggesting that alpha-synuclein may abnormally aggregate into filamentous or membranous cytoskeletal components including neurofilaments and synaptic vesicles in DLBD. A 'dying back' degenerating process due to a blockage of axonal transport may explain why the degenerative terminals and LB share similar alpha-synuclein-positive components, but the origin cells of the perforant pathway contain only a few LB.

Goetz, C. G., C. Vogel, et al. (1998). "Early dopaminergic drug-induced hallucinations in parkinsonian patients." Neurology 51(3): 811-4.
OBJECTIVE: To characterize patients who develop hallucinations early in the course of dopaminergic therapy for Parkinson's disease (PD) and contrast them with patients developing hallucinations after chronic drug treatment. METHODS: Parkinsonian patients who met diagnostic criteria for PD, experienced hallucinations, had a detailed hallucination interview at the onset time of their first hallucination, and had a 5-year clinical follow-up or an autopsy in those 5 years were identified and divided into two groups for comparison: 12 patients who developed early hallucinations within 3 months of starting levodopa therapy and 58 PD patients who developed hallucinations after 1 year of dopaminergic therapy. We contrasted the quality, content, diurnal nature, and emotional elements of the hallucinations, as well as the 5-year follow-up data on diagnosis, disease course, community home or nursing home outcome, and mortality. RESULTS: Both groups experienced a predominance of visual hallucinations, visions of people and animals, and vivid colors and definition. Features distinctive to the early onset hallucinating patients included visions that persisted in daytime as well as nighttime, frightening content with paranoia, and accompanying nonvisual hallucinations, either auditory, olfactory, tactile, or combinations thereof. At the 5-year follow-up, none of the early onset hallucinators had PD as their sole disorder. Four of the 12 had an underlying psychiatric illness that included hallucinations or psychosis preceding their parkinsonism by several years. In the other eight patients at the 5-year follow-up, their parkinsonism evolved to include additional signs that were no longer consistent with PD. The primary diagnoses were diffuse Lewy body disease and Alzheimer's disease (AD) with extrapyramidal signs. Patients with early drug-induced hallucinations had significantly greater placement to nursing homes and greater mortality. CONCLUSIONS: Early onset drug-related hallucinations are not typical of PD. Their presence should signal an investigation of two alternative diagnoses, either a comorbid psychotic illness (often unrevealed by the patient initially) or an evolving parkinsonism-plus syndrome.

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

de la Monte, S. M., Y. K. Sohn, et al. (1998). "P53- and CD95-associated apoptosis in neurodegenerative diseases." Lab Invest 78(4): 401-11.
Apoptosis is likely to be an important mechanism of cell loss in neurodegenerative diseases, but the signaling cascades activated before DNA fragmentation have not yet been determined. p53 or CD95 gene up-regulation precedes apoptosis in many cell types, and a potential role for these molecules in apoptosis of neurons and glial cells has already been demonstrated in Alzheimer's disease (AD). To determine whether apoptosis in other neurodegenerative diseases is mediated by similar mechanisms, p53 and CD95 expression were examined in postmortem central nervous system tissues from patients with diffuse Lewy body disease (DLBD), Pick's disease (PkD), progressive supranuclear palsy (PSP), multiple system atrophy (MSA), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Down's syndrome plus Alzheimer's disease (DN+AD). Quantitative immunoblot analysis demonstrated higher temporal lobe levels of p53 and CD95 proteins in DLBD, PkD, and DN+AD, and higher temporal lobe levels of CD95 only in MSA and PSP relative to PD and aged controls (for all, p < 0.01). In histologic sections, increased p53 immunoreactivity was localized in neuronal and glial cell nuclei, neuronal perikarya, and dystrophic neuritic and glial cell processes in the frontal (Area 1 1) and temporal (Area 21) lobes in DLBD, PkD, and DN+AD, the motor cortex and spinal ventral horns in ALS, and the striatum and midbrain in DLBD, MSA, PD, and PSP. Increased CD95 expression and nuclear DNA fragmentation were present in the same cell types and structures that manifested increased nuclear p53 immunoreactivity. The results suggest that p53- or CD95-associated apoptosis may be a common mechanism of cell loss in several important neurodegenerative diseases. In addition, the presence of abundant p53-immunoreactive neurites and glial cell processes appears to be a novel feature of neurodegeneration shared by these distinct diseases.

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

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

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

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

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

Tortosa, A., E. Lopez, et al. (1997). "Bcl-2 and Bax proteins in Lewy bodies from patients with Parkinson's disease and Diffuse Lewy body disease." Neurosci Lett 238(1-2): 78-80.
Double-labelling immunohistochemistry of Bcl-2 and Bax, and ubiquitin (as a marker of Lewy bodies) was examined in the brains of patients with Parkinson's disease and Diffuse Lewy body disease to learn about possible modifications of protein expression and the presence of Lewy bodies. Bcl-2 and Bax immunoreactivities were observed in Lewy body-bearing and non-Lewy body-bearing neurons in patients with parkinsonism. These results show that Bcl-2 and Bax are probably not implicated in Lewy body formation and that the presence of Lewy bodies does not have a direct impact on the expression of Bcl-2 and Bax proteins in individual neurons.

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

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

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