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Chronic Creutzfeldt-Jakob disease, presenting in later life, may be difficult to distinguish from other dementing illnesses. Patients with this disease may lack the characteristic myoclonus and electroencephalographic complexes. We report four patients with a slowly progressive dementia who were misdiagnosed during life and had a spongiform encephalopathy at autopsy. All four patients had early extrapyramidal rigidity, primitive reflexes, and other neurologic signs. The presence of these neurologic findings early in the course of a dementia suggests that clinicians should consider chronic Creutzfeldt-Jakob disease, evaluate the patient with electroencephalographic studies, and emphasize universal tissue precautions.

A second member of the original family with the valine to isoleucine substitution at codon 717 of the amyloid precursor protein died after the clinical diagnosis of Alzheimer's disease had been made in life. Neuropathological examination of the brain revealed not only severe Alzheimer type pathology, with senile plaques and neurofibrillary tangles, but also Lewy bodies both in the cortex and brainstem. Lewy bodies also occurred in our first case, thus showing striking similarities in these two members of the same family. The possibility exists that the occurrence of Lewy bodies may not be coincidental, but could be genetically determined: the same genetic abnormality which determines the deposition of beta A4 protein, thus triggering of a chain of events leading to Alzheimer's disease, may result in, or predispose to Lewy body formation.

The ATP-ubiquitin-dependent proteolytic pathway (ubiquitin pathway) is believed to be involved in the formation of various neuronal inclusion bodies including Lewy bodies (LBs), a pathological hallmark of Parkinson disease and diffuse Lewy body disease (DLBD). Since multicatalytic proteinase (MCP) is involved in the ubiquitin pathway, an investigation of whether MCP is involved in neuronal inclusion bodies would provide a clue to the mechanism underlying the formation of neuronal inclusion bodies as well as to the pathogenesis of degenerative neurological disorders. In this study, we investigated detailed immunolocalization of MCP in LBs in DLBD brains using light and electron microscopy. We raised three different monoclonal antibodies against purified human MCP. Each of them recognized different sets of MCP subunits on Western blotting. Immunohistochemically, anti-MCP antibodies recognized all ubiquitin-positive cortical LBs in situ as well as those isolated from frozen DLBD cortices, suggesting that MCP is present in LBs as a whole molecule exhibiting protease activity. In electron microscopy, MCP immunoreactivity (MCP-IR) was exclusively localized on a characteristic oval structure with an approximate diameter of 100 nm. This structure was distributed throughout the LBs and was devoid of ubiquitin immunoreactivity. Treatment of isolated LBs with 2% SDS, but not with 0.5% Triton X-100, removed this structure from LBs in which fibrous materials predominated. Ubiquitin immunoreactivity was also decreased in isolated LBs treated with 2% SDS, suggesting that the fibrous structures in LBs were not ubiquitinated in situ. Thus, it is suggested that LBs are subjected to a proteolytic process in which MCP plays a role via processing of specific components of LBs.

Samples of 9 brains of autopsied patients suffering from Parkinson's disease were examined. In H & E stained 20 microns thick sections of substantia nigra 10 Lewy body containing and 20 unaffected pigmented nerve cells of substantia nigra per case were measured for size of the perikarya and nucleolar size utilizing an interactive image processing unit. In affected cells the size of Lewy bodies was measured too. There was no significant difference in the size of the perikarya and nucleolar size between affected and unaffected cells. In Lewy body bearing cells nucleolar size was not correlated with the size of the Lewy bodies. There was a significant negative correlation between nucleolar size of substantia nigra neurons and the duration of the disease. Since nucleolar volume can serve as indicator of RNA synthesis of a cell, Lewy bodies do not seem to disturb nerve cell metabolism.

We determined the number of immunocytochemically identified oxytocin (OXT) and vasopressin (AVP) neurons in the paraventricular nucleus (PVN) of the human hypothalamus of six Parkinson's disease (PD) patients ranging from 59 to 83 years of age. Six subjects without a primary neurologic or psychiatric disease, ranging from 69 to 88 years of age, served as controls. The OXT-immunoreactive cell number in the PVN of the PD patients was 22% lower than that of the control subjects. Although Lewy bodies were present in the nucleus basalis of Meynert, there were no Lewy bodies in the PVN of these patients. Doubt is raised about the presumed direct relationship between the presence of Lewy bodies and neuronal degeneration in PD. The AVP-immunoreactive cell number in the PD patients showed a similar decreasing trend, but the 18% reduction failed to reach statistical significance. The presence of tyrosine hydroxylase-positive neurons in the PVN was not affected in PD patients, supporting the notion that dopaminergic neurons of the mesencephalon, but not of the hypothalamus, are affected in PD. The decreased number of OXT-containing neurons in the PVN suggests that dopamine may be important for the function of these neurons and may provide a neural basis for some autonomic and endocrine disturbances in PD.

Ubiquitinated cytoplasmic inclusions are a characteristic feature of the neuronal pathology of neurodegenerative diseases. Immunocytochemical techniques have identified intermediate filaments associated with ubiquitin-immunoreactive inclusions in Alzheimer's disease (AD), Parkinson's disease (PD), and Pick's disease; however, no core protein has been detected in the ubiquitinated inclusions in amyotrophic lateral sclerosis (ALS). The pathogenesis of these inclusions is not known, but the inclusion may result from an accumulation of an abnormal proteins. Here we report a novel protein of 32.5 kDa detected by polyacrylamide gel electrophoresis, in the spinal cord in ALS patients. A polyclonal antibody raised against this protein and used for Western blotting, suggests that the novel protein is related to actin. Immunocytochemical studies using this antibody indicate that the protein is found in Lewy body-like inclusions in anterior horn cells of ALS, and in Lewy bodies in the substantia nigra in PD.

Alzheimer's disease (AD) is the most common cause of dementia (32). Although the majority of cases of AD are sporadic, the most consistent risk factor detected in several epidemiological studies has been a positive family history of the disease (14,21). In addition, many large pedigrees have been described in which AD appears to be inherited as an autosomal dominant disorder. In one such pedigree (F23) a point mutation within the beta-amyloid precursor protein (APP) gene at codon 717 was identified and hypothesized to be pathogenic (10). The mutation results in a valine to isoleucine change in APP (APP717 Val-->Ile). Subsequent screening has revealed four other pedigrees, detailed in this study, in which this mutation co-segregates with AD (13,26,37). In addition, one other pedigree (Tor3) with this mutation has been described (15) and detailed clinical, neuropsychological, and neuropathological data are reported. Tor3 is discussed below in comparison to the findings in the families in this study. The five families we report with the mutation were identified in Britain (1 family), the United States (1 family), and Japan (3 families). The mutation has not been reported in the general population of any of these countries (3,13,26,33). On this basis alone it seems this mutation is pathogenic. Other APP codon 717 mutations have been identified which co-segregate with the disease (4,25). Also, a double mutation in APP at codons 670/671 has been shown to cosegregate with the disease in two large Swedish pedigrees (22). In all cases, there is complete co-segregation of the APP mutation with early onset AD, providing overwhelming statistical evidence that these mutations are pathogenic. We present the clinical features and limited neuropathology of AD in these families with the APP 717 Val-->Ile mutation.

A 30-year-old woman suffered from a progressive extrapyramidal syndrome, myoclonic jerks, spasticity, and organic brain syndrome; she was clinically suspected to suffer from Creutzfeldt-Jakob disease and died after 4 years of illness. At autopsy, widespread dystrophic axons and Lewy bodies (LBs) were found in her brain. Neuronal loss and diffuse reactive astrogliosis involved the gray matter including the cerebral cortex. Dystrophic axons occurred throughout the nervous system except for the cerebellar cortex and peripheral nerves. LBs involved the cerebral cortex as well as subcortical regions including amygdala and claustrum, brainstem including substantia nigra and locus coeruleus, and spinal cord. LBs were distributed extensively enough to be compatible with diffuse Lewy body disease (DLBD). Ubiquitin immunostaining labeled both dystrophic axons and LBs. The combination of neuroaxonal dystrophy and DLBD may result from cytoskeletal pathology which affects both neuronal cell bodies and axons with subsequent deficient proteolysis and ubiquitination.

At post-mortem, Lewy bodies (LBs) were found in the brainstem and neocortex of eight out of 65 patients who had been collected during a prospective long-term study on clinically diagnosed Alzheimer's disease. All eight patients had accompanying Alzheimer pathology which was less severe than in a sample of eight age- and sex-matched patients from the same study with neuropathologically verified Alzheimer's disease. Parkinsonian features were more common in patients with LBs. There were no particular differences in duration of illness, severity of cognitive impairment, presence of hallucinations, or fluctuations in the course of illness. Frontal cerebral atrophy was more marked in patients with LBs, as was the loss of neurons in the basal nucleus of Meynert and the substantia nigra. Cognitive performance correlated with the number of pigmented neurons in the substantia nigra. We conclude that the differential diagnosis of LB dementia should be considered in patients satisfying NINCDS-ADRDA criteria for Alzheimer-type dementia who show marked Parkinsonian features and a frontal accentuation of cerebral atrophy.

A case is reported of a patient with autopsy-confirmed idiopathic Parkinson's disease in addition to chronic paranoid schizophrenia. Difficulties in the diagnosis and management of these two conditions are described. Because of the treatment implications, clinicians should be aware that idiopathic Parkinson's disease and schizophrenia can coexist.

The clinical details of 100 cases of histologically confirmed Parkinson's disease were examined and correlated with pathologic findings. Age at disease onset (mean, 62.4 years), disease duration (mean, 13.1 years), and age at death (mean, 75.5 years) were similar to those in previous smaller series. Asymmetric, tremulous onset was most common, although 23% of patients had no rest tremor. Motor fluctuations and dyskinesias occurred in 60% of levodopa-treated patients. All patients had clinical parkinsonism; however, 12 had atypical clinical features of Parkinson's disease, including severe early dementia, fluctuating confusional states, no response to levodopa, and early marked autonomic disturbance. Neuropathologic examination found coexistent Alzheimer-type change in 17 cases and striatal abnormality--mainly vascular--in 34 cases. Cortical Lewy bodies were present in all cases, but only four satisfied proposed criteria for diffuse Lewy body disease. Dementia occurred in 44% of cases; 29% had Alzheimer's disease, 10% had numerous cortical Lewy bodies, and 6% had a possible vascular cause; in 55% no definite pathologic cause was found. Nigral cell loss correlated with disease duration and severity. Although the general pattern of disease conformed to traditional descriptions, the findings broaden the present clinical and pathologic spectrum of Parkinson's disease.

The possibility of a major contribution of hereditary factors to the cause of Parkinson's disease (PD) is being reconsidered by many. The studies preceding the 1980s presented conflicting evidence and suffered from procedural difficulties. The emergence of the MPTP hypothesis and the failure of three twin studies to document a strong hereditary component in the early 1980s turned attention toward an environmental cause of PD. However more recent descriptions of deficiencies in genetically-coded biochemical functions in PD, more sophisticated clinical family analyses, re-analysis and extension of the twin studies and the emergence of several large autopsy-proven PD kindreds raise the possibility of an important heritable factor in PD.

In order to elucidate the pathological differences between demented and nondemented patients with Lewy body disease, brains from 35 patients were clinicopathologically examined. In diffuse Lewy body disease, cortical lesions, including numerous Lewy bodies and senile changes, were found to be responsible for the dementia. In some of the cases with the brain-stem type of Lewy body disease, the dementia was attributed to an Alzheimer pathology, while in many cases the various combinations of degeneration in the subcortical nuclei, mainly the nucleus basalis of Meynert and locus ceruleus, played a major role in the dementia. Forty-four Japanese cases with diffuse Lewy body disease were reviewed. Then diffuse Lewy body disease was divided into two forms: a common form (33 cases) and a pure form (11 cases). In the common form, all cases showed progressive cortical dementia in the presenile or senile period. Parkinson syndrome was usually marked in the terminal stage. However, about a fifth of the cases had no parkinsonism. Neuropathologically, the common form had many concomitant senile changes in the cerebral cortex. Most cases with the pure form showed juvenile Parkinson syndrome followed by progressive cortical dementia, while a few cases were of presenile or senile occurrence. Neuropathologically, the pure form had no or few senile changes. This suggests that numerous cortical Lewy bodies alone can cause cortical dementia.

Idiopathic parkinsonism (Parkinson's disease) makes up the largest diagnostic subgroup of patients with parkinsonism. Various hypotheses exist regarding the pathogenesis of idiopathic parkinsonism: these include genetic predilection aging, environmental factors, oxidative stress, excitotoxicity, autoimmunity, and trauma. We suggest that the pathogenesis of idiopathic parkinsonism is likely to be multifactorial, deriving from environmental factor(s) acting upon a genetically predisposed individual. Because of the compelling evidence indicating common clinical and pathological findings in idiopathic parkinsonism, Alzheimer's disease, and amyotrophic lateral sclerosis, we believe that these conditions result from pathological processes with more similarity than diversity. A primary glutamatergic cell neocortical abnormality provides an attractive unifying explanation which may explain the overlapping abnormalities found in idiopathic parkinsonism, Alzheimer's disease, and amyotrophic lateral sclerosis.

We report the distribution of Lewy bodies in an 83-year-old man who was diagnosed histopathologically as having Parkinson's disease. Many sections were taken from the brain, spinal cord, spinal dorsal root ganglia and peripheral autonomic systems. In the central nervous system, Lewy bodies were present in many of the areas already reported by previous authors. In the peripheral nervous system, Lewy bodies were present in the sympathetic ganglia, enteric nervous system of the alimentary tract and the submandibular ganglion, which is a peripheral parasympathetic ganglion. The present case indicates that the peripheral parasympathetic ganglia are involved in the disease process of Parkinson's disease.

The MPTP monkey model for PD has continued to display similarities as well as differences from the human disease, also in respect to its neuropathology. In 65 MPTP-treated squirrel monkeys with survival for more than 2 days, the main similarities consisted of nerve cell degeneration, not only of SN, but also, in the majority of cases, of the LC. In 13 animals that survived for from 1 to 7 years after their first exposure to MPTP, the nerve cells in the ventrolateral portion of the SN compacta were particularly vulnerable, just as in PD. The principal differences were the lack of progression of the disease process in these long-term animals (although this has yet to be systematically tested) and the absence of formation of typical Lewy bodies in the SN, LC, and other predilection sites for Lewy bodies. Since inclusion bodies, now observed in 16 monkeys, could be produced fairly consistently in aged MPTP-treated squirrel monkeys, they appeared to represent a bridge between these similarities and differences. They had some features, especially their location in predilection sites for Lewy bodies, such as the SN, in common with Lewy bodies, but did not display the fully convincing morphological and immunocytochemical features, characteristics of the human inclusion bodies in PD. Overall, these studies continue to provide tantalizing hints that this model could lead to important new insights into the pathologic process that underlies PD.

Subsumed under the rubric of Lewy body disease are idiopathic Parkinson's disease (PD), pure diffuse Lewy body disease (DLBD), and, most commonly, combined brainstem and neocortical Lewy bodies with Alzheimer's disease (AD) pathology in a relatively early developmental stage. Clinical correlates are dementia with psychiatric and subcortical features plus mild extrapyramidal signs (EPS).

A 67-year-old man with a family history of parkinsonism had visual complaints due to difficulty in convergence, which was followed 2 years later by development of bradykinesia and rigidity. The diagnosis of Steele-Richardson-Olszewski syndrome was made on the basis of a supranuclear gaze palsy, bradykinesia, rigidity, and poor response to levodopa. However, subsequent neuropathological examination revealed diffuse Lewy body disease with no evidence of neurofibrillary tangles involving either subcortical or brain stem structures.

Atypical dementias confront the adequacy of current diagnostic concepts. The two patients with atypical dementia syndromes described here shared common postmortem features of numerous neocortical neuritic (senile) plaques and microvascular amyloid, sparing of hippocampus and substantia nigra, and the virtual absence of neurofibrillary tangles. Microscopically, the two differed only by the presence of a few subcortical Lewy bodies in case 1. These similar morphologic features were associated with dramatically different clinical presentations. In the first patient, visual hallucinations, Capgras' syndrome, cognitive slowing, myoclonus, parkinsonism, and primitive reflexes evolved over 3 years. Memory and language were relatively spared. In the second, dysphagia, nonfluent aphasia, hypophonia, motor perseveration, and a severe disorder of attention developed during this 18-month illness. At autopsy, an unrecognized colon malignancy was found. Despite high neuritic plaque counts in cortex, neither the clinical nor the pathologic criteria for Alzheimer's disease adequately describe either case. The cases will be examined first as clinical, then as neuropathologic, entities. From this approach, we conclude that a specific clinical dementia syndrome may be expressed by several neuropathologic "diseases" and that a variety of clinical syndromes may represent a single neuropathologic diagnosis. This strategy identifies a conceptual dichotomy between Alzheimer's syndrome and postmortem Alzheimer's disease. Meticulous clinical and neuropathologic observation is essential in advancing an understanding of the relationship between the two.

The distribution of beta-amyloid protein (beta A4) was examined in the medial temporal lobes from cases of Alzheimer's disease (AD) (n = 13), senile dementia of Lewy body type (SDLT) (n = 12) and age matched controls (n = 9). Using a previously described image analysis technique the extent of beta A4 pathology was determined in ten distinct anatomical sites within the medial temporal lobe. AD and SDLT cases contained very similar amounts of beta A4 in the areas sampled and both contained significantly more beta A4 than the age matched controls, particularly in the dentate and parahippocampal gyri. The similarity of the beta A4 load in the two conditions is in contrast to reported differences in the number of neurofibrillary tangles which can be observed. It is suggested that AD and SDLT represent a spectrum of pathology which centres around the aberrant processing of the beta A4 precursor protein.

An autopsied case of juvenile parkinsonism and dementia is described. The patient is a 48-year-old man who had a ten-year history of parkinsonian syndrome and progressive dementia. Neuropathological examination revealed a widespread occurrence of Lewy bodies and spheroids in the central nervous system. Lewy bodies were found not only in the brain stem and diencephalon, but also in the cerebral cortex. Massive numbers of small spheroids were observed in the globus pallidus, substantia nigra, mamillary bodies and hippocampus. Electron microscopical examination showed that most spheroids were composed of degenerative organelles with only a few neurofilaments, and were different from those of Hallervorden-Spatz disease. There was also marked neuronal loss with gliosis in the CA3-4 of the hippocampus. Some neurofibrillary tangles occurred in the hippocampus, subcortical and brain stem nuclei, but senile plaques were absent. This case may represent an atypical form of pure diffuse Lewy body disease.

We carried out an immunocytochemical examination of the brainstem and sympathetic ganglia of 5 autopsied patients with Parkinson's disease, using monoclonal antibodies against microtubule-associated protein 2 (MAP2) and synaptic vesicle-specific 38 kDa protein (SVP38). Lewy bodies (LBs) in the nerve cell somata were often immunoreactive for MAP2. Immunoreactivity of SVP38 in the somata of nerve cells was rarely demonstrated in the peripheral portion of the LBs. On the other hand, SVP38-immunoreactive (IR) LB-containing nerve cell processes were frequently found in the brainstem and sympathetic ganglia, considerably outnumbering MAP2-IR LB-containing nerve cell processes. These findings suggested that SVP38 is stored in LB-containing nerve cell processes and indicate that the majority of these processes are axons.

The Lewy body is an intraneuronal inclusion body that is one of the histologic hallmarks of Parkinson's disease, a degenerative disease of the brain. Ultrastructural analysis has shown that the Lewy body is composed of straight 7-20 nm filaments and amorphous elements. Previous light microscopic, immunocytochemical studies have suggested the presence of neurofilament, microtubule, ubiquitin, and paired helical filament-related epitopes in Lewy bodies. Yet the biochemical composition of the Lewy body remains incompletely elucidated. The ultrastructural and immunocytochemical similarities and differences between the Lewy body and the neurofibrillary tangle of Alzheimer's disease raise questions as to their relation to each other and possible shared mechanisms of formation. In this study the authors examine whether ultrastructural immunocytochemical analysis of Lewy bodies confirms the light microscopic data, whether the structures and epitopes of Lewy bodies share with Alzheimer's disease neurofibrillary tangles the property of insolubility in sodium dodecyl sulfate, and speculate about the subunit composition of Lewy body filaments.

The prevalence of pale bodies and Lewy bodies was studied in the substantia nigra of 12 patients with typical Parkinson's disease (PD), in 5 patients with diffuse Lewy body disease (DLBD), and in a group of neurologically normal controls. Anti-ubiquitin antibodies labelled pale bodies and Lewy bodies in typical PD and DLBD, and there was a strong positive correlation between numbers of ubiquitin-immunoreactive pale bodies and Lewy bodies. BF10, a monoclonal antibody against a phosphate-dependent epitope of neurofilament 155-kDa polypeptide subunit, immunolabelled 57% of Lewy bodies and 15% of pale bodies in typical PD. Some pale bodies and Lewy bodies were seen in the substantia nigra of 2 of 5 neurologically normal, aged controls, probably representing "incidental PD". We conclude that there is a close relationship between pale bodies and typical Lewy bodies in the substantia nigra in clinical varieties of PD, and that these inclusions share antigenic determinants. If pale bodies and Lewy bodies reflect separate aspects of the cellular pathology in PD, their formation probably occurs in parallel. Alternatively, these observations may suggest that pale bodies represent a stage in the formation of Lewy bodies.

In a 62-year-old man with an 8-month course of sporadic classical amyotrophic lateral sclerosis, many Lewy body-like hyaline inclusions (LI) were observed in spinal anterior horn cells, hypoglossal nuclei, nucleus ambiguus, and motor nuclei of the trigeminal nerve. These motor neurons showed a mild degree of neuronal loss, several Bunina bodies, spheroids and chromatolytic neurons. Tract degeneration was limited to pyramidal tracts. In addition to intensely stained LI, immunoreactive skeins or granules were recognized by a polyclonal anti-ubiquitin antibody. Thick filaments of 15 to 20 nm in diameters with granules formed conglomerated masses with varying amounts of neurofilaments in the anterior horns, corresponding to light microscopically observed LI. More commonly, these thick granulofilamentous profiles were dispersed in small bundles or individually in the cytoplasm. Electron microscopically, there was no close association of filaments with Bunina bodies.

A Lewy body dementing syndrome in the elderly has been recently described and designated senile dementia of Lewy body type (SDLT) on the basis of a distinct clinicopathological profile. The pathological changes seen in SDLT include the presence of cortical Lewy bodies (LB) frequently, but not invariably, associated with senile plaque (SP) formation. Whilst neocortical neurofibrillary tangles (NFT) are sparse or absent, a proportion of these cases show involvement of the temporal archicortex by lesions comprising Alzheimer-type pathology (ATP, i.e. NFT, SP and granulovacuolar degeneration [GVD]). Thus the relationship between SDLT and senile dementia of Alzheimer type (SDAT) is complex and controversial. In this study quantitative neuropathology was used to compare the intensity and distribution of ATP in the hippocampus and entorhinal cortex of 53 patients from 3 disease groups (SDLT, SDAT, Parkinson's disease (PD)) and a group of neurologically and mentally normal elderly control patients. For most brain areas examined the extent of ATP between the patient groups followed the trend SDAT greater than SDLT greater than PD greater than control. Statistical comparison of these groups revealed significant differences between the mean densities of NFT, SP and GVD although individual cases showed considerable variability. These results confirm additional pathological differences between SDAT and SDLT regarding the intensity of involvement of the temporal archicortex by ATP. Many patients with Lewy body disorders (LBdis) show a predisposition to develop ATP albeit in a more restricted distribution (e.g. low or absent neocortical NFT) and at lower densities than is found in SDAT. Some cases of SDLT show minimal SP and NFT formation in both neocortex and archicortex supporting previously published data distinguishing this group from Alzheimer's disease.

Entorhinal cortex is the major source of hippocampal afferents. Its neurons, especially in layer 2, develop neurofibrillary tangles (NFTs) in Alzheimer disease (AD). We quantified entorhinal NFTs in cases of AD, elderly controls, and in brains with both AD pathology and subcortical and neocortical Lewy bodies, (a Lewy body variant, LBV). A nosologic controversy hinges on whether LBVs are a form of AD or a different disease, since they have few neocortical NFTs and their neuritic plaques often lack paired helical filament immunoreactivity. The LBVs had more entorhinal NFTs than controls (P less than 0.001), but fewer than ADs (P less than 0.02), despite comparable numbers of neuritic plaques. AD pathology in LBVs is of moderate severity, or perhaps in an earlier developmental stage.

Dendritic spheroid bodies (SBs) and Lewy bodies (LBs) were identified in comparable numbers in the substantia nigra pars compacta (SBC) of nine parkinsonian cases and one case of striatonigral degeneration but were not found in cases of Huntington's disease or neurologically normal controls. The immunohistochemical profile of the SBs in dystrophic dendrites of nigrostriatal dopaminergic neurons was remarkably similar to that of the LBs found within dendrites or free of the SNC neuropil. Both types of inclusions stained positively with antibodies to tyrosine hydroxylase, ubiquitin and microtubule-associated protein-2 (MAP2), and negatively for Tau-2, although they had different ultrastructural appearances. A few intracellular LBs were stained by antibodies to neurofilament proteins (NFs) 68, 160, and 200 kD, but dendritic SBs and extracellular LBs were not so stained. These data indicate that dendritic SBs and extracellular LBs may have a common molecular pathogenetic origin in Parkinson's disease. On the other hand, the SBs seen in the pars reticulata (SNR) and in the distal nigrostriatal axons even in control cases were generally stained by antibodies to NFs and ubiquitin but not to MAP2. This latter staining pattern in similar to that shown by SBs in the anterior horn in ALS and in the cerebellum of neurologically normal brains and is believed typical of axonal as opposed to dendritic SBs.

Ca2+/calmodulin-dependent protein kinase II (CaM kinase II) is one of the predominant protein kinases in the brain. We found that CaM kinase II immunoreactivity was concentrated in the peripheral halos of Lewy bodies (LBs) in Parkinson's disease and Lewy body-like hyaline inclusions (LBHIs) in amyotrophic lateral sclerosis. An immunoelectron microscopic examination of LBs revealed that the filaments at the periphery of LBs were decorated with immunopositive deposits. Since CaM kinase II has a broad substrate specificity and can phosphorylate neurofilaments and other cytoskeletal proteins, it may play some role in the formation of LBs and LBHIs through the aberrant phosphorylation of the cytoskeletal elements in these inclusions.

The clinical and postmortem findings of a patient with Lewy body pathology combined with multiple-system atrophy are described. When alive the patient was diagnosed as having Parkinson's disease. Pathological examination found evidence of striatonigral and olivopontocerebellar degeneration, together with Lewy bodies at a number of sites characteristic for idiopathic Parkinson's disease. Taken together, the clinical history and histological findings support the coexistence of two disease processes.

Four cases of Parkinson's disease with advanced dementia are described. Postmortem examination revealed cell loss in the substantia nigra, with Lewy bodies present, and loss of cells in the basal nucleus of Meynert. A few tangles were observed in the hippocampus, but no senile plaques or neurofibrillary tangles were found in the neocortex. The authors note that a dramatic dementia syndrome may occur with Parkinson's disease alone, without the associated cytoskeletal markers of Alzheimer's disease. Cases were characterized by disorientation, episodic confusion and hallucinations persisting off medication, disturbed behavior, and the absence of aphasia.