Lewy bodies of Parkinson's disease contain neurofilament antigens.

The Lewy body, a histological hallmark of Parkinson's disease, is a filamentous inclusion residing most prominently in pigmented neurons of the brainstem. Immunocytochemical reactions of Lewy bodies were examined with antisera to several filamentous proteins of the nervous system and positive reactions were found with those against neurofilaments. An abnormal organization of the neuronal cytoskeleton may be a pathological feature of Parkinson's disease.

Differential expression of TGF-beta 1, 2 and 3 isotypes in Alzheimer's disease: a comparative immunohistochemical study with cerebral infarction, aged human and mouse control brains.

Based upon the hypothesis that growth regulatory and inflammatory mechanisms participate in the pathogenesis of Alzheimer's disease, we studied cases of Alzheimer's disease for immunoreactivity to each of the three mammalian transforming growth factor beta (TGF-beta) isotypes: TGF-beta 1, TGF-beta 2, TGF-beta 3. Results were compared with those seen in control brains and in a destructive pathological process, subacute infarction. In the cases of Alzheimer's disease, TGF-beta 1 immunoreactivity was limited to neuritic profiles within senile plaques. Neuronal neurofibrillary tangles, plaque neurites, microglia, astrocytes and macrophages expressed TGF-beta 2 immunoreactivity. TGF-beta 3 produced strikingly selective staining of Hirano bodies. In contrast, in cases with infarction, reactive astrocytes and macrophages were positive with all three antibodies. Ramified microglia labeled selectively, as in the Alzheimer brains, with the TGF-beta 2 antibody. Subtle generalized astrocyte and microglial immunoreactivity for TGF-beta 2 was seen in pathological and control brains. The localization of TGF-beta isotypes to the lesions of Alzheimer's disease supports the hypothesis that these cytokines may influence lesion expression. Their presence in reactive cells associated with cerebral infarction suggest that they may play a broader role in the pathogenesis of CNS disease.

The choroid plexus in passive serum sickness.

Immunofluorescent microscopy of the choroid plexus revealed the presence of rabbit IgG and either rat or mouse C3 in a high percentage of young male Wistar rats and CF1 mice who had received intravenous injections of preformed BSA-rabbit anti BSA complexes over a 3 day period. Electron dense deposits were observed in the basement membrane region of the choroid plexus in these animals. These findings were comparable to those noted in their renal glomeruli. This is the first description of involvement of the choroid plexus in passive immune complex disease. This experimental model is rapidly inducible and should be of value in future pathophysiological studies of this important structure.

The immunopathophysiological effects of chronic serum sickness on rat choroid plexus, ciliary process and renal glomeruli.

The immunopathological findings and their effects upon the vascular permeability of the ciliary process, choroid plexus and renal glomeruli to intravenously injected 125I-bovine serum albumin (BSA) have been studied in 26 rats who survived a prolonged period of bovine serum albuminemia following the experimental chronic serum sickness model of Fennell and Pardo (8). Rat IgG and C3 and BSA were demonstrated in the experimental rats by direct immunofluorescence in glomeruli, ciliary process and choroid plexus of 85, 38 and 39 percent of animals respectively. Age and sex matched control tissues were negative. Statistically significant differences in the 125I-BSA content of urine, eye and brain were observed between the experimental and control groups. This experimental model offers an approach to the understanding of ocular and central nervous system involvement in clinical situations characterized by circulating immune complexes as well as an experimental tool with which to explore further the physiological consequences of immune deposits within the choroid plexus and ciliary body.

Increased risk of experimental central nervous system listeriosis in rats with chronic serum sickness. An immunohistopathological study.

The incidence and severity of central nervous system (CNS) infection were increased following the intraperitoneal innoculation of Listeria monocytogenes in adult Wistar rats with experimental chronic serum sickness. The results were attributed to an alteration in the blood-cerebrospinal fluid barrier induced by immune complex deposits in the choroid plexus of animals hyperimmunized with bovine serum albumin. CNS inflammation occurred in 16 of 40 (40%) of the test animals studied; one of 36 (2.8%) controls had CNS inflammation. There were extensive pathological changes in the choroid plexus, subarachnoid space, and neural parenchyma of the test animals, as compared with only small inflammatory foci limited to the choroid plexus and subarachnoid space in the one affected control. This experimental model for inducing bacterial CNS infection simulates certain predisposing conditions in chronic immune disease, and may therefore be useful in studying the pathogenesis of CNS infection in such cases.

Postmortem neuropathological features secondary to boron neutron capture therapy for glioblastoma multiforme.

This postmortem study of 12 patients with glioblastoma multiforme (GBM) treated with boron neutron capture therapy (BNCT) employing an epithermal neutron beam and p-boronophenylalanine describes the neuropathological findings in patients receiving a relatively high radiation dose to the tumor, but a relatively low radiation dose to the normal brain. In addition to a standardized neuropathology panel of sections, we used individual treatment dosimetry maps to select sections along the projected maximum radiation beam pathway. We found that the normal neuroparenchyma exposed to the highest radiation dose exhibited a single instance of radiation-induced focal venular fibrinoid necrosis and a single instance of multifocal demyelination. Semiquantitative analysis of pretreatment neurosurgical and postmortem tumor samples revealed only two radiation ascribed histopathological findings to be particular to therapy, fibrinoid necrosis and vascular hyalinization. In this relatively small series of cases we found an unexpectedly high frequency of cases (3 of 12) with neurodegenerative histopathology (Lewy bodies, neurofibrillary tangles, and neuritic senile plaques), which appeared, by distribution, to be independent of the radiation beam. Two of these patients were over 70 yr of age. One was only 41. Our findings suggest an acceptable radiation-induced level of neurotoxicity at the lower doses employed, but raise the possibility of unexpected boron neurodegenerative toxicity.

The neuromuscular pathology of the Eosinophilia-Myalgia syndrome.

The Eosinophilia-Myalgia Syndrome (EMS) is a recently reorganized disorder in patients ingesting pharmacologic doses of L-tryptophan. We studied the lesions of skeletal muscle, peripheral nerve and skin in 12 cases of EMS. Perimyositis was severe in four, moderate in two, mild in three and absent in three cases. The lesions contained many eosinophils, T-helper cells, mast cells and activated macrophages. Type 2 myofiber atrophy was present in five cases and in one, this was the only pathologic finding. Severe epineurial inflammation was seen in the three sural nerve biopsies. Indirect evidence for peripheral neurologic involvement in three other cases consisted of inflammation surrounding intramuscular nerve twigs (two cases) and neurogenic atrophy (one case). Phlebitis accompanied the connective tissue inflammation in five cases and endarteritis in one. Fasciitis was present in three of four skin biopsies and dermal fibrosis in one.

Isolation and partial characterization of neurofibrillary tangles and amyloid plaque core in Alzheimer's disease: immunohistological studies.

Fractions enriched in neurofibrillary tangles (NFT) and amyloid fibrils were isolated from the cerebral cortex of three cases of senile dementia of the Alzheimer type. Distilled water suspensions of these fractions were excluded from all pore size gels and resisted digestion with various proteolytic enzymes. Formic acid/chloroform treatment of each fraction resulted in the appearance of 4,000-6,000, 15,000-17,000 and 24,000 molecular weight proteins, with concomitant diminution in the amount of excluded material at the top of each gel. The 4,000-6,000 dalton band was best seen in fractions containing randomly arranged amyloid fibrils, and its amino acid composition resembled that of the recently reported "beta" protein. A polyclonal antiserum to purified NFT reacted with tangles in neurons and in dystrophic neurites around plaques by immunoperoxidase staining. No reaction was obtained with cerebrovascular or plaque core amyloid immunohistologically, or with the 4-6 kD protein on immunoblots. Cross-reactivity with the neurofibrillary lesions occurring in Pick's disease, progressive supranuclear palsy, postencephalitic Parkinsonism and dementia pugilistica was also seen. Specific binding of this antiserum to the double filamentous structure was confirmed by immunoelectron microscopy. Although the presence of "beta" protein in both NFT and amyloid-containing fractions suggests that it may be an important constituent of both, cross-contamination cannot be excluded.

Demonstration of antibodies to testicular basement membrane by immunofluorescence in a patient with multiple primary endocrine deficiencies.

Circulating antibodies directed against testicular basement membrane and germinal cells are demonstrated in a patient with multiple primary endocrine gland deficiencies involving the thyroid, adrenals, testes, and pernicious anemia. Testicular biopsy revealed focal destruction of seminiferous tubules and interstitial fibrosis. The tubular basement membranes showed sharply positive immunofluorescence when stained with the patient's FITC conjugated gamma globulins.

Neuropathology of the brain stem in psychiatric disorders.

The brain stem was examined in a series of 27 autopsy cases for a possible association of microscopic changes and primary psychiatric disorder. Seven cases were found to have brain stem microglial nodules or perivascular infiltrates in association with a range of CNS pathological conditions. One of eight schizophrenic and none of four primary affective disorder patients showed brain stem pathology. While evident in many forms of coarse brain disease, brain stem microscopic changes do not appear related to primary psychiatric disorder.

Circumventricular organs in chronic serum sickness: a model for cerebral lupus.

The pathogenesis of the CNS manifestations of systemic lupus erythematosus (SLE) has been the subject of considerable investigation. The focus of many of these studies has concerned immune complex deposition within the choroid plexus (CP). Involvement of the other brain fenestrated vascular beds, the small, paraventricular circumventricular organs, has not been ascertained. For this purpose, chronic serum sickness, a good immunopathological experimental model of naturally occurring systemic immunological disorders such as SLE, was induced in Wistar rats by prolonged immunization with bovine serum albumin (BSA). The involvement of circumventricular vascular beds by immune deposits was ascertained immunohistochemically. The choroid plexus was found to be the most intensely involved circumventricular structure. Immune complex deposits were also present, in descending order of frequency, in the area postrema, subfornical organ, and pineal gland.

Combined myelopathy and radiculoneuropathy with malignant lymphoproliferative disease.

Clinicopathological findings for two similar patients in whom myelopathy and radiculoneuropathy developed in association with malignant lymphoma were reviewed. This pattern of neurological disease has not been reported in association with the malignant lymphoproliferative disorders, and it provides ground for speculation concerning lymphocyte function and viral infection in cases of neurological disease in association with remote neoplasm.

Adult polysaccharidosis. Clinicopathological, ultrastructural, and biochemical features.

An abnormal polysaccharide in the form of cytoplasmic spheroids was found in the nervous system and systemic organs of a man with a progressive neurological disorder characterized by onset at 47 years of age, severe weakness, sensory loss, and dementia. Results of biochemical analysis showed a marked increase in brain and heart polysaccharide that was resistant to digestion by a mixture of glucosidases and that exhibited an iodine-complex spectrum higher than that of normal glyocgen. Results of histochemical studies were consistent with the results of biochemical analysis and further defined the branching characteristics of the stored polysaccharide. Electron microscopy showed the cytoplasmic location of the spheroids, which were granular and filamentous.

Glial transforming growth factor (TGF)-beta isotypes in multiple sclerosis: differential glial expression of TGF-beta 1, 2 and 3 isotypes in multiple sclerosis.

We studied glial transforming growth factor (TGF)-beta isotype expression in 14 cases of multiple sclerosis. Acute active lesions exhibited selective TGF-beta 2 immunoreactivity of lesion encircling ramified microglia. In contrast, astrocytes within chronic active white matter lesions expressed all three isotypes. Chronic active lesions which extended into cortex exhibited selective cortical astrocyte TGF-beta 2 expression. This isotype was also selectively expressed by astrocytes in apparently normal white matter. A similar pattern of glial TGF-beta expression was seen in the pathological control, progressive multifocal leukoencephalopathy. The results suggest that TGF-beta cytokines are locally expressed in demyelination and that the beta 2 isotype may be uniquely regulated.

Identification of Fc gamma RI, II and III on normal human brain ramified microglia and on microglia in senile plaques in Alzheimer's disease.

Using monoclonal antibodies to the three known human leukocyte IgG receptors, Fc gamma R, we examined the expression of Fc gamma R in normal brains and in Alzheimer's disease. We found Fc gamma RI, II and III immunoreactivity in senile plaques and on ramified microglia throughout the cortex and white matter of normal and Alzheimer's disease brains. Fc gamma RI expression was independently confirmed by a murine isotype binding study. These findings suggest that intrinsic Fc gamma R may play an important role in normal and disordered immune-related processes in the brain. They support the idea that microglia are brain macrophages.

Pericapillary permeability of the ciliary processes: role of molecular charge.

The pericapillary permeability of the ciliary processes to intravenously injected native (anionic) ferritin, neutral ferritin, and two cationic ferritin derivatives was studied in normal rats by electron microscopy. Anionic and neutral ferritin were largely confined to the circulatory compartment. Those particles that entered the pericapillary region of the ciliary processes were randomly scattered within the basal lamina. In contrast, cationic ferritin left the circulatory compartment and accumulated in the pericapillary region in association with the endothelium, the endothelial fenestrations, and the subendothelial basal lamina. The most cationic of the tracers used exhibited the greatest penetration and accumulation. The results indicate that the localization of tracer within the pericapillary region of the ciliary processes is directly related to the tracer's isoelectric point. The findings suggest that this region of the ciliary processes contains fixed anionic groups that influence its permeability.

Immunoglobulin G receptor-mediated phagocytosis by the pigmented epithelium of the ciliary processes.

The current ultrastructural study of cultured explants of bovine and rabbit posterior ciliary processes using immunoglobulin (Ig) G-opsonized red blood cells (E-IgG) showed specific IgG Fc receptor-mediated attachment, ingestion, and digestion of IgG-coated erythrocytes by the pigmented epithelium (PE). Nonpigmented epithelial cells (NPE) in the cultured explants and a transformed cell line of bovine NPE, with and without lymphokine stimulation, did not have IgG-receptor activity. The interaction between PE and E-IgG involved the extension of micropseudopods toward adherent E-IgG, the formation of a linear uniform cap of roughly 200 A between opposing cell membranes, the ingestion of E-IgG by PE into a membrane-lined compartment, and the disintegration of the ingested ligand into membranous debris. Disintegration of some surface-associated E-IgG was also observed and was consistent with the release of a lytic substance by the receptor-activated PE.

TGF-beta 2 and TGF-beta 3 immunoreactivity within the ciliary epithelium [corrected].

PURPOSE: To determine whether the ciliary epithelium exhibits immunoreactivity for antibodies to transforming growth factor beta (TGF-beta) 2 and TGF-beta 3. The hypothesis was that because the aqueous humor contains mainly biologically active TGF-beta 2, with little TGF-beta 1, the epithelium largely responsible for its composition would also contain this isoform of TGF-beta. The authors anticipated TGF-beta 3 immunoreactivity because TGF-beta 3 often co-localizes with TGF-beta 2. METHODS: The authors followed a standard immunohistochemical protocol using the avidin-biotin complex and newly available rabbit antibodies to synthetic peptide sequences of TGF-beta 2 and TGF-beta 3. Formalin-fixed, paraffin-embedded samples of freshly obtained rabbit and human autopsy eyes were studied. Specificity was supported by specific peptide absorption of antisera before tissue incubation. RESULTS: The pigmented and nonpigmented ciliary epithelia of rabbit and human eyes were stained by antibodies to both TGF-beta 2 and TGF beta-3, and the staining was inhibited by preabsorption of antibodies by peptides of TGF-beta 2 and TGF-beta 3. CONCLUSIONS: The authors conclude that the ciliary epithelium exhibits TGF-beta 2- and TGF-beta 3-like immunoreactivity that, based upon complementary work from other laboratories, is probably synthesized by this epithelium and is not simply absorbed by it from the aqueous humor.

Binding sites for immunoglobulin G in rabbit ciliary processes.

This article demonstrates the presence of selective binding activity for the Fc fragment of IgG on the ciliary processes of rabbit eye. Other parts of the eye, including the cornea, iris, choroid, and retina, were negative for such activity. Binding activity was demonstrated in vitro by the specific adherence of IgG-coated sheep red blood cells (IgGEA) to the ciliary processes in frozen sections of whole rabbit eye. IgGEA binding was specifically blocked by IgG but not by albumin or the F(ab')2 fragment of IgG. The data suggest that the ciliary processes, like the choroid plexus and the renal interstitium, have intrinsic binding activity for Fc IgG, which might be involved in the local entrapment of immune components present either in the circulation or in the aqueous humor.

Biodistribution of boronophenylalanine in patients with glioblastoma multiforme: boron concentration correlates with tumor cellularity.

Boron-10 (10B) concentrations were measured in 107 surgical samples from 15 patients with glioblastoma multiforme who were infused with 95 atom% 10B-enriched p-boronophenylalanine (BPA) intravenously for 2 h just prior to surgery at doses ranging from 98 to 290 mg BPA/kg body weight. The blood 10B concentration reached a maximum at the end of the infusion (ranging from 9.3 to 26.0 microg 10B/g) and was proportional to the amount of BPA infused. The boron concentrations in excised tumor samples ranged from 2.7 to 41.3 microg 10B/g over the range of administered BPA doses and varied considerably among multiple samples from individual patients and among patients at the same BPA dose. A morphometric index of the density of viable-appearing tumor cells in histological sections obtained from samples adjacent to, and macroscopically similar to, the tumor samples used for boron analysis correlated linearly with the boron concentrations. From that correlation it is estimated that 10B concentrations in glioblastoma tumor cells were over four times greater than concurrent blood 10B concentrations. Thus, in the dose range of 98 to 290 mg BPA/kg, the accumulation of boron in tumor cells is a linear function of BPA dose and the variations observed in boron concentrations of tumor specimens obtained surgically are largely due to differences in the proportion of nontumor tissue (i.e. necrotic tissue, normal brain) present in the samples submitted for boron analysis. The tumor:blood 10B concentration ratio derived from this analysis provides a rationale for estimating the fraction of the radiation dose to viable tumor cells resulting from the boron neutron capture reaction based on measured boron concentrations in the blood at the time of BNCT without the need for analysis of tumor samples from individual patients.