Time course changes of estrogen receptor α expression in the adult rat hippocampus after kainic acid-induced status epilepticus

Although estrogens possess neuroprotective and epileptogenic properties, the expression pattern of the estrogen receptor (ER) following status epilepticus (SE) remains unclear. We therefore examined the expression pattern of ER in the adult rat hippocampus after SE. SE was induced in rats by kainic acid (KA; 12 mg/kg, i.p.). ER expression was assessed by immunostaining and Western blotting at various times (24 h, and 7, 14, and 21 days) after SE onset. Immunohistochemistry disclosed ER expression in the CA1 and CA3 pyramidal cells of control rats, whereas, after SE, ER-immunoreactive neurons decreased in number due to neuronal death in the CA1 from days 7 to 21. On the other hand, ER-immunoreactive cells with astrocytic morphology were observed in the CA1 beginning on day 7 after SE. This immunoreactivity increased in proportion to the hypertrophy of astrocytes up to day 21. Western blotting revealed a significant decrease in ER expression on day 7 after SE in comparison with control level. However, ER expression on days 14 and 21 were similar when comparing KA-treated and control rats. These results indicate that reactive astrocytes are important sites of estrogen action in the hippocampal CA1 after SE.     

Comparison of integrin adhesion molecules expressed by primary brain lymphomas and nodal lymphomas

The expression of 17 adhesion molecules was immunohistochemically examined in 5 primary cerebral lymphomas (PCL) and in 5 histologically similar nodal lymphomas (NL) to evaluate their possible involvement in selective targeting of lymphoma cells to the brain. PCL and NL tumor cells showed very similar expression patterns: they were consistently positive for ₃, ₄ and ₁ integrin chains; negative for ₂, ₆, ₃ and ₄ integrin chains; and heterogeneous for ₅, _L, _M, _X, ₂ and ₇ integrin chains, as well as for intercellular adhesion molecule-1 (ICAM-1) and the selectin LECAM-1. Loosely infiltrating PCL showed lower levels of the _L2 integrin than compact cell clusters. Vessels stained for ICAM-1 and vascular cell adhesion molecule-1 (VCAM-1). We conclude that the adhesion molecules implicated in the extravasation of non-neoplastic leukocytes (₄₁/VCAM-1 and _L2/ICAM-1) are also expressed by both PCL and NL. The adhesion molecules examined are apparently not selective mediators of lymphoma cell homing to the brain, but at least _L2 integrin might be related to the infiltration pattern of PCL within the brain parenchyma.Supported by the Sander Foundation     

Colocalization of growth hormone (GH) and glycoprotein subunit α in GH-producing pituitary adenomas in acromegalic patients

Thirty-one consecutive cases of pituitary adenoma in acromegalic patients were studied by immunohistochemistry. All adenomas contained cells immunoreactive with the anti--subunit of gonadotropic hormones (; 0.6–53% of tumor cells) as well as with anti-growth hormone (GH; 4–74% of tumor cells). In serial section study, most cells immunoreactive with anti- were identical to cells immunoreactive with anti-GH. There was a positive correlation between the percentages of cells immunoreactive for in GH cells [(%)/GH(%)] and those for prolactin (PRL) in immunoreactive tumor cells {PRL(%)/[PRL(%)+GH(%)]} in mixed GH cell-PRL cell adenomas, suggesting that the -subunit may play a role in emergence of PRL cells.     

Expression of αB-crystallin in Alzheimer's disease

B-crystallin is a member of the small heatshock protein family. Under pathological conditions, the expression of B-crystallin increases in proliferating astrocytes, which suggests that this protein, in addition to glial fibrillary acidic protein (GFAP), can be a marker for gliosis in neurodegenerative diseases. Immunoblotting and immunohistochemical methods were used for the detection of B-crystallin in the brains of Alzheimer's disease (AD) patients and nondemented controls. An increase in B-cyrstallin expression was found in the brains of AD patients. Immunoreaction was present in reactive astrocytes, microglia, and oligodendrocytes, indicating that all types of glia respond to the stress associated with AD pathology. Colocalization of GFAP and B-crystallin was found in fibrous astrocytes. However, the intensity and range of B-crystallin expression appeared to be limited as compared with the large increase in the number of GFAP-positive astrocytes. This indicates that expression of B-crystallin is not a marker for gliosis in AD. Immunoreactivity to B-crystallin in both astrocytes and microglia was found mainly restricted to areas with senile plaques and neurofibrillary tangles, suggesting the association of B-crystallin with amyloid deposition in AD.Supported by a grant (No. EY08202) from the National Institutes of Health, Bethesda, USASupported by a fellowship of the Royal Netherlands Academy of Arts and Sciences     

Progressive accumulation of ubiquitin and disappearance of α-synuclein epitope in multiple system atrophy-associated glial cytoplasmic inclusions: triple fluorescence study combined with Gallyas-Braak method

-Synuclein (S) and ubiquitin (Ub) are shared constituents of glial cytoplasmic inclusions (GCIs) and Lewy bodies (LBs), both composed of fibrillary structures. Staining profiles of GCIs were investigated with triple immunofluorescence involving immunostaining for S and Ub, both amplified with catalyzed reporter deposition, and a fluorochrome, thiazin red (TR) that has an affinity to fibrillary structures. After observation for the triple-fluorescent images, the sections were subsequently stained with the Gallyas-Braak method. Sections of putamen, cerebellar white matter and motor cortex from patients suffering from multiple system atrophy (MSA) with varying duration of the disease (4–15 years) were quantified for these staining profiles of Gallyas-positive GCIs. Although most of GCIs were positive for Ub and variably positive for S, they were consistently negative for TR. The result was opposite in LBs in Lewy body disease with variable affinity to TR, suggesting that the construction of GCIs is different from that of LBs. These four staining features (S, Ub, TR and Gallyas) alone failed to exhibit apparent correlation with disease duration, lesion site or severity of degeneration as reported previously. The fraction of S-negative and Ub-positive GCIs, however, linearly increased along the disease progression, while that of S-positive and Ub-negative GCIs decreased in contrast. This reciprocal change suggests that S immunoreactivity in GCIs is being replaced by Ub immunoreactivity during the disease progression, which resulted in the ultimate predominance of S-negative and Ub-positive GCIs in the most advanced case. Interestingly, this predominance of S-negative and Ub-positive GCIs was a feature of motor cortex, where degeneration usually remains mild in spite of robust appearance of Gallyas-positive GCIs. Another fraction, S-positive and Ub-positive GCIs were frequent in cerebellar white matter, suggesting that GCI evolution is heterogeneous and dependent also on area examined. Progressive accumulation of Ub with concomitant disappearance of S epitope and their colocalization, partly shared with LBs, may represent a process of GCI formation, possibly linked to an aspect of degeneration in MSA.     

Myopathy with tubular aggregates in a patient adrenalectomized for cushing's syndrome

Summary We report a patient with attacks of muscle weakness and mild myopathy with tubular aggregates, following bilateral adrenalectomy for adrenal Cushing's syndrome and replacement therapy with cortisone acetate and 9-fluorohydrocortisone. The replacement of 9-fluorohydrocortisone therapy by desoxycorticosterone acetate therapy led to the cessation of the attacks.     

α-Synuclein-immunoreactive structure formation is enhanced in sympathetic ganglia of patients with multiple system atrophy

We immunohistochemically examined the sympathetic ganglia (SG) and brains of 26 patients with multiple system atrophy (MSA), 19 age-matched controls, and 25 patients with amyotrophic lateral sclerosis (ALS). -Synuclein-immunoreactive structures were found in the neuronal cytoplasm and processes of the SG in 11 of the 26 MSA cases (42.3%) and 1 of the 25 ALS cases (4%), but not in the 19 controls. No -synuclein-immunoreactive structures were found in Schwann cells or the neuronal nucleus. Mean disease duration of MSA cases with -synuclein-immunoreactive structures was significantly longer than that of MSA cases without -synuclein-immunoreactive structures. -Synuclein-immunoreactive structures in 4 cases proved to be Lewy bodies (LB) based on hematoxylin-eosin staining. A few LB were also found in the brains of 3 of these 4 cases. In the other 7 MSA cases, diffuse or focal neuronal cytoplasmic aggregates and swollen neurites were detected with -synuclein immunostaining, but not with hematoxylin-eosin staining. However, a few LB-like structures with ring-like staining were observed in those aggregates, which suggested those aggregates had progressed to form LB. Immunoelectron microscopically, those aggregates were composed of filaments and granular materials which closely resembled the ultrastructural features of LB. We inferred that -synuclein aggregates found in the SG in our study evidenced LB-related pathologies. MSA, a type of synucleinopathy, is characterized by glial cytoplasmic inclusions in oligodendrocytes, but also frequently develops LB pathology in the late stage, especially in the SG.     

On areas of transition between entorhinal allocortex and temporal isocortex in the human brain. Normal morphology and lamina-specific pathology in Alzheimer's disease

Summary The allocortical entorhinal region does not gradually transform into the temporal isocortex. Instead, there is an extended stretch of transentorhinal cortex with interdigitation of allocortical and isocortical laminae. The main feature of this transition zone is that the superficial layer of large multipolar nerve cells (Pre-) of the entorhinal region gradually sweeps downward and follows an oblique course through the outer layers. During this course the starshaped nerve cells of Pre- are transformed into pyramidal cells.The layer Pre- projection cells are particularly prone to the development of neurofibrillary changes of the Alzheimer type. In cases of presenile and senile dementia almost all of the layer Pre- projection neurons are changed pathologically. The isocortical pyramidal cells of layers II to IV are far less inclined to develop neurofibrillary changes. In the transentorhinal cortex, the tangle-bearing neurons follow an oblique course through the superficial laminae and are finally located between the isocortical layers III and IV, findings that confirm the assumption that these neurons are constituents of the allocortical layer Pre-.Layer-specific pathology of the profound stratum as well confirms the transentorhinal region as being formed by interdigitating allocortical and isocortical layers.Supported by grants from the Deutsche Forschungsgemeinschaft     

Intracytoplasmic vacuoles in αW fibers of dystrophic chicken muscle —Probable early pathologic event initiates massive fiber necrosis

Summary An electron-microscopic study on dystrophic chicken white muscle, posterior latissimus dorsi (PLD), was performed with histochemical identification of three fiber types of R (red), R and W (white) fibers to evaluate the pathophysiology in fiber necrosis. As seen in histochemically stained sections, vacuolar formation in the cytoplasm, an outstanding pathologic feature in chicken dystrophy, was recognized in the W fibers by electron microscopy. The vacuole was membrane-bound and thought to originate from coalescence or dilatation of extensively proliferated sarcotubular system. There was evidence of a delay in fiber type transformation from R to W in dystrophic white muscle, while the initial pathologic event of sarcotubular system proliferation might be expressed only after muscle fibers had attained histochemical characteristics of W fibers. Localized myofibrillar degeneration was encountered in the vicinity of the vacuole with focal membrane defect. An influx of extracellular fluid through the vacuolated sarcotubular system into the sarcoplasm may activate certain proteases, such as calcium-dependent protease because the extracellular fluid contains high concentration of calcium ion. The activated protease then degrades structural protein, especially Z-line protein, followed by fiber necrosis with phagocytosis.Supported in part by grant no. 4, 1980, from the National Center for Nervous, Mental, and Muscular Disorders (NCNMMD) of the Ministry of Health and Welfare, Japan     

Histopathological effects of intracerebral injections of human recombinant tumor necrosis factor-α in the rat

Summary Human recombinant tumor necrosis factor- (rTNF-) was administered to normal Fischer 344 rats by stereotaxic intracerebral (IC) injection. Animals received a single injection of either 6×10⁴ UrTNF- or excipient in their right parietal lobe. Others received three consecutive daily injections of either 6×10⁴ U rTNF- or excipient to examine effects of higher accumulative doses. Histological examination of the brain revealed that both single and multiple IC injections of rTNF- triggered an immigration of circulating leukocytes into the site of TNF- injection. After one injection, this cell population was composed mainly of macrophages and neutrophils. Maximal leukocytic influx occurred by 48 h and was composed mostly of neutrophils which were limited to the injection site and perivascular space. Quantitation of the inflammatory reaction by measurement of tissue myeloperoxidase levels supported these histological observations. One day after multiple rTNF- injections, leukocytic adhesion to endothelium, vascular cuffing and leukocytic infiltration into the neuropil was observed at levels comparable to those seen 3 days following a single rTNF- injection. We conclude that while one or more IC injection(s) of 6×10⁴ U rTNF- was well tolerated in normal rats, at this dose the cytokine triggers a pronounced leukocytic infiltration at the site of injection. These results support a role for TNF- as a mediator in inflammatory responses within the central nervous system.Supported in part by a grant from the A. D. Williams Research Fund and by gifts from the Kellogg Foundation, the Lind Lawrence Fund, and the family and friends of Christine Armstrong, Jack Harvey, Christopher Wemple, and Pearl Ylonen.     

Lectin histochemistry of scrapie amyloid plaques

Summary Peroxidase-labeled lectins were used for detection of specific monosaccharide residues in amyloid plaques in brains of scrapie-infected mice. The lectins tested recognize the following residues: -d-galactosyl (Ricinus communis agglutinin 120, RCA-1), -d-galactosyl and -d-galactopyranoside (Bandeirea simplicifolia aggl., BSA), -d-mannosyl and -d-glucosyl (Concanavalin A, Con A), N-acetylglucosaminyl and sialyl (Wheat germ aggl., WGA), sialoglycoconjugates (Limulus polyphemus aggl., LPA), -l-fucosyl (Ulex europeus aggl., UEA-1 and Tetragonolobus aggl., TPA), N-acetyl-d-galactosaminyl (Helix pomatia aggl., HPA). The most intense staining reaction in amyloid plaques was observed with BSA and WGA; it was less intense with RCA-1, Con A, and HPA. This indicates that the plaque material contains glycoproteins with abundance of accessible residues of - and -galactose, N-acetyl-d-glucosamine and N-actyl-d-galactosamine, and some types of sialoglycoconjugates recognized by WGA. Such residues, like -l-flucosyl recognized by UEA-1 and TPA, were almost undectectable in the examined plaques.There were also some differences in the staining intensity between small and large plaques (WGA and HPA) and between central and peripheral areas of the plaques.In the wall of micro-blood vessels relatively strong staining reaction was observed with RCA and BSA and less intense with WGA and Con A.Support in part by grant no. 5PO1 AG 04220-03 from the National Institute of Aging, NIH     

Immunoelectron microscopic study of tubulin and microtubule-associated proteins after transient cerebral ischemia in gerbils

Summary Differential vulnerability of microtubule components to cerebral ischemia has been reported previously. We investigated the disintegration of microtubules using immunoelectron microscopy for -tubulin and microtubule-associated protein 1A and 2 (MAP1A and 2). Mongolian gerbils were subjected to bilateral carotid occlusion for 10 to 30 min and reperfusion for up to 72h following ischemia for 10 min. After ischemia for 10 min, some dendrites in the stratum moleculare of the subiculum-CA1 region lost immunoreaction products for -tubulin and MAPs. Loss of the reaction products spread to the medial CA1 region during progressive ischemia for 30 min. In some dendrites, electron-dense precipitates for MAPs were dispersed in the dendritic cytoplasm with little reaction product on microtubules and without alteration of the reaction for -tubulin. After recirculation, loss of electron-dense precipitates for -tubulin and MAPs, as well as disintegration of microtubules, propagated further to the medial CA1 region and to the proximal dendrites. The present study demonstrated prompt disintegration of microtubules with rapid disappearance of the reaction for MAPs which seemed to be caused by detachment of MAPs from the microtubule cores.     

Immunoglobulin heavy chain gene associations in myasthenia gravis: new evidence for disease heterogeneity

Summary Susceptibility to myasthenia gravis (MG) is known to involve genes residing in the major histocompatibility complex class I and II regions (HLA-B8 and DR3). Immunoglobulin heavy chain constant region (IgCH) allotypes have also shown some associations with MG. We have used restriction fragment length polymorphism analysis with probes to the IgCH switch (S) regions and 1 and the downstream marker D14S1 to investigate 189 Caucasoid patients with well-defined MG. A highly significant increase in the frequency of the 2.6 kilobase (kb) S homozygous genotype and the 2.6 kb S allele was found in patients with disease onset after the age of 40 years (late onset) compared with normal controls (P<0.00075 andP<0.025 respectively). No association was found at the S1 or D14S1 loci. In patients with an associated thymoma there was a moderate increase in the frequency of the 2.6 kb S and 7.4 kb S1 genotypes. These results independently support the previous separation of the late-onset subgroup. Finally, the stronger associations at S rather than at the downstream Sl, Gm and D14S1 loci suggest that the genes predisposing to MG are located within the variable region of the Ig heavy chain loci.     

Chronic treatment with the potential antidepressant drug rolipram: the effect on the behavioural responses to adrenergic and dopaminergic receptor agonists with some biochemical correlates

Summary We studied the effect of acute and chronic treatment with rolipram, a potential antidepressant drug, on the behavioural responses induced by adrenergic and dopaminergic receptor agonists in mice and rats, and on (³H)prazosin and (³H)dihydroalprenolol binding to cortical membranes and whole brain noradrenaline and dopamine utilization in rats. Chronic, but not acute, administration of rolipram potentiated a behavioural response mediated through central ₁-adrenoceptors, attenuated an ₂-adrenoceptormediated response and inhibited a-adrenoceptor-mediated response. Neither treatment affected the behavioural responses to dopaminergic stimulants. Repeated treatment with rolipram decreased the density of cortical (³H)dihydroalprenolol, but not (³H)prazosin bindings sites, and reduced brain noradrenaline, but not dopamine utilization. These results suggest that chronic administration of rolipram induces the down-regulation of the central- and ₂-adrenoceptors and enhances the responsiveness of the central ₁-adrenoceptors with no apparent changes in the ₁-adrenoceptor density.     

Use of interferon alpha in intratumoral chemotherapy for cystic craniopharyngioma

Objectives This study analyzed the intratumoral activity of interferon alpha (IFN-) in the treatment of cystic craniopharyngiomas.Patients and methods From January 2000 to January 2004, nine patients presenting with cystic craniopharyngiomas were treated with intratumoral injection of IFN- at the Pediatric Oncology Institute of the Federal University of São Paulo–Escola Paulista de Medicina. Age ranged from 1 year and 10 months to 18 years (mean 10 years). All intratumoral catheters were inserted by a subfrontal approach. Doses varied from 36 to 108 MU.Results There was complete disappearance of the lesion in seven cases. In two cases, partial reduction of tumor size was observed at follow-up. Follow-up varied from 1 year to 3 years and 6 months (mean 1 year 8 months).Conclusions IFN- proved to be an effective drug in the control of cystic craniopharyngiomas. Additional studies should be carried out to determine the optimal dose of IFN- in the treatment of cystic craniopharyngioma. In addition, other drugs possessing high efficacy and low neurotoxicity should be analyzed.     

Tumour necrosis factor-mediated cell death pathways do not contribute to muscle fibre death in dystrophinopathies

There is evidence that apoptotic cell death mechanisms contribute to muscle fibre loss in dystrophinopathies, but little knowledge about the activators of the final degrading caspase cascade in muscle fibre apoptosis. As mitochondria-related activation of this caspase cascade, through e.g. APAF-1, could not be proven in dystrophin-deficient muscle, this study searches for other prospective candidates that may directly trigger apoptotic cell degradation by mitochondria-independent pathways involving the interaction of tumour necrosis factor- (TNF-) and TRAIL with death receptors and subsequent activation of caspase-8. The expression of TNF-, TNF-R1, TRAIL, NF-B and caspase-8 were studied in muscle biopsy specimens from 14 patients with a dystrophinopathy [10 Duchenne muscular dystrophies (DMD), 2 Becker MD, and 2 DMD carriers] by immunohistochemistry and Western blotting. In all types of dystrophinopathies, necrotic muscle fibres undergoing myophagocytosis displayed strong expression of TNF-, TNF-R1, and TRAIL, which, however, was attributed to phagocytosing cells and not to the muscle fibres themselves. There was no up-regulation in normal-shaped or atrophic non-necrotic muscle fibres, or in intact muscle fibre segments adjacent to segmental necrosis and myophagocytosis. The expression profiles of caspase-8 and NF-B resembled that of normal control muscle. There were likewise no significant differences in the Western blot analyses between normal control and dystrophin-deficient muscle. Based on these findings, a contribution of TNF- or TRAIL-mediated cell death pathways to muscle fibre apoptosis or necrosis in dystrophinopathies could not be confirmed.     

Ganglioside mapping of a human medulloblastoma xenograft

Summary The ganglioside patterns of medulloblastomas have never been established; in this study we report the ganglioside profile of the human medulloblastoma cell line TE-671 grown as a xenograft in nude mice. Gangliosides were isolated and structurally analyzed by fast atom bombardment mass spectometry following permethylation. Identification of individual gangliosides was also performed by immunostaining of high-performance thin-layer chromatography-separated bands. Total ganglioside levels of 0.20 mol/g of tissue were obtained, consistent with those reported for human glioma cell lines grown as xenografts; predominant monosialogangliosides of TE-671 xenografts were II³--NeuAc-LacCer (GM3) and II³--NeuAc-GgOse₃ Cer (GM2) but there were also relatively large proportions of IV³--NeuAc-LcOse₄Cer (3-isoLM1), IV³--NeuAc-nLcOse₄Cer (3-LM1) and a further ganglioside of the neolactoseries with an extra lactosamine moiety. The only oligosialoganglioside detected was IV³, II³--NeuAc₂-GgOse₄Cer (GD1a).Abbreviations: The gangliosides have been designated according to Svenerholm [18] GM3 II³--NeuAc-LacCer - GM2 II³--NeuAc-GgOse₃Cer - GM1 II³--NeuAc-GgOse₄Cer - 3-LM1 IV³--NeuAc-nLcOse₄Cer - 3-isoLMI IV³--NeuAc-LcOse₄Cer - Fuc-3-isoLMI IV³--NeuAc, III⁴-Fuc-LcOse₄Cer - GD1a IV³, II³--NeuAc₂-GgOse₄Cer - FAB-MS Fast atom bombardment-mass spectometry - GC-MS gas chromatography-mass spectometry Supported by NC1 RO1 CA11898 to Dr. Bigner and B8803X-00627-24B from the Swedish Medical Research Council to Dr. L. Svennerholm     

Immunohistochemical study on the distribution of α and β subunits of S-100 protein in brain tumors

Summary The immunohistochemical distribution of and subunits of S-100 protein (S-100, S-100, respectively) in 138 cases of human brain tumors was investigated by the avidin-biotin immunoperoxidase method. Brain tumors can be divided into four groups: group 1 [S-100 (+) and/or S-100 (+)]; astrocytoma, glioblastoma, ependymoma, subependymoma, oligodendroglioma, choroid plexus papilloma, gangliocytoma, meningioma, chordoma, malignant melanoma. Group 2 [S-100 (+) and S-100 (-)]; pineoblastoma, pituitary adenoma, craniopharyngioma, rhabdomyosarcoma. Group 3 [S-100 (-) and S-100 (+)]; acoustic Schwannoma. Group 4 [S-100 (-) and S-100 (-)]; medulloblastoma, malignant lymphoma, germinoma. The S-100 immunoreactivity pattern in brain tumors was similar to those obtained using conventional anti-S-100 protein sera. In the first group of brain tumors both the number of positively stained tumor cells and the staining intensity were generally greater for S-100 than for S-100 with a few exceptions including one gemistocytic astrocytoma, one subependymoma, one malignant melanoma, and some cases of glioblastomas. As to the relationship between malignancy and S-100 protein in glioma, S-100 immunoreactivity decreased according to degree of malignancy, while that of S-100 varied, suggesting a heterogeneity of tumor cells in glioblastomas. Immunostaining for S-100 and S-100 might become a useful diagnostic procedure in brain tumors and may give us more detailed and precise data of S-100 protein in brain tumors.     

Serum α<Subscript>1</Subscript>-antitrypsin level and phenotype associated with familial moyamoya disease

Background Obstructive vascular lesions at the terminal portion of the internal carotid arteries are thought to be the primary and essential lesions in moyamoya disease. The etiology remains unknown. To detect possible mediators of the thickened intima of moyamoya disease, we measured serum alpha-1-antitrypsin (1-AT) levels and characterized the phenotype of patients with familial moyamoya disease.Patients and methods Fifty-six individuals were examined, including 29 patients with moyamoya disease from 14 families. Serum 1-AT levels were analyzed by electroimmunoassay and genomic phenotype by isoelectric focusing.Results All individuals had a normal 1-AT phenotype. The average serum 1-AT level in moyamoya disease patients was significantly higher than that of normal individuals, although both were within the normal range.Conclusions These findings suggest that serum 1-AT level may be a marker, rather than an etiologic factor, indicating the progression of moyamoya disease.     

Alpha-synuclein pathology in Parkinson's and Alzheimer's disease brain: incidence and topographic distribution--a pilot study

To study the incidence and topographic distribution of -synuclein-positive inclusions in Parkinsons disease (PD), dementia with LB (DLB), and Alzheimers disease (AD), 206 brains of elderly patients, including 53 patients with clinical PD, 110 autopsy-proven AD cases, 22 with dementia with LB (DLB), 1 case with essential tremor, and 20 age-matched controls were investigated using -synuclein immunohistochemistry. For technical reasons, the olfactory system was not studied. In all PD brains, -synuclein-positive inclusions and neuronal losses were present in medullary and pontine nuclei, locus coeruleus, and substantia nigra, with additional lesions in amygdala (24%), allocortex (58%), cingulate area (34%), and isocortex (26.5%). All PD cases corresponded to pathology stage 4–6 suggested by Braak et al. (2003, Neurobiol Aging 24:197). In most cases of DLB, the distribution of -synuclein pathology and neurodegeneration corresponded to stages 5 and 6 of PD pathology. The case with essential tremor and 48.2% of the AD cases showed no LB pathology; in the other AD brains -synuclein-positive inclusions were seen in various brain areas. None of the controls showed LB pathology. Among 12 cases of incidental Lewy body disease (without clinical parkinsonian signs), 7 corresponded morphologically to PD stage 3 or 4. In further 6 AD cases, 2 with parkinsonian symptoms, considerable damage to locus coeruleus, substantia nigra, nucleus basalis and allocortex with preservation of the medullary nuclei was seen. The preliminary data largely confirm the Braak staging of brain pathology, although some of the clinical PD cases corresponded to stage 3 often considered as preclinical. In addition, some cases without demonstrable involvement of medullary nuclei showed extensive PD-like pathology in other brain areas, suggesting deviation from the proposed stereotypic expansion pattern and that incidental LB pathology may affect solely the locus coeruleus and substantia nigra. Striking similarity of LB pathology between DLB and PD suggests close morphological relationship between both disorders. Widespread LB lesions occurred in many sporadic AD cases without parkinsonian symptoms, the pathogenesis and clinical impact of which are unclear. The relationship between AD and PD with particular reference to synaptophysin-positive lesions needs further elucidation.An erratum to this article can be found at