Nachweis und Verteilung der Enzyme: β-d-Glucuronidase, β-d-Galaktosidase, β-d-Glucosidase und Arylsulfatase in Neurinomen

Zusammenfassung In 17 Neurinomen wurden Verteilung und Aktivität der hydrolytischen Enzyme -d-Glucuronidase, -d-Glucosidase, -d-Galaktosidase und Arylsulfatase untersucht.Die höchste Aktivität der Enzyme zeigten die verfetteten Neurinome. Es bestand eine enge Beziehung zwischen Lipidablagerung und Fermentaktivität.Daraus wurde geschlossen, daß die im Neurinom gebildeten Markscheidenlipide unter Mitwirkung der untersuchten Hydrolasen abgebaut werden.

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Demonstration and distribution of the enzymes: -d-glucuronidase, -d-galactosidase, -d-glucosidase, and arylsulfatase in neurinomas

Summary In 17 neurinomas, distribution and activity of the hydrolytic enzymes -d-glucuronidase, -d-glucosidase, -d-galactosidase, and arylsulfatase were examined. Highest enzyme activity was seen in neurinomas stuffed with lipid material. There was close relationship between lipid deposition and enzyme activity. From these findings it was concluded that myelin lipids formed in neurinomas are degradated by means of the examined hydrolases.

     

Ultrastructural localization of lectin receptors on cerebral endothelium

Summary Oligosaccharide residues on the endothelial luminal plasma membrane of rat cerebral cortical vessels were localized using biotinylated lectins. In addition, the effect of pretreatment of brain slices with neuraminidase prior to the binding of cationized ferritin (CF) and certain lectins was studied.Conjugates of biotinylated lectins and avidin-d horseradish peroxidase reaction product were evenly distributed on the endothelium of arterioles, capillaries, and venules. Lectin binding sites were observed on the plasma membrane of pinocytotic vesicles open onto the vascular lumen and at the luminal end of the interendothelial space only. The following sugar residues were localized: -d-mannosyl, -d-glucosyl, -N-acetylglucosaminyl, sialyl,d-galactosyl, -l-fucosyl, and -N-acetyl-d-galactosaminyl.Following pretreatment of brain slices with neuraminidase -d-gal-(1–3)-d-galN-acetyl groups were demonstrated on endothelium. In this respect, cerebral endothelium differs from noncerebral endothelium which is reported to have peanut agglutinin binding sites without neuraminidase pretreatment.Anionic groups on cerebral endothelium were demonstrated at the same locations as the lectin binding sites. Following neuraminidase pretreatment there was reduction, but not absence, of CF binding supporting the observation that surface charge is not wholly due to sialyl groups.The role of monosaccharide residues in states of altered cerebrovascular permeability remains to be determined.Supported by Ontario Heart Foundation grant no. 2-6     

Hydrolytic enzymes in meningiomal subtypes

Summary Estimation of activity of five hydrolytic enzymes was made in four histologically different types of human meningiomas derived from surgery. The hydrolytic enzymes examined in 13 tumors included four lysosomal enzymes: -glucuronidase, N-acetyl--d-glucosaminidase (hexosaminidase), -galactosidase, and acid phosphatase. The fifth enzyme studied was alkaline phosphatase. The one papillary-type meningioma examined appeared to contain generally greater activities of the lysosomal enzymes than the other tumor types. Alkaline phosphatase was decidedly greater in transitional type meningiomas. The correlation of histological types with alkaline phosphatase activity is discussed with regard to previous observations.     

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     

Cerebral endothelial plasma membrane alterations in acute hypertension

Summary This study was undertaken to localize oligosaccharide residues on the endothelial luminal plasma membrane of cerebral vessels of normotensive animals and vessels permeable to horseradish peroxidase (HRP) in angiotensin-induced acute hypertension. Wistar-Furth rats were injected with HRP intravenously and hypertension was induced by an intravenous infusion of angiotensin amide. Animals were fixed 2.5, 10 and 15 min later and the HRP reaction product was demonstrated in brain slices, followed by lectin localization using the avidin-biotinperoxidase method. Oligosaccharide residues demonstrable on the luminal plasma membrane of cerebral endothelium of normotensive controls and both permeable and nonpermeable vessels of hypertensive animals were: -d-mannosyl, -d-glucosyl, -N-acetylglucosaminyl, sialyl, -d-galactosyl, -l-fucosyl and -N-acetyl-d-galactosaminyl groups. Peanut agglutinin did not bind to the endothelium of normotensive controls or of nonpermeable vessels in hypertensive animals, but did bind to endothelium of vessels permeable to HRP 2.5 min after the onset of hypertension. At 10 min, the luminal plasma membrane of vessels regained their normal characteristics and peanut agglutinin binding was no longer demonstrable. Our studies suggest that increased cerebrovascular permeability to protein in acute hypertension is associated with loss of the terminal sialic acid groups on the luminal plasma membrane of permeable vessels. This results in the observed reduction of charge on the endothelium and an exposure of -d-gal-(1,3)-d-gal N-acetyl groups leads to binding of peanut agglutinin. Both alterations are rapidly reversible and no longer demonstrable 10 min after the onset of hypertension, when blood pressures reach resting levels and the blood-brain barrier is restored.Supported by Heart and Stroke Foundation of Ontario Grant 2-6     

Caspase-cleaved tau accumulation in neurodegenerative diseases associated with tau and α-synuclein pathology

Alzheimers disease (AD), Picks disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and dementia with Lewy bodies (DLB) are diseases associated with the accumulation of tau or -synuclein. In AD, -amyloid (A)-associated caspase activation and cleavage of tau at Asp⁴²¹ (Tau) may be an early step in neurofibrillary tangle (NFT) formation. To examine whether Tau accumulates in other diseases not characterized by extracellular A accumulation, we examined PiD, PSP, and CBD cases in comparison to those without extensive tau accumulation including frontotemporal lobar degeneration without Pick bodies (FTLD) and control cases. Additionally, we studied Tau accumulation in DLB cases associated with intracellular -synuclein. Tau was observed in all disease cases except non-PiD FTLD and controls. These results demonstrate that the accumulation of Tau may represent a common pathway associated with abnormal accumulation of intracellular tau or -synuclein and may be relatively less dependent on the extracellular accumulation of A in non-AD dementias.     

Apolipoprotein E co-localizes with newly formed amyloid β-protein (Aβ) deposits lacking immunoreactivity against N-terminal epitopes of Aβ in a genotype-dependent manner

Different types of amyloid -protein (A)-containing plaques occur in brains of Alzheimers disease (AD) patients. Diffuse plaques seen during early stages of AD differ from neuritic plaques in later stages both with respect to the length of the A peptides and the presence of other proteins, e.g., apolipoprotein-E (apoE). Since apoE is involved in A transport and clearance, and the 4-allele of the apolipoprotein-E gene (APOE) is a major risk factor for sporadic AD, it is plausible to speculate that apoE plays a pathophysiological role in the initiation of A deposition. To address the issue of whether binding of apoE to A is involved in initial A deposition, we studied the human medial temporal lobe of 60 autopsy cases encompassing the full spectrum of AD-related pathology. In temporal lobe regions, which become involved for the first time at a given stage of -amyloidosis, all plaques represent newly formed plaques, and these were studied with immunohistochemical methods. ApoE was present in 36 cases, and was frequently co-localized with newly formed A deposits detectable with anti-A₄₂ but not with antibodies raised against N-terminal epitopes of A. In 10 additional cases, immunoreactivity against apoE was completely lacking in newly formed plaques, which, at the same time, displayed immunoreactivity against N-terminal epitopes of A. The failure of N-terminal epitopes of A to co-localize with apoE in newly formed plaques indicates that these deposits presumably contain apoE-A complexes, in which the N-terminal epitopes of A are often concealed after complexing with apoE, thus preventing subsequent binding of antibodies. Moreover, apoE-positive newly formed plaques were seen more frequently in APOE 4/4 cases than in non-APOE 4/4 individuals, thereby underlining the potentially crucial role of apoE for the development of A deposits.     

Histochemische Untersuchungen zur Verteilung und Aktivität hydrolytischer Enzyme in Gliomen

Zusammenfassung Es wird über Aktivität und Verteilung der -Glucuronidase, -Galaktosidase, -Glucosidase und Arylsulfatase in 49 Gliomen berichtet. Die höchste Aktivität in den Tumorzellen weisen die Glykosidasen auf. Mit zunehmender Malignität der Tumorart ist eine Zunahme der Glykosidasenreaktion festzustellen. Alle untersuchten Enzyme sind infolge Diffusion in zerfallenden Markscheiden und ihren Fragmenten nachweisbar.

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Summary Activities and distribution patterns of -glucuronidase, -galactosidase, -glucosidase and arylsulfatase were demonstrated histochemically in 49 gliomas. The activities of the glycosidases were higher than that of the sulfatase, and also higher in malignant tumors than in benign ones. The enzymes tested are seen within damaged and disintegrating portions of the myelin sheath.

     

Amyloid β peptide 1–42 highly correlates with capillary cerebral amyloid angiopathy and Alzheimer disease pathology

Recent studies reported both positive [Thal et al. (2003) J Neuropathol Exp Neurol 62:1287–1301] and negative [Tian et al. (2003) Neurosci Lett 352:137–140] correlations between cerebral amyloid angiopathy (CAA) and Alzheimers disease (AD) pathology. We have recently shown high correlations between neuritic AD pathology and amyloid peptide (A) deposits in the capillary/pericapillary compartment (CapCAA) with only low correlations to general CAA (non-capillary). We have now studied the relationship between CapCAA and AD pathology with respect to the distribution of A40 and 42 in the frontal cortex of 100 human postmortem brains from both male and female, demented and non-demented patients (mean age ± SD 84.3±9.3 years). Using polyclonal antibodies to A40 and 42, capillary and plaques positivity were assessed semiquantiatively on a four-point scale. A42 deposits in capillaries correlated highly with both A42 deposits in plaques and morphological AD criteria (CERAD, Braak stages, and NIA-Reagan-Institute criteria), while only a low correlation with CAA was observed. A40 deposits in capillaries differed morphologically from A42 ones: they were limited to capillary walls, were significantly less frequent in both capillaries and plaques compared to A42 (P<0.01), and showed a low correlation with morphological AD criteria (P<0.05) and general CAA (P<0.01). By contrast, A42 deposits were seen in the glia limitans rather than in capillary walls themselves, and showed high correlation with morphological AD criteria (P<0.01). These data indicate that CapCAA is characterized by A42 deposits in pericapillary spaces or in the glia limitans. A low correlation between CAA and CapCAA, but high correlations between morphological AD criteria and CapCAA suggest different pathomechanisms for both types of CAA, and a close relation between CapCAA and AD pathology (both neuritic and plaque type). These data support the concept of a neuronal origin of A via drainage from interstitial fluid from the central nervous system along basement membranes to capillaries.List of Abbreviations AD Alzheimer disease - A beta amyloid peptide - A 40/42 CapS score of deposits of A 1–40/42 in capillaries - A 40/42 C number of A 1–40/42 positive cortical vessels - A 40/42 PS score of deposits of A 1–40/42 in plaques - A 40/42 TS total score of A 1–40/42 deposits - A 40/42 Csev severity of A 1–40/42 affection of cortical vessels - A 40/42 CS A 1–40/42 cortical score - A 40/42 L percentage of A 40/42 positive leptomeningeal vessels - A 40/42 Lsev severity of A 40/42 affection of leptomeningeal vessels - A 40/42 LS A 40/42 leptomeningeal score - ACTS A cortical total score - ALTS A leptomeningeal total score - CAA cerebral amyloid angiopathy - CAATS CAA total score - CapCAA capillary CAA - CERAD Consortium to Establish a Registry of Alzheimers Disease - NFT neurofibrillary tangle - NIA National Institute of Aging - NIA-RI National Institute of Aging and Reagan Institute - NP neuritic plaque - SP senile plaque - TS total scoreAn erratum to this article can be found at     

Gerstmann-Sträussler-Scheinker disease showing β-protein type cerebellar and cerebral amyloid angiopathy

Cerebral amyloid angiopathy is observed in several brain degenerative disorders, but this pathological condition has received little attention in Gerstmann-Sträussler-Scheinker disease (GSS). We report a 69-year-old man who showed the cardinal features of GSS together with typical and extensive congophilic angiopathy. Immunohistochemical studies revealed that the vast majority of the amyloid plaques present in the brain of this patient were consistently labeled by anti-prion protein (PrP) antibody. Double immunostaining disclosed many additional -protein immunoreactive plaque-like lesions, including a special type of hybrid plaque with colocalization of PrP and -protein (-PrP). The vascular amyloid deposits seen in both the cerebellum and cerebrum were immunoreactive only to anti--protein antibody. It seems likely that the extensive deposition of -protein amyloid (including brain vascular amyloidosis) seen in this and other similar cases is part of pathology of GSS, although the possibility that this finding is due to ageing or concomitant Alzheimer's disease cannot be completely ruled out.Supported by a research grant from the Intractable Disease Division, Ministry of Health and Welfare, Primary Amyloidosis Research Committee, Japan     

Gestalt- und erkenntnispsychologischer Beitrag zum melancholischen Wahn

Zusammenfassung Gestalt- und erkenntnispsychologische Zusammenhänge ergeben, daß dem melancholischen Wahn ein ametrisches Verhältnis der das menschliche Weltbild mitkonstituierenden Strukturtendenzen der Prägnanztendenz sowie des antiprägnanten Gestaltreizes der Welt zugrunde liegt. Dabei verstehen wir unter Weltbild die Erkenntnisgestalt der Welt, die vorweg (a priori) bestimmt, was je—individuell wirklich erkannt und verstanden wird. In der Melancholie kommt es nun durch eine Reduktion der Prägnanztendenz zu einem extrem einseitigen Bestimmtsein des Weltbildes durch den antiprägnanten Gestaltreiz der Welt. Die Folge dieser ametrischen Strukturiertheit des Weltbildes ist eine pathologische Wirklichkeitsgewißheit (Wahngewißheit) in allen Erkenntnisfunktionen also auch in der Vorstellung, in der Phantasie und in der Einbildung. Die Inhalte der melancholischen Wahnerlebnisse aber gehen auf den antiprägnanten Gestaltreiz der Welt zurück, der im Verlauf der normalen aktualgenetischen Entwicklung des Weltbildes zunehmend auf den Abbau und Zerfall der von der Prägnanztendenz intendierten Erkenntnisinhalte z. B. der immer intakten und integren Leib-, Ich- und Kommunikationsgestalt des Menschen aus ist, damit vom Erwachsenen auch Nichtintegres und Nichtintaktes sowie Zerfall in jeder Form verstanden und bewältigt werden kann. Die Gerichtetheit des antiprägnanten Gestaltreizes der Welt erkennt man in den melancholischen Wahnerlebnissen des Zerfalls des Leibes bis zur Verwesung bei lebendigem Leibe oder des Zerfalls der Ichgestalt bis zum nihuil unmittelbar wieder.Keine eindeutigen Aussagen jedoch erlauben unsere Beobachtungen über einen Wandel im Strukturverhältnis der Tendenz nach Wesenseigenschaften zur rein sachlichen Sinngehaltlichkeit der Individualgestalten in der Melancholie, während nach Matussek (1963) Wesenseigenschaften in der schizophrenen Wahrnehmungswelt einen Vorrang haben.     

Cytoplasmic and axoplasmic density variations in relation to hyperactivity

Summary The density of the cytoplasm and axoplasm of the anterior horn cell in rats was determined by X-ray microradiography. The average density of the cytoplasm of more than 400 cells from control rats was 0.31 g/³, while that of over 600 cells from rats fed IDPN (- iminodipropionitrile) was 0.43 g/³.Hyperactivity developed during the first 5 weeks and was associated with a gradual increase in cytoplasmic density to 0.51 g/³.At 6 weeks there was a drop in density to 0.36 g/³ which coincided with the appearance of axonal balloons having a density of 0.17 g/³.During the 7–12th week on the diet, the cytoplasmic density showed a gradual increase to 0.59 g/³ and the balloons to 0.29 g/³.The volume of the nerve cells remained fairly constant. The density increases were discussed in relation to hypertrophy, dystrophy, and hyperactivity.

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Zusammenfassung Die Dichte des Cytoplasmas und Axoplasmas der Vorderhornzellen von Ratten wurde durch Röntgenmikroradiographie bestimmt. Die mittlere Dichte des Cytoplasmas von mehr als 400 Zellen der Kontrollratten war 0,31 g/³, während die mittlere Dichte von mehr als 600 Zellen der Ratten, die mit IDPN (- iminodipropionitrile) gefüttert waren, 0,43 g/³ war.Hyperaktivität entwickelte sich während der ersten 5 Wochen und war mit einer progressiven Zunahme der Cytoplasmadichte bis auf 0,51 g/³ verbunden.Nach 6 Wochen sank die Dichte auf 0,36 g/³. Diese Tatsache traf mit dem Auftreten der Axonauftreibungen zusammen, die eine Dichte von 0,17 g/³ hatten.Nach 7–12 Wochen zeigte die Cytoplasmadichte eine progressive Zunahme auf 0,59 g/³ und die der Auftreibungen eine Zunahme auf 0,29 g/³.Das Volumen der Nervenzellen blieb ziemlich konstant.Die möglichen Zusammenhänge zwischen Zunahme der Dichte, Hypertrophie, Dystrophie und Hyperaktivität werden dargestellt.

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Supported by U. S. Public Health Grant NB 1305.     

Lectin histochemistry of plaques and tangles in Alzheimer's disease

Summary Biotinyl derivatives of several lectins and avidin-horseradish peroxidase were used to study the localization of glycoconjugates in amyloid plaques and in neuritic tangles in brains of patients with Alzheimer's disease (AD), Downs syndrome (DS) and Gerstmann-Sträussler syndrome (GSS). The lectins tested recognize the following residues: -d-galactosyl [Ricinus communis agglutinin 120, (RCA-1) and peanut agglutinin, (PNA)]; -d-galactosyl [Griffonia simplicifolia agglutinin (GSA)]; -d-mannosyl>-d-glucosyl [concanavalin A (Con A) andLens culinaris agglutinin (LcH)];N-acetyl- andN-glycolylneuraminic acid [Limax flavus agglutinin (LFA) andLimulus polyphemus agglutinin (LPA)];N-acetyl-glucosaminyl and sialyl [wheat germ agglutinin (WGA)];N-acetyl-d-galactosaminyl [Helix pomatia agglutinin (HPA) andDolichos biflorus agglutinin (DBA)] and -l-fucosyl [Ulex europeus agglutinin (UEA-1)]. The majority of lectins listed above bind preferentially to the peripheral area of AD plaques, whereas in plaques of DS they are mainly bound to central amyloid core. In neurofibrillary tangles of AD brains only residues recognized by WGA and HPA or DBA were found, whereas in DS brains, in addition to above mentioned, -d-galactose (RCA-1) and sialic acid (LFA) were also present. In brain microblood vessels the strongest reaction in endothelia appeared with UEA-1 and RCA-1, indicating the abundance of -l-fucosyl and -d-galactosyl residues. In AD brains deposits of amyloid were noted in the wall of some blood vessels, where monosaccharide residues recognized by RCA-1, GSA, UEA and WGA but not by Con A and LFA were present. However, our studies of some organs (liver, kidney, heart and testes) of patients with generalized amyloidosis revealed a lack of these sugar residues. It indicates, that the composition of amyloid present in brains of AD is different to that in other organs in generalized amyloidosis.Supported in part by grant no. AG 04220-03 from the National Institute of Aging, NIH     

Über angeborene Mischgeschwülste des Kleinhirns

Zusammenfassung Es wird über neun umschriebene Geschwülste der hinteren Schädelgrube berichtet, die feingeweblich aus zwei verschiedenen, in Feldern und Zügen angeordneten Gewebsanteilen bestehen. Die Zellen der Felder sind kleine, körnerzellähnliche Elemente mit runden, stark chromatinreichen Kernen. Die Zellen der Züge sind größere Elemente mit rund-ovalen, kommaartigen, chromatinarmen Kernen. In den Zügen läßt sich regelmäßig ein ausgedehntes Reticulinfasernetz nachweisen. Die Felder sind dagegen reticulinfrei, sie bestehen aus einer feinfaserigen neuroectodermalen Grundsubstanz. Charakteristikum dieser Tumoren ist, daß das Mengenverhältnis der zwei Gewebsanteile von Fall zu Fall und sogar innerhalb des gleichen Falles stark variieren kann, so daß die Beobachtung von nur einzelnen Geschwulstpartien oft nicht erlaubt, die gesamte Struktur des Tumors zu erfassen und zu falschen Diagnosen führt.Diese als angeborene Mischtumoren des Kleinhirns bezeichneten Geschwülste sind feingeweblich von den Mischgewächsen des Unterwurmes Ostertags zu trennen. Sie zeigen hingegen gewisse Ähnlichkeiten mit dem sogenannten umschriebenen Arachnoidealsarkom des Kleinhirns (Foerster u. Gagel), von dem sie aber ebenfalls zu trennen sind.Die formale Genese dieser Geschwülste wird unter Berücksichtigung histogenetischer, feingeweblicher und lokalisatorischer Aspekte diskutiert. Sie werden als Kombinationstumoren angesehen mit einer mesodermalen Züge- und einer neuroectodermalen Felder-Gewebskomponente. Ihre dysembryogenetische Natur bzw. ihr früher Entstehungszeitpunkt wird durch das Vorkommen von Kleinhirnmißbildungen bestätigt. Schließlich werden ihre Beziehungen zu den Geschwülsten der sogenannten Medulloblastomgruppen erörtert.

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Summary Nine circumscribed tumors of the posterior cerebral fossa are described; histologically, they were characterized by two different types of tissue components arranged in strands and fields. The parvicellular fields are of neuroectodermal origin, the mesodermal strands consist of large cells and are rich in reticulin containing fibers. One of the two components may considerably outgrow the other one and become responsible for quantitative alterations.These tumors show some resemblance with the so-called circumscribed arachnoidal sarcoma of Foerster-Gagel, but should not be confused with it. They are morphologically also different from Ostertag's mixed tumors of the posterior vermis.This group of tumors is generally combined with cerebellar malformations which underline their dysontogenetic nature or at least the early onset of their development. As to their formal genesis they may be compared with the congenital mixed tumors of other organs (kidney, liver), and therefore be classified as combination tumors according to Meyer.Finally, their relation to so-called medulloblastomas is discussed.

     

Deposition of β/A4 protein along neuronal plasma membranes in diffuse senile plaques

Summary The origin of the extracellular -amyloid protein (/A4) found in senile plaques and the cellular mechanisms responsible for its deposition in cerebral tissues are still an unresolved issue in Alzheimer's disease. In this study we analyzed in detail the distribution of various epitopes of /A4 in relation to local cellular elements in diffuse plaques of the hippocampal region. We also correlated our findings with the presence and distribution of non-/A4 epitopes of the amyloid precursor protein (APP) and with synaptophysin immunoreactivity in the cortical neuropil. Discontinuous /A4-immunoreactive deposits were found along dendrites, and around the soma of neurons included in the plaques. Furthermore, increased synaptophysin reactivity with slightly dilated synaptophysin-immunolabeled presynaptic terminals were found in diffuse plaques. APP epitopes could not be found in diffuse plaques. However, some of the APP antibodies, mainly those to the C-terminal portion of APP, and antibodies to /A4 recognized clusters of flat vesicular profiles (0.6–1.4 m in width and 2–3 m in length) in the neuropil of cortical areas where plaques had developed. Our findings are compatible with a neuronal origin of /A4 in diffuse plaques and with a primary release of /A4 at synaptic sites along the immunostained neurites. They also suggest that diffuse plaques might be preceded by minute lesions of the neuropil where /A4 is not yet released from the precursor molecule.     

Testosterone decreasesβ-adrenoceptor sites in rat pineal gland and brain

Summary Testosterone administration to orchidectomized rats brought about a significant, 55% decrease of-adrenoceptor sites in the pineal gland, assessed from the specific binding of radioactive dihydroalprenolol (DHA). The changes in density of binding sites were not accompanied by significant modifications of the Kd. FSH or LH treatment of acutely castrated animals did not affect pineal-adrenoceptor binding. The depressive effects of testosterone in-adrenergic receptors were also observed in crude membrane fractions of medial basal hypothalamus and cerebral cortex. Sympathetic denervation of the pineal gland by superior cervical ganglionectomy did not abolish the changes in pineal-adrenoceptor density caused by testosterone. Hormone effects did not depend on a direct effect of the hormone on-adrenoceptor sites because testosterone did not compete with [³H]-DHA for the binding sites,in vitro. These results suggest that testosterone depresses pineal-adrenergic sites by acting mainly on post-synaptic sites.These studies were supported by grant no. 6638 from Consejo Nacional de Investigaciones Cientifícas y Técnicas de la República Argentina (CONICET).Established Investigator, CONICET.     

Fluctuating parkinsonism: a pilot study of single afternoon dose of levodopa methyl ester

Thirty-four patients with idiopathic fluctuating Parkinson's disease and early afternoon delayed on or severely resistant off periods, in spite of long-term antiparkinsonian therapy, were studied. The first afternoon levodopa administration was substituted with an equimolar dosage of the liquid formulation levodopa methyl ester (LDME). The major end-points for efficacy were latency to on and duration of on periods. The patients were divided into five subgroups according to their baseline treatment and they were evaluated monthly for 6 months using the Unified Parkinson's Disease Rating Scale. The patients completed weekly self-evaluation using an on-off chart. LDME was well tolerated by all the patients. A statistically significant reduction in latency to on was observed in all patients. The clinical effect of LDME remained stable during the treatment period (repeat measures ANOVA). The more rapid clinical effect of LDME and its stable and predictable antiparkinsonian activity represents a new and useful approach for treating patients with complicated Parkinson's disease.     

SPECT imaging of dopamine and serotonin transporters with [123I]β-CIT. Binding kinetics in the human brain

Summary Single photon emission computerized tomography (SPECT) studies in non-human primates have previously shown that the cocaine derivative [¹²³I]-2--carbomethoxy-3--(4-iodophenyl)-tropane ([¹²³I]-CIT) labels dopamine transporters in the striatum and serotonin transporters in the hypothalamusmidbrain area. Here, we report on the regional kinetic uptake of [¹²³I]-CIT in the brain of 4 normal volunteers and 2 patients with Parkinson's disease. In healthy subjects striatal activity increased slowly to reach peak values at about 20 hours post injection. In the hypothalamus-midbrain area peak activities were observed at about 4 hours with a slow decrease thereafter. Low activity was observed in cortical and cerebellar areas. The striatal to cerebellar ratio was about 4 after 5 hours and 9 after 20 hours. In 2 patients with idiopathic Parkinson's disease striatal activity was markedly decreased while the activity in hypothalamus-midbrain areas was only mildly diminished. Uptake into cortical and cerebellar areas appeared to be unchanged in Parkinson's disease. Consequently, in Parkinson's disease the striatal to cerebellar ratio was decreased to values around 2.5 after 20 hours. These preliminary methodological studies suggest that [¹²³I]-CIT is a useful SPECT ligand for studying dopamine and possibly also serotonin transporters in the living human brain.     

β-CIT SPECT demonstrates blockade of 5HT-uptake sites by citalopram in the human brain in vivo

Summary The cocaine analogue 2--carbomethoxy-3--(4-iodophenyl)-tropane (-CIT) is a potent ligand for both dopamine- and serotonin uptake sites which in its¹²³I labeled form can be used for single photon emission computerized tomography (SPECT). It was demonstrated previously by SPECT-studies in non-human primates that¹²³I--CIT binds to dopamine transporters in the striatum and to serotonin transporters in hypothalamus and midbrain. The aim of the present study was to compare¹²³I--CIT binding in the brain stem of normal controls and a group of subjects under treatment with the selective serotonin reuptake inhibitor (SSRI) citalopram.¹²³I--CIT- SPECT was performed in 12 depressed patients under 20 mg (n=5), 40 mg (n=6) and 60 mg (n=1) citalopram daily, in one untreated depressed patient and in 11 controls at regular time intervals up till 24 hours p.inj. A highly significant reduction of -CIT binding was found in an area including mesial thalamus, hypothalamus, midbrain and pons in patients under citalopram compared to controls (44.1 ± 14.4 vs. 82.3 ± 18.6 cpm's/mCi × kg body weight; specific binding 4 hrs p.inj.; p=0.0001). No differences were seen between the high and low dose group and no changes were found in the striatum.¹²³I--CIT binding in the brain stem and striatum in one untreated depressed patient fell within the range of control values.To our knowledge this is the first report directly demonstrating the effect of a selective serotonin uptake inhibitor in the brain in humans in vivo. SPECT measurements of serotonin uptake sites in patients with depression and other psychiatric disorders might provide better insights into the pathophysiology of these disorders and into mechanisms of drug action.     

β-Amyloid formation by myocytes of leptomeningeal vessels

Ultrastructural study of the leptomeningeal vessels of three subject with Alzheimer's disease (AD) shows that -amyloid deposits in the media of arteries and arterioles are produced by smooth muscle cells. It appears that the soluble -protein secreted by sarcolemmal vesicles of the muscle cell polymerizes into amyloid fibrils in basal lamina. Myocytes trapped in amyloid deposits degenerate and die. The most common and severe degeneration of smooth muscle cells in seen in the external and medial zone of the vascular media. In more advanced stages of amyloidotic changes, the internal zone of media is also involved. The media of vessels with severe changes consists of amyloid deposits and cell debris. Amyloid fibrils around the dead myocytes also undergo degradation. They lose their fibrillar appearance and become floccular, granular, amorphous proteinous material; however, this material is continually positive in immunostaining for -amyloid. This study suggests that amyloid formation by smooth muscle cells involves a secretory path. Our data indicate that the smooth muscle cell secretes nonfibrillar -protein or -protein containing peptides and that conversion of nonfibrillar into fibrillar -amyloid takes place in the environment of the basement membrane.Supported in part by funds from the New York State Office of Mental Retardation and Developmental Disabilities and a grant from the National Institutes of Health, National Institute of Aging No. PO1-AGO-4220