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     

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     

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     

Ultrastructural studies of glycoconjugates in brain micro-blood vessels and amyloid plaques of scrapie-infected mice

Summary Lectin or glycoprotein-gold complexes and samples of scrapie-infected mouse brain embedded in Lowicryl K4M were used for ultrastructural localization of glycoconjugates. The lectins tested recognize the following residues: -D-galactosyl [RCA,Ricinus communis agglutinin (aggl.) 120], N-acetyl and N-glycolyl neuraminic acid (LFA,Limax flavus aggl.), N-acetyl-D-glucosaminyl and sialyl (WGA, Wheat germ aggl.), N-acetyl-D-galactosaminyl (HPA,Helix pomatia aggl., and DBA,Dolichosbiflorus aggl.), -D-mannosyl/-D-glucosyl (Con A, Concanavalin A), -D-galactosyl and -D-galactopyranoside (BSA,Bandeirea simplicifolia aggl., izolectin B₄). Labeling of the majority of micro-blood vessels (MBVs) located outside the plaque area and in the remaining cerebral cortex was similar to that which has been previously observed in non-infected animals. Some MBVs, however, located inside the plaque area and surrounded directly by amyloid fibers showed attenuation of the endothelium, the surface of which was scarcely and irregularly decorated with RCA, LFA, WGA and Con A. These abnormalities in the composition of glycoconjugates can be associated with previously noted increased permeability of some MBVs in the brains of scrapie-infected mice. Some vessels in the plaque area were encapsulated by perivascular deposits of homogenous or flocculogranular material containing several glycoconjugates. A very intimate structural relation between reactive (microglial-like) cells and amyloid fibers suggests the participation of these cells in elaboration of plaque material. Labeling of the cell surface and adjacent amyloid fibers with the same lectins (RCA, WGA, DBA, Con A) suggests the possibility that the glycosylation of these fibers occurs extracellularly. Only WGA and DBA were occasionally labeling some Golgi elements of the reactive cells.Supported in part by a grant from NINCDS No. 17271-06     

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     

Ultrastructural studies of concanavalin A receptors and 5′-nucleotidase localization in normal and injured mouse cerebral microvasculature

Summary Plant lectin concanavalin A conjugated with ferritin (Con A-F) injected i.v. was used for the detection of the specific monosaccharide residues (-d-mannosyl and -d-glucosyl) on the luminal surface of endothelial cells (ECs) in brain micro-blood vessels (MBVs). Both normal mice and animals with mechanically damaged blood-brain barrier (BBB) were used in this study. In addition, the activity of 5-nucleotidase (5N), the putative receptor for Con A, was studied cytochemically.Various methodologic experiments indicated that the reaction product formed on the luminal plasmalemma of ECs after incubation of samples in the cytochemical medium for the detection of 5N activity results from the action of unspecific phosphatase hydrolyzing both specific and nonspecific substrates. The abluminal side of the wall of MBVs seems to be a major location of 5N activity. Thus, no correlation between cytochemically demonstrable 5N activity and Con A receptor sites on the luminal surface of ECs was noted.After damage of the BBB, extensive internalization of the luminal plasmalemma forming the limiting membranes of pinocytotic vesicles, vacuoles, and endothelial channel-like structures was observed. This process was represented by a relatively rapid translocation of Con A receptors from luminal surface into the interior of the ECs and to the abluminal side of the vessel wall.Abbreviations AP Alkaline phosphatase - 5N 5-nucleotidase phate - AMP adenosine 5-monophosphate - CMP cytidine 5-monophosphate - GMP guanosine 5-monophosphate - UMP uridine 5-monophosphate - Con A concanavalin A - BBB blood-brain barrier - EC endothelial cell - HRP horseradish peroxidase - MBVs micro-blood vessels - NDPase nucleoside diphosphatase Supported in part by a grant from NINCDS No.17271-03     

Lectin histochemistry of gangliosidosis

Summary Lectin histochemical studies were performed on selected formalin-fixed, paraffin-embedded tissues of patients affected with the O variant of G_M2-gangliosidosis (i.e., Sandhoff's disease). The purpose was to identify specific sugar residues of undegraded stored substances in cytoplasm of affected cells. We studied neural tissues from 13 patients, visceral tissues from four patients, and placentae from three affected fetuses. Neurons in all 13 cases studied stained withConcanavalia ensiformis agglutinin (Con A) and withUlex europaeus agglutinin-I (UEA-I). Succinylated wheat germ agglutinin (S-WGA) stained affected visceral cells and astrocytes and macrophages in the central nervous system. These results demonstrate that -d-mannosyl and -l-fucosyl residues, which bind Con A and UEA-I, respectively, are present in affected neurons. Furthermore, they revealed the affected nonneuronal cells and astrocytes contain complex carbohydrates with nonreducing terminal -N-acetylglucosamine, which binds S-WGA.Supported by grant NS 2176 from the National Institute of Neurological and Communicative Disorders and Stroke     

Lectin histochemistry of the rat brain following thioacetamide-induced hepatic failure

Biotinyl derivatives of several lectins were used to study the localization of glycoconjugates in the cerebral microcapillaries and various brains of rats given at 24-h intervals two ip administrations of a hepatotoxin-thioacetamide (TAA) and examined 21 d posttreatment. At this time, the rats were asymptomatic with regard to hepatic encephalopathy but showed specific and selective changes in the blood-brain-barrier (BBB) transport of basic amino acid, but no BBB damage, and region-specific neuronal injury in the hippocampus and neocortex. The lectins tested recognized the following sugar residues: β-d-galactosyl (Ricinus communis agglutinin [RCA-1]);N-acetyl-glucosaminyl andN-acetyl-neuraminic acid (wheat-germ agglutinin [WGA]);N-acetyl-d-galactosaminyl (Helix pomatia agglutinin [HPA]); β-d-galactosyl andd-galactosyl neuraminic acid (peanut agglutinin [PNA]), and α-d-galactosyl and α-d-mannosyl (concanavalin A [Con A]). The treatment markedly decreased the binding to the cerebromicrovascular network of the hippocampus and neocortex of RCA-1 and WGA. The binding of these two lectins to their complementary monosaccharide residues appears to reflect subtle changes in BBB function, with a detection threshold below the conventional BBB permeability tests. The changes in the binding of the other two lectins: an increase of HPA binding and a decrease of Con A binding, confined to neocortical neurons and pyramidal cells of hippocampus injured by TAA treatment.     

Lectin histochemistry of infantile lysosomal storage disease associated with osteopetrosis

In infantile lysosomal storage disease associated with osteopetrosis the nature of the enzyme deficiency as well as the type of material accumulated are both unknown. We used lectin histochemistry to characterize the storage material of previously reported cases. Using paraffin sections neurons stained positively with Luxol fast blue (LFB), periodic acid-Schiff (PAS), Concanavalia ensiformis agglutinin, Datura stramonium agglutinin, Griffonia simplicifolia-I, Lens culinaris agglutinin, Ricinus communis agglutinin-I, succinylated wheat germ aggluninin and wheat germ agglutinin, indicating an accumulation of fucosylated N-glycosidically linked oligosaccharides containing - and -galactosyl residues and compounds containing N-acetyllactos-amine. Reticuloendothelial cells in liver and in spleen did not stain with LFB, but did stain with PAS and the above lectins. These results indicate that there is storage of both carbohydrates and lipids in neurons, and stored carbohydrates with similar residues in reticuloendothelial cells in this disease, where the primary defect is still unknown.     

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.

     

A new form of ovine GM1-gangliosidosis

neurological signs were observed in 3 lambs at approximately 1 month of age, in a flock of 1 ram and 29 ewes with 43 lambs. Deterioration occurred such that the lambs had either died or been killed by 4 months of age. Necropsies of two of these lambs revealed a diffuse encephalopathy in which the most prominent feature was ballooned neurons. Sections of frozen brain showed PAS-positive, oil red O-negative, and weak Sudan Black-positive material in the swollen neuronal cytoplasm. The ultrastructure of the neuronal inclusions showed characteristic whorled membranes, suggesting diagnosis of a gangliosidosis. The underlying enzymic defect was investigated by assaying 11 lysosomal enzymes in extracts of kidney from an affected lamb and from normal lambs. A deficiency (90%) of acidic -d-galactosidase was found in the affected lamb. All other activities, including N-acetylneuraminidase, were normal. A specific deficiency of lysosomal -d-galactosidase was demonstrated by separating the lysosomal and cytosolic -d-galactosidase by chromatography on concanavalin A-Sepharose. Diagnosis of G_M1-gangliosidosis, analogous to the severe infantile form of the human disease, was made on the basis of the pathology and enzymology. The -d-galactosidase activity in the white blood cells of the ram and several of the ewes was consistent with their being heterozygotes. This disorder is different from a previously described lipidosis in sheep, in which there was a combined deficiency of -d-galactosidase and -neuraminidase.     

The yield of laboratory investigations in children with infantile autism

Summary. Purpose: To evaluate the yield of laboratory investigations in infantile autism. Methods: We retrieved and evaluated the results of investigative procedures recorded in the medical files of autistic infants in four child developmental centers and two pediatric psychiatric outpatient clinics. Results: One-hundred and thirty-two infants were included in the study of whom 47 (36%) underwent autistic regression at an average age of 20 months. The investigative procedures included electroencephalogram (n=132), neuroimaging (n=70), genetic studies to detect Fragile-X (n=59) and a metabolic workup (n=53). Except for the molecular diagnosis that revealed Fragile-X syndrome in two children (3%), all other tests were negative. The two infants with the Fragile-X syndrome belonged to the non-regressive group. Conclusions: The only investigative study that contributed to the diagnosis of autistic infants was the molecular diagnosis detecting Fragile-X. In spite of the high frequency of epilepsy and epileptiform abnormalities in the electroencephalograms of autistic children in general, the contribution of epilepsy, both clinical and subclinical, to the etiology of autism is apparently minimal.     

Adult-onset lysosomal storage disease in a Schipperke dog: clinical,morphological and biochemical studies

Summary An adult-onset lysosomal storage disorder was diagnosed in a 5-year-old Schipperke dog with progressive cerebellar and central vestibular signs. It was characterized by cerebellar atrophy with extensive loss of Purkinje and granular cells, and hydrocephalus. Enlarged and vacuolated neurons were observed in spinal cord and brain; pancreatic centrolobular and islet cells were also vacuolated. Ultrastructurally, enlarged secondary lysosomes laden with lamellated membrane structures were present in neurons and empty enlarged vacuoles were found in pancreatic centroacinar, ductal, and islet cells. On frozen sections neurons stained with Ricinus communis agglutinin-I and wheat germ agglutinin. On paraffin sections neurons stained with luxol fast blue, periodic acid-Schiff, Concanavalia ensiformis agglutinin, and were autofluorescent. These findings indicate an accumulation of glycolipids containing terminal -galactosyl and -sialyl residues, and N-linked oligosaccharides. Tissue activity of lysosomal -galactosidase was 50% of normal and the activity of -hexosaminidase was elevated. Brain lipid-bound sialic acid was twice normal, with a small increase of G_M1-ganglioside, but there was a significant elevation of G_M2 (G_D2) and G_M3 (G_D3). In addition, significant elevations of sialylated and non-sialylated oligosaccharides were noted. These clinical, biochemical and pathological findings are similar to those observed in human patients with adult-onset galactosialidosis.     

Effect ofd,l-α-aminoadipate on the mediobasal hypothalamus and endocrine function in the rat

Summary Using the glutamate analog,d,l--aminoadipic acid (d,l-AA), experiments were conducted to examine the nature, extent, and specificity of its toxicity in the mediobasal hypothalamus and to determine its effect on endocrine homeostasis. Neonatal rats received daily injections ofd,l-AA (4 g/kg BW) on postnatal days 5–10 and were killed at various post-treatment intervals. Sex-matched littermates were given equimolar amounts of NaCl and served as controls. Treated rats killed 18 days post injection weighed slightly less than controls and had reduced testicular, ovarian, and uterine weights, but the differences were not statistically significant. Ind,l-AA treated rats serum and pituitary levels of TSH and PRL were comparable to control values. Pituitary content of LH ('s and 's) and FSH ('s), however, was lower (P<0.05) ind,l-AA treated rats than in controls, but serum levels were not significantly different. Distinct cytopathologic changes were evident in the arcuate nucleus and median eminence ofd,l-AA-treated rats killed at 2 and 6 h post injection only. By 12 h evidence of acute damage had largely disappeared. Both glial and ependymal cells underwent edematous swelling and necrosis, but neurons were largely unaffected. Evidence of reactive changes, such as gliosis, infiltration of microglia, and removal of debris, however, were not very conspicious. A random sample of mediobasal hypothalami of rats killed 18 days post injection failed to show any detectable lesion or residual effects of earlier pathology. Age at the time of exposure to the gliotoxin was found to be an important variable affecting both extent and duration of injury. The most deleterious effects were observed when the gliotoxin was administered in the form of a single injection on postnatal day 5 only. The results suggest that normal neuronal activity and endocrine homeostasis, specifically gonadotropin, may be irreversibly altered as a consequence of transient disruption of the glial compartment.Supported by grants from the Medical Research Council of Canada, the St. Boniface General Hospital, and Mrs. James A. Richardson Research Foundations     

Synaptic vesicle transport and synaptic membrane transporter sites in excitatory amino acid nerve terminals in Alzheimer disease

Summary. The apparent l-[³H]glutamate uptake rate (v) was measured in synaptic vesicles isolated from cerebral cortex synaptosomes prepared from autopsied Alzheimer and non-Alzheimer dementia cases, and age-matched controls. The initial synaptosome preparations exhibited similar densities of d-[³H]aspartate membrane binding sites (B_MAX values) in the three groups. In control brain the temporal cortex d-[³H]aspartate B_MAX was 132% of that in motor cortex, parallel with the l-[³H]glutamate v values (temporal=139% of motor; NS). Unlike d-[³H]aspartate B_MAX values, l-[³H]glutamate v values were markedly and selectively lower in Alzheimer brain preparations than in controls, particularly in temporal cortex. The difference could not be attributed to differential effects of autopsy interval or age at death. Non-Alzheimerdementiacasesresembled controls. The selective loss of vesicular glutamate transport is consistent with a dysfunction in the recycling of transmitter glutamate.Present address: Department of Anesthesiology, Cornell University Medical College, New York, NY, USAReceived January 20, 2003; accepted April 3, 2003 Published online June 30, 2003     

Skeletal muscle pathology of mannosidosis in two siblings with spastic paraplegia

Summary Deficiency of -d-mannosidase was found in two siblings with muscle weakness and spastic paraplegia. A biopsy of the vastus lateralis muscle was studied by light and electron microscopy. Cryostat sections showed mild fiber size variation but no necrosis. Semithin Epon sections revealed many vacuoles in the muscle cells and fibroblasts. Electron microscopy showed that the vacuoles, presumably lysosomal, had a single limiting membrane and contained finely granular or granulo-reticular material, membranous structures, and electron-dense ovoids. The vacuoles were identical with those in lymphocytes and other cells of patients with mannosidosis. Disorganization of sarcomere alignment and widening of intermyofibrillar spaces were also observed. Deficiency of -d-mannosidase is considered to cause slowly progressing degeneration of muscle fibers.     

Differentialdiagnose perniciöser Involutionspsychosen,praeseniler Psychosen und Psychosen bei Involutionspellagra

Zusammenfassung Im Umkreis der involutiven und praesenilen Psychosen interessieren in besonderem Maße jene nicht allzu seltenen Verläufe, welche nach anfänglich endogen-psychotischer Symptomatik in exogenpsychotische, hirnorganische Endzustände übergehen. Die hierbei zu beobachtenden Übergangsstadien und Umschläge vom Endogenen zum Exogenen (Intermediärphänomene) stellen ein bemerkenswertes klinisches Charakteristikum für sehr verschiedene zentralnervöse Prozesse in Involution und Praesenium dar. In neurologischer Hinsicht kann dem eine oft schwer analysierbare Verquickung ausdrucksmotorischer Störungen mit neurologisch objektivierbaren Dyskinesien entsprechen.Zwischen den perniciösen Involutionspsychosen mit hirnorganischem Endzustand, einigen Formen praeseniler Hirnerkrankungen mit endogen anmutenden Initialpsychosen und Psychosen bei Involutionspellagra finden sich psychiatrischneurologische, internistische und neuropathologische Beziehungen.Die neuropathologischen Basisprozesse lassen sich nur bedingt unterscheiden: so etwa diejenigen der Creutzfeldt-Jakobschen und Kraepelinschen Krankheit, gewisser praeseniler Erkrankungsformen (McMenemey und Pollak), [einschließlich praeseniler Demenz bei Thalamusdegeneration (Stern) oder Cerebellardegeneration (Akelaitis)], — der sogenannten unspezifischen Hirnatrophien, der perniciösen Involutionspsychosen und der pellagroiden Involutionspsychosen. Der nähere Vergleich läßt jedoch erkennen, daß es sich hierbei um quantitativ, qualitativ und lokalisatorisch einander überlagernde Gewebssyndrome handelt, deren Unterscheidung sich lediglich aus der Variabilität einzelner Prozeßkomponenten ergibt. Das kann auch zu differentialdiagnostischen Abgrenzungsschwierigkeiten gegenüber manchen Fällen von subakuten generalisierten spongiösen Atrophien mit dyskinetischem Endstadium und gegenüber Beobachtungen von sogenannter akuterPickscher Krankheit, führen.Bei allen involutiven und praesenilen Psychosen können sich mitunter jene internistische Komplikationen einstellen, welche differentialdiagnostisch an eine Involutionspellagra denken lassen. Die hierbei auftauchenden differentialdiagnostischen Fragen zeigen sich an sieben eigenen Beobachtungen von perniciöser Involutionspsychose mit hirnorganischem Endzustand besonders deutlich. Die Krankheitsverläufe ähnelten in mancher Hinsicht dem klinischen Bilde der Kraepelinschen Krankheit und der erstarrenden Rückbildungsdepression (Medow) [chronisches endogen-psychotisch anmutendes Initialstadium mit allmählichem Übergang in hirnorganisch-exogene Psychosen mit extrapyramidalen Zügen].Manches spricht dafür, daß dem Gesamt der hier erörterten involutiven und praesenilen Psychosen einschließlich der pellagrösen Involutionspsychosen generalisierte und wechselnd organgebundene Rückbildungsvorgänge primär zugrunde liegen können. Involutionspsychose und Involutionspellagra können jedenfalls auf primäre Rückbildungsvorgänge an verschiedenen Organen und Organsystemen hinweisen. Angesicht seines wechselnden Zueinanders von Rückbildungsprozessen innerhalb des Gesamtorganismus und seiner Teüe empfiehlt es sich, eine allzuscharfe Abgrenzung der hier genannten Krankheiten eher zu vermeiden, als sich den Blick für die gemeinsamen Grundzüge der klinischen und neuropathologischen Syndrome und für den vieldeutigen pathogenetischen Stellenwert der internistischen Komplikationen zu verdecken. Es wird vermutet, daß auch andere Formen involutiver Psychosen mit hirnorganischen Zügen: z.B. die erstarrenden Rückbildungsdepressionen (Medow), die sogenannten komplizierten Formen der Involutionsmelancholie und die vorzeitigen Versagenszustände im Praesenium (Behringer und Mallison) auf ähnlichen neuropathologischen Basisprozessen beruhen, wenngleich entsprechende neuropathologische Untersuchungen noch nicht vorliegen. Nur ein kleiner Anteil der hirnorganisch gefärbten Rückbildungspsychosen und praesenilen Psychosen betrifft Patienten mit cyclothymen Vorerkrankungen.Nach Vorträgen vor der Gesellschaft bayrischer Psychiater, München 1958 und der Frankfurter nervenärztlichen Gesellschaft, Frankfurt 1959.     

Histochemical similarities between human and animal globoid cells in Krabbe's disease: a lectin study

Summary Lectin-histochemical studies were performed on paraffin-embedded brain tissue sections to identify the specific sugar residues of undegraded stored substances in the cytoplasm of globoid cells from patients with globoid cell leukodystrophy. We studied brain tissues from six human patients with galactosylceramide lipidosis (i. e., Krabbe's disease) and compared them to brain tissues from animals with a similar enzyme deficiency including seven Twitcher mice, three dogs and two cats. The globoid cells in all 18 cases studied stained with succinylated-wheat germ agglutinin (S-WGA), but did not stain withDilichos biflorus agglutinin, soybean agglutinin orUlex europaeus agglutinin-I.Bandeirea simplicifolia agglutinin-I stained the globoid cells in Twitcher mice, dogs and cats but not those in humans.Concanavalia ensiformis agglutinin, wheat germ agglutinin andRicinus communis agglutinin-I all stained each of the globoid cells in the mouse, dog and cat tissues, but only in some of the human cases. Peanut agglutinin, however, variably stained globoid cells in the mouse and dog cases but not at all in the human and cat cases. These results demonstrate a common terminal carbohydrate residueN-acetyl glucosamine, which binds S-WGA in the undergraded material stored within the globoid cells in galactoceramide lipidosis. These cells also contained various other stored molecules with sugar residues whose nature is determined by species or individually.Supported by grants NS21765 and HD05515 from the National Institutes of Health     

Aspartylglucosaminuria II: biochemical studies on brain,liver, kidney and spleen

Summary Brain, liver, kidney and spleen biopsy and autopsy specimens were taken from patients with aspartylglucosaminuria for biochemical investigations. Total cholesterol values for brain and liver were normal as were also the values for N-acetylneuraminic acid in brain. Lipid phosphate was slightly increased both in the brain and liver. The thin-layer chromatographic patterns of brain gangliosides and phospholipids were normal.In the group of fourteen different lysosomal enzymes the activity of N-aspartyl--glucosaminidase was markedly decreased in the brain, liver and spleen but not in the kidney. The activities of a number of other enzymes, especially those of N-acetyl--d-glucosaminidase and N-acetyl--d-galactosaminidase were high in the same three tissues and again normal in the kidney. No consistent abnormalities were recorded in the groups of three microsomal and three other enzymes.The biochemical findings seem to be characteristic to aspartylglucosaminuria and delineate it as a special disease entity.     

Refraktärperioden und frequente Impulsfortleitung im gemischten N. ulnaris des Menschen bei Polyneuropathien

Zusammenfassung Bei 30 Patienten mit Neuropathien unterschiedlichen Schweregrades (subklinisch, leicht, mittelschwer und schwer) wurden am N. ulnaris neben den üblichen neurophysiologischen Parametern [distale Latenz, maximale motorische und gemischte Nervenleitgeschwindigkeit (Nlg.)] die Refraktärperioden (Rp.) (absolute Rp. und relative Rp.-Amplitude und -Latenz) und die unteren Grenzfrequenzen (u. F.) (u. F.-Amplitude und -Latenz) bestimmt.Beim Vergleich mit einem Normalkollektiv (n=31, s. Lowitzsch u. Hopf, (1972a)) war die Nlg. nur in 37% der Fälle pathologisch verlangsamt, während die relative Rp.-Latenz in ca. 80% und die u. F.-Latenz in ca. 60% pathologisch verändert waren.In zwei Stichproben (13 Normalfälle und 13 Polyneuropathien) mit einer normalen gemischten Nlg. von 51,0–63,5 m/sec unterschieden sich die Mittelwerte für die distale Latenz sowie die motorische und gemischte Nlg. statistisch nur auf dem 1%-Niveau, für die relative Rp.-Latenz und die u. F.-Latenz hingegen auf dem 0,5-Niveau.Die Bestimmung der Refraktärperioden, insbesondere der rel. Rp. L., sowie der unteren Grenzfrequenz (u. F. L.), stellt eine im Vergleich mit den üblichen neurophysiologischen Verfahren (Nlg.-Bestimmung) wesentlich empfindlichere Untersuchungsmethode zur Erfassung auch geringer (subklinischer) Funktionsstörungen des peripheren Nervensystems dar.Die unterschiedliche Beeinflussung der Refraktärperioden und der Grenzfrequenzen durch die Art des zugrundeliegenden pathologischen Prozesses (axonale Degeneration — segmentale Demyelinisierung — Mischtyp) wird an Hand der in 9 Fällen nervenbioptisch (N. suralis) gewonnenen Befunde diskutiert.

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Refractory periods and frequent impulse conduction in mixed N. ulnaris of man in polyneuropathies

Summary Some electrophysiological parameters were studied in the ulnar nerve of 30 patients suffering from neuropathy of various origin and severity.Absolute and relative refractory periods and lower limiting frequencies were measured and compared to the usual parameters (distal motor latency, conduction velocity of motor fibres, and the mixed nerve action potential).The conduction velocity was indicative of the diseased function in 37% whereas the relative refractory period (latency) was abnormal in nearly 80% and the lower limiting frequency (latency) in about 60%.Two samples taken at random, each of them consisting of 13 patients with normal conduction velocities between 51.0 and 63.5 m/sec showed differences only at the 1% level (p<0.01) as far as the mean values of the distal latency and the maximum conduction velocity were concerned. The difference between the mean values of the relative refractory period (latency) and of the lower limiting frequency (latency), however, was highly significant (p<0.0005). Thus, in our experience, the relative refractory period (latency) and the lower limiting frequency (latency) are more sensitive indicators of mild functional disturbances of peripheral nerves than the maximum conduction velocity.

Die Untersuchungen wurden in dankenswerter Weise von der Deutschen Forschungsgemeinschaft unterstützt.