Interhemispheric asymmetries of the modular structure in human temporal cortex.

Language-relevant processing of auditory signals is lateralized and involves the posterior part of Brodmann area 22. We found that the functional lateralization in this area was accompanied by interhemispheric differences in the organization of the intrinsic microcircuitry. Neuronal tract tracing revealed a modular network of long-range intrinsic connections linking regularly spaced clusters of neurons. Although the cluster diameter was similar in both hemispheres, their spacing was about 20 percent larger in the left hemisphere. Assuming similar relations between functional and anatomical architecture as in visual cortex, the present data suggest that more functionally distinct columnar systems are included per surface unit in the left than in the right area 22.

Non-tau based neuronal degeneration in Alzheimer's disease -- an immunocytochemical and quantitative study in the supragranular layers of the middle temporal neocortex.

In Alzheimer's disease (AD), cortical neurons develop neurofibrillary tangles (NFTs) consisting of hyperphosphorylated tau. The neurons eventually die. There are some hints that cortical neurons may also degenerate without the development of cytoskeletal changes. We investigated this possibility by comparing changes in APP staining and neuronal size with respect to the presence or absence of hyperphosphorylated tau. Adjacent sections of the medial temporal neocortex (Brodmann's area 22) of 5 male AD patients aged 60-88 years (Braak V-VI) and 5 age-matched male non-demented control subjects were i) stained with a modified Bielschowsky silver method in order to reveal NFTs and 'ghost' tangles, ii) single-stained with anti-APP, and iii) double-labeled with anti-APP and AT8. Anti-APP is directed against the beta-amyloid precursor protein and stains virtually all perikarya and proximal neurites of the cortical neurons. AT8 stains pre-tangles, NFTs and extracellular 'ghost' tangles due to the recognition of hyperphosphorylated tau. The study was focused on the supragranular cortical layers II-III, since these layers can be clearly delineated from the adjacent molecular and granular cell layers. The results showed that i) APP staining intensity in neurons was variable in the AD cortex, being clearly different from the invariably intense neuronal staining in all controls. Reduced cytoplasmic APP staining was observed, particular in small neurons, while lack of anti-APP staining in proximal neurites, too, was associated with AD. In addition, ii) cross-sectional area measurement on anti-APP-stained neurons revealed that in AD, as compared to controls, a clear decrease in the number of mainly large-sized neurons (>150 microm2) was accompanied by a significant increase in the percentage of neurons in the smaller size classes, indicating that many large-sized neurons became smaller in AD. iii) Reduced APP staining and decreased neuronal size were not necessarily associated with the presence or absence of hyperphosphorylated tau in these cells. iv) Twenty-six percent of the neurons contained hyperphosphorylated tau, while the level of NFT-related neuronal loss was low in AD. The present study suggests that non-tau based neuronal degeneration is a major phenomenon in the AD neocortex.

Distribution of nuclear size and internuclear distance are important criteria for grading astrocytomas.

AIM: The differentiation between low-grade astrocytomas and anaplastic astrocytomas is susceptible to considerable inter-observer variability. In order to contribute to a better standardization of astrocytoma-grading based on quantitative data, the present study focuses on two important aspects not being considered in previous morphometric studies: elaboration of a decision flow chart for tumor grading based on morphometric parameters and appropriate cut-off-values, easily performed using low-cost equipment such as measuring oculars; investigation of the distribution (histograms) of parameters describing nuclear size and internuclear distance, which had been represented in previous studies by their mean and standard deviation only. MATERIAL AND METHODS: At least 300 tumor cell nuclei per case were investigated in paraffin sections from surgical specimen of 75 patients with astrocytomas WHO grade II (n = 23) and anaplastic astrocytomas WHO grade III (n = 52) by means of a digital image analysis system. RESULTS: The morphometric data showed significant differences between both groups of tumors. According to multivariate analysis, the best contribution to tumor grading was achieved by means of parameters concerning the distribution of values for nuclear diameters and internuclear distances. A decision tree was constructed using a knowledge based algorithm, which provided astrocytoma grading based on the distribution of values for nuclear diameter, as well as the numerical nuclear density and proliferation index. Measurements using a measuring ocular took an acceptable amount of time (1.5 hour per case) and showed good reproducibility when compared with measurement by means of digital image analysis. CONCLUSION: The study demonstrates that a morphometric examination of tumor cell nuclei in paraffin sections supports the clinically important differential diagnosis between low-grade and high-grade astrocytomas. The method for classification and the data published in the present study constitute a good basis for a standardized and reproducible grading procedure for astrocytomas, which can be performed in any histologic laboratory even without a digital image analysis system.

Variations of the ultrastructure of neuronal lipofuscin during childhood and adolescence in the human Ammon's horn.

The ultrastructure of lipofuscin (Lf) was studied in hippocampal and neocortical neurons of children and youngsters between 3 months and 24 years of age. As a standard, regions CA1 and CA4 of Ammon's horn and the gyrus centralis anterior of the left hemisphere were examined, and the ratio of the two components of Lf, the pigment part, and the usually droplet-like lipid part was looked at. Few and small granules with typical linear structures in the pigment part and little lipid droplets were found as early as at the age of 3 months in all brain regions. There were no morphological differences of Lf in the areas of Ammon's horn up to 3 years, but the Lf ultrastructure in Ammon's horn differed clearly from that in the neocortical region. Differences of Lf between the areas CA1 and CA4 were found to appear at the age of 6-8 years, to have a rather variable pattern between age 11 and about 20 years, and to be relatively constant thereafter. The Lf pigment part consisted of irregularly arranged three laminar linear structures. Some varieties could be seen in the size and shape of the Lf granules and in the lipid/pigment ratio. As to the question of Lf being an "age pigment," the findings that the number of Lf granules did not further increase after the period of early adolescence was not consistent with the age pigment hypothesis. No regional or age-dependent differences were found in the Lf of astro- and oligodendroglia.

Inherited cholesterol lipidosis: cerebrotendinous xanthomatosis (van Bogaert Scherer Epstein disease). A clinicopathological study.

Cerebrotendinous xanthomathosis (CTX) is a rare autosomal-recessively transmitted disease of the lipid storage system with an array of general and neurological symptoms, based on the pathological storage of cholestanol and cholesterol. The histologic manifestations are foamy cell granulomata and cholesterol crystals within various tissues, associated with a loss of both nerve cells and demyelination inside the CNS. We present a case of CTX with clinical progression as well as the pathomorphologic autopsy findings. The CNS affection in our case will be demonstrated and the pathogenesis be discussed. Medical treatment of CTX is possible but with variable success. In the case shown, the patient profited only marginally from a long-term application of chenodeoxycholic acid.

Localisation and association of pathomorphological changes at the brainstem in Alzheimer's disease.

The brainstems of ten patients with Alzheimer's disease were examined with specific silver impregnations for beta-amyloid deposits, neurofibrillary tangles, neuropil threads and neuritic plaques. The results show a selective and focal involvement of brainstem nuclei, which are diffusely connected to the cortex or are neuronally connected with other damaged subcortical and cortical regions. Therefore, it is concluded that neuronal connectivity plays an important role in the pathogenesis of Alzheimer's disease lesions. This may be due to the intraneuronal transport of beta-amyloid precursor protein. There was a local association between neurofibrillary tangles and neuropil threads, but not between beta-amyloid structures on the one hand and neurofibrillary structures on the other hand. Neuritic plaques were rarely found.

Ultrastructural differences of hippocampal lipofuscin in human development.

The lipofuscin of pyramidal cells in each hippocampal subfield of each of seven human autopsy cases without brain disease at the age of 3-12 months (infants) and of 17-23 years (young adults) was comparatively investigated at the electron microscopic level. In infant pyramidal neurons of the hippocampal subfields CA 1, CA 2, CA 3 and CA 4 O-2, very small lipofuscin particles were observed. The lipofuscin composition showed a slightly larger granular component compared to the vacuolar component with one or two small lipid droplets. No obvious ultrastructural variability of lipofuscin granules was observed. The CA 1 lipofuscin in young adults consists of larger particles than in infants, but no obvious difference in the composition of granular and vacuolar components from the infant lipofuscin was seen. The amount of lipofuscin in CA 1 strongly increased in young adults compared to infants and appeared in a perinuclear distribution. In young adults, in contrast to the infant group, the amount of lipofuscin in the subfields CA 2, CA 3 and CA 4 was significantly higher than in CA 1. In CA 2, CA 3 and CA 4 pyramidal neurons, the vacuolar component was significantly larger than the granular component. The similarity of infant hippocampal lipofuscin patterns in all subfields is discussed as a state of immaturity. To explain the observed differences between the CA 1 and the other subfields during neuronal development, as shown in the young adult group, several factors are discussed: the effects of cell specific metabolism, cellular functional activity, cytoprotective mechanisms and effects of efferent and afferent pathways connected with the subfields.

[Myopathia myotonica. A new type of hereditary muscle disease (author's transl)]. / Myopathia myotonica. Fallbericht über eine neuartige hereditäre metabolische Myopathie

A new type of hereditary muscle disease, characterized by weakness and painful spasms during effort, without electrical activity in the shortened muscles, is described. These phenomena are limited principally to the upper limbs. In addition we found electromyographical signs of a generalized myotonic syndrome. The histological and histochemical investigations reveal only minimal non-specific signs of myopathy. The activities of CPK and aldolase in the blood serum are increased at times. A normal elevation of venous lactate was observed during ischemic work. The biochemical studies of muscular tissue exhibit normal activities of the analyzed enzymes, especially as regards phosphorylase. An increased concentration of calcium ions in blood serum may be related to the contraction during strenuous work; it is known that calcium ions are an important factor in the contraction-relaxation cycle of striated muscle. The age of manifestation varied from 4 to 33 years in 4 cases of the relatives observed. The disease shows no signs of aggravation as to the severity and extent of the disorders. The nature of the underlying metabolic defect is still unknown.

Adrenoleukodystrophy in an adult female. A clinical, morphological, and neurochemical study.

A 43-year-old female with adrenoleukodystrophy (ALD) is described, who developed spastic tetraparesis, suffered grand mal seizures, and became stuporous and demented during the last 5 years of her life. Computed tomography revealed symmetrical hypodense lesions in the peritrigonal regions. Adrenal insufficiency was not evident except for skin pigmentation. The ultrastructure of a rectal biopsy specimen showed inclusions with lamellae and interspersed clefts in macrophages of the submucosal layer. At autopsy, the adrenals were found to contain large foam cells filled with similar inclusions. The brain cortex and the spinal cord were histologically normal. However, cerebral white matter exhibited widespread demyelination which spared only the arcuate fibres. In regions of less severe demyelination scattered inflammatory cells were seen. On electron microscopy, aggregates of typical paired leaflets with distinct intermediate lines were demonstrated in perivascular macrophages. Histochemical study showed these cells to contain free as well as esterified cholesterol. Gas chromatographic analysis of very long chain fatty acids (VLFA) from the demyelinated cerebral white matter showed a marked increase of C26:0 fatty acid in cholesterol esters and above-normal values for C24:0 and C24:1 in gangliosides. It is suggested that the condition was a heterozygote form of X-linked ALD. Patients with neurodegenerative symptoms with or without adrenal insufficiency can easily be screened for X-linked ALD by VLFA analysis in blood or cultured fibroblasts.

UDP-glucuronyltransferase in perfused rat liver and in microsomes. Effects of CCl4 injury.

To elucidate the disparity between glucuronidation rates in vivo and UDP-glucuronyltransferase in vitro after CCl4 injury, the time course of the effects of CCl4 (0.25 ml/kg) on kinetic properties of UDP-glucuronyltransferase (l-naphthol as substrate) was examined in rat liver homogenates and microsomes. These experiments were compared with l-naphthol glucuronidation by the perfused liver which was studied at various time points after CCl4 administration. Phenobarbital-treated rats were used to enhance the hepatotoxicity of CCl4. 1. Within 24 h UDP-glucuronyltransferase activity increased 8-fold in liver homogenates and 3-fold in microsomes. During this time the allosteric activator, UDP-N-acetylglucosamine, lost its effect whereas the inhibitor UPD showed greater inhibitory properties, thus counteracting the activation. 2. l-Naphthol glucuronidation in perfused livers was significantly decreased by 24 h. Sulfate ester formation was little affected. 3. The content of UDP-glucuronic acid was not significantly altered although liver histology revealed about 45% necrotic and prenecrotic cells and an uniform fatty degeneration of hepatocytes after 24 h. The results suggest that during CCl4 injury, UDP-glucuronyltransferase is activated. At the same time the kinetic properties of the enzyme are altered in a way leading to inefficient glucuronide synthesis, when assays are carried out under conditions presumed to exist in vivo. Nevertheless the capacity to form glucuronides is retained in the acutely injured liver.