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Biomedical subjects

G Leuba

Publications and source records attributed to G Leuba.

At least 19 recordsLinked to original sources
PubMed2004

Differential expression of LMO4 protein in Alzheimer's disease.

The molecular bases of late-onset and sporadic Alzheimer's disease (AD) still have to be unraveled. Among putative candidates for molecular variations in AD, we propose LMO4 protein, a transcription regulator, involved in multiple protein complexes. We investigated changes in LMO4 immunoreactivity in vulnerable brain regions of AD cases and controls of comparable age. Immunocytochemical analysis revealed a high level of LMO4 expression in the entorhinal cortex (EC) and in the CA1 hippocampal region of the control brains and a consistent decrease in the AD brains, correlated with the amount of neurofibrillary tangles (NFT) degenerating neurones and the severity of senile plaques deposition. The decrease in LMO4 immunoreactivity resulted both from weaker immunoreactive signals and from a loss of immunoreactive neurones. LMO4 immunocytochemical staining appeared not to be colocalized with NFT in a majority of neurones. Its expression was weak in the dentate gyrus and stronger in CA3-4, two regions with no or low numbers of NFT, but there was no decrease in AD compared to control cases. In the frontal cortex, the ventro-infero-median region (area 12) showed a greater LMO4 expression than the polar one (area 9), but no decrease in AD was observed. As LMO4 has been proposed to inhibit cellular differentiation, it can be hypothesized that a reduced expression is associated in EC and CA1 with attempts of diseased neurones to differentiate (e.g. compensatory neuritogenesis). Taken together, these data indicate that LMO4 protein is involved in the complexity of the disease phenotype, at least as a secondary factor.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Involvement of microglia-neuron interactions in the tumor necrosis factor-alpha release, microglial activation, and neurodegeneration induced by trimethyltin.

Trimethyltin (TMT) is a neurotoxicant known to induce early microglial activation. The present study was undertaken to investigate the role played by these microglial cells in the TMT-induced neurotoxicity. The effects of TMT were investigated in monolayer cultures of isolated microglia or in neuron-enriched cultures and in neuron-microglia and astrocyte-microglia cocultures. The end points used were morphological criteria; evaluation of cell death and cell proliferation; and measurements of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and nitric oxide (NO) release in culture supernatant. The results showed that, in cultures of microglia, TMT (10(-6) M) caused, after a 5-day treatment, an increased release of TNF-alpha, without affecting microglial shape or cell viability. When microglia were cocultured with astrocytes, TNF-alpha release was decreased to undetectable levels. In contrast, in neuron-microglia cocultures, TNF-alpha levels were found to increase at lower concentrations of TMT (i.e., 10(-8) M). Moreover, at 10(-6) M of TMT, microglia displayed further morphological activation, as suggested by process retraction and by decrease in cell size. No morphological activation was observed in cultures of isolated microglial cells and in astrocyte-microglia cocultures. With regard to neurons, 10(-6) M of TMT induced about 30% of cell death, when applied to neuron-enriched cultures, whereas close to 100% of neuronal death was observed in neuron-microglia cocultures. In conclusion, whereas astrocytes may rather dampen the microglial activation by decreasing microglial TNF-alpha production, neuronal-microglial interactions lead to enhanced microglial activation. This microglial activation, in turn, exacerbates the neurotoxic effects of TMT. TNF-alpha may play a major role in such cell-cell communications.

Animals↗
PubMed2000

Search for a mutation in the tau gene in a Swiss family with frontotemporal dementia.

Frontotemporal dementia (FTD) is considered to have a heterogeneous aetiology. To date the tau gene located on chromosome 17 has been shown to be implicated in the pathogenesis of several FTD families with parkinsonism, the so called FTDP-17 families. The mutations reported so far are located within exons 9 to 13, a region coding for the microtubule-binding sites. They are causing various cytoskeletal disturbances. We are describing here the main clinical and neuropathological features of a Swiss FTD family with members presenting a FTDP-like clinical phenotype. However, if we except two silent polymorphic sites at position 227 and 255 in exon 9, neither a known FTDP-17 mutation nor a novel one was detected in this region of the tau gene. Thus, the existence of a yet unknown mechanism of neurodegeneration, other than via mutations near or within the microtubule-binding sites, or the exon 10 splice sites of the tau gene, has to be considered to explain dementia in this family. A mutation in another gene is still possible.

Binding Sites↗
PubMed2000

Familial frontotemporal dementia with ubiquitin inclusion bodies and without motor neuron disease.

Frontotemporal dementia (FTD) is the second most common degenerative dementia after Alzheimer's disease and its Lewy body variant. Clinical pathology can be subdivided in three main neuropathological subtypes: frontal lobe dementia, Pick's disease and FTD with motor neuron disease (MND), all characterised by distinct histological features. Until recently the presence of ubiquitin-positive intraneuronal inclusions in the dentate gyrus, and the temporal and frontal cortex was usually associated with the MND type. Such inclusions were also observed in a few sporadic cases of FTD without or with parkinsonism (FTDP) in the absence of MND. We present here clinical, neuropathological and immunohistochemical data about a Swiss FTD family with FTDP-like features but without MND. Spongiosis and mild gliosis were observed in the grey matter. No neurofibrillary tangles, Pick bodies, Lewy bodies, senile plaques or prion-positive signals were present. However, ubiquitin-positive intracytoplasmic inclusions were detected in various structures but predominantly in the dentate gyrus. These observations support the existence of a familial form of FTDP with ubiquitin-positive intracytoplasmic inclusions (Swiss FTDP family).

Aged↗
PubMed1998

Quantitative distribution of parvalbumin, calretinin, and calbindin D-28k immunoreactive neurons in the visual cortex of normal and Alzheimer cases.

The distribution of parvalbumin (PV), calretinin (CR), and calbindin (CB) immunoreactive neurons was studied with the help of an image analysis system (Vidas/Zeiss) in the primary visual area 17 and associative area 18 (Brodmann) of Alzheimer and control brains. In neither of these areas was there a significant difference between Alzheimer and control groups in the mean number of PV, CR, or CB immunoreactive neuronal profiles, counted in a cortical column going from pia to white matter. Significant differences in the mean densities (numbers per square millimeter of cortex) of PV, CR, and CB immunoreactive neuronal profiles were not observed either between groups or areas, but only between superficial, middle, and deep layers within areas 17 and 18. The optical density of the immunoreactive neuropil was also similar in Alzheimer and controls, correlating with the numerical density of immunoreactive profiles in superficial, middle, and deep layers. The frequency distribution of neuronal areas indicated significant differences between PV, CR, and CB immunoreactive neuronal profiles in both areas 17 and 18, with more large PV than CR and CB positive profiles. There were also significantly more small and less large PV and CR immunoreactive neuronal profiles in Alzheimer than in controls. Our data show that, although the brain pathology is moderate to severe, there is no prominent decrease of PV, CR and CB positive neurons in the visual cortex of Alzheimer brains, but only selective changes in neuronal perikarya.

Aged↗
PubMed1997

Colocalization of parvalbumin, calretinin and calbindin D-28k in human cortical and subcortical visual structures.

Several studies have demonstrated that three calcium-binding proteins parvalbumin (PV), calbindin D-28k (CB) and calretinin (CR) mark distinct subsets of cortical interneurons. This study demonstrates, in cortical and subcortical visual structures, the coexistence of two calcium-binding proteins in some neuronal subpopulations. The human visual cortex (VC), lateral geniculate nucleus (LGN). lateral inferior pulvinar (LIP) and superior colliculus (SC) were examined by a double-labelling immunocytochemical technique. The VC showed mostly separate populations of PV, CB and CR immunoreactive (-ir) interneurons, but also small populations of double-stained PV + CR and CR + CB neurons, while PV + CB neurons were less frequent. An average of 2.5% of the immunoreactive neurons were double-stained for PV + CR and 7.1% for CR + CB in area 17, while this percentage was slightly higher in association area 18 (3.3 and 7.4%, respectively). In the LGN and LIP, double-stained neurons were scarce, but in the fibre capsule of these nuclei, as well as in the optic radiation (OR) and white matter underlying area 17, both double-stained PV + CR or CR + CB and separate populations of PV-ir, CB-ir and CR-ir neurons and fibres were observed. Unlike the thalamic regions, the SC showed some double-stained PV + CR and CR + CB neurons, scattered both in the superficial and deep layers. These findings are discussed in the light of similar observations recently reported from other regions of the human brain.

Adult↗
PubMed1995

Pathology of subcortical visual centres in relation to cortical degeneration in Alzheimer's disease.

Subcortical visual centres such as the lateral geniculate nucleus, the lateral inferior pulvinar and the superior colliculus, together with the primary visual cortex and its adjacent white matter, were studied in 12 Alzheimer brains and five age-matched controls. The periodic acid methenamine technique was used for the demonstration of senile plaques and the Gallyas technique for neurofibrillary tangles and neuritic threads in the neuropil. In the lateral geniculate nucleus and inferior pulvinar, the presence of periodic acid methenamine-positive senile plaques was observed in variable numbers in all Alzheimer cases. In the lateral geniculate nucleus, senile plaques were encountered more often in parvocellular than in magnocellular layers, in the interlaminar zones, in the optic radiation and in the adjacent pre-geniculate nucleus. Gallyas staining did not reveal any neurofibrillary tangles, neuritic threads or neuritic plaques, meaning that in this thalamic region there are mainly amyloid deposits without neuritic degeneration. In the superior colliculus both amyloid and neuritic plaques, as well as neurofibrillary tangles and neuritic threads were encountered in the superficial and deep layers. In the primary visual cortex, all types of senile plaques were observed as well as a rather high number of neurofibrillary lesions in pyramidal neurons, mainly in layers 5 and 6, but also in several types of non-pyramidal neurons. In the underlying white matter there was a morphologically heterogeneous population of neurofibrillary tangle-bearing neurons and a considerable number of threads representing degenerating axons, suggesting that degeneration could follow corticosubcortical connections. These data demonstrate that lesions in the primary visual structures and pathways are more prevalent than previously observed and could partly explain the visual disturbances in Alzheimer's disease.

Aged↗
PubMed1994

Changes in volume, surface estimate, three-dimensional shape and total number of neurons of the human primary visual cortex from midgestation until old age.

Macroscopic features such as volume, surface estimate, thickness and caudorostral length of the human primary visual cortex (Brodman's area 17) of 46 human brains between midgestation and 93 years were studied by means of camera lucida drawings from serial frontal sections. Individual values were best fitted by a logistic function from midgestation to adulthood and by a regression line between adulthood and old age. Allometric functions were calculated to study developmental relationships between all the features. The three-dimensional shape of area 17 was also reconstructed from the serial sections in 15 cases and correlated with the sequence of morphological events. The sulcal pattern of area 17 begins to develop around 21 weeks of gestation but remains rather simple until birth, while it becomes more convoluted, particularly in the caudal part, during the postnatal period. Until birth, a large increase in cortical thickness (about 83% of its mean adult value) and caudorostral length (69%) produces a moderate increase in cortical volume (31%) and surface estimate (40%) of area 17. After birth, the cortical volume and surface undergo their maximum growth rate, in spite of a rather small increase in cortical thickness and caudorostral length. This is due to the development of the pattern of gyrification within and around the calcarine fissure. All macroscopic features have reached the mean adult value by the end of the first postnatal year. With aging, the only features to undergo significant regression are the cortical surface estimate and the caudorostral length. The total number of neurons in area 17 shows great interindividual variability at all ages. No decrease in the postnatal period or in aging could be demonstrated.

Adolescent↗
PubMed1989

Comparison of neuronal and glial numerical density in primary and secondary visual cortex of man.

The numerical density of neurons and glial cells was estimated in visual area 18 of the adult human cerebral cortex and compared with that of area 17. Blocks of areas 17 and 18 came from the same brains and this allowed the comparison of 1) neuronal and glial numerical densities through the whole cortical depth with calculation of the neuron/glia ratio, 2) neuronal and glial numbers under one square millimeter of cortical surface, and 3) neuronal numerical densities in three groups of identified layers. The mean neuronal density is approximately 40,000 neurons/mm3 in area 17 and 31,500/m3 in area 18. The mean glial density is around 27,000/mm3 in area 17 and 32,000/mm3 in area 18. This gives a neuron/glia ratio of approximately 1.5 in area 17 and of 1.0 in area 18, but the total cellular density is similar in both areas. There are about 90,000 neurons and 64,000 glial cells under one square millimeter of cortical surface in area 17, and some 73,000 neurons and 74,000 glial cells in area 18. The higher neuronal density in area 17 is found through the whole depth of cortex and does not seem to be more pronounced in layer IVc of area 17 compared to layer IV in area 18 than in the groups of layers II-III and V-VI.

Adolescent↗
PubMed1989

Sample size and statistical power in the hierarchical analysis of variance: applications in morphometry of the nervous system.

Analysis of variance is commonly used in morphometry in order to ascertain differences in parameters between several populations. Failure to detect significant differences between populations (type II error) may be due to suboptimal sampling and lead to erroneous conclusions; the concept of statistical power allows one to avoid such failures by means of an adequate sampling. Several examples are given in the morphometry of the nervous system, showing the use of the power of a hierarchical analysis of variance test for the choice of appropriate sample and subsample sizes. In the first case chosen, neuronal densities in the human visual cortex, we find the number of observations to be of little effect. For dendritic spine densities in the visual cortex of mice and humans, the effect is somewhat larger. A substantial effect is shown in our last example, dendritic segmental lengths in monkey lateral geniculate nucleus. It is in the nature of the hierarchical model that sample size is always more important than subsample size. The relative weight to be attributed to subsample size thus depends on the relative magnitude of the between observations variance compared to the between individuals variance.

Aging↗
PubMed1987

Evolution of neuronal numerical density in the developing and aging human visual cortex.

Neuronal numerical density in area 17 of the human cerebral cortex was estimated over a wide range of ages from mid-gestation to old age. The density at 21 weeks of gestation is very high (over one million/mm3) and decreases steeply but regularly until birth, when it is around 90,000 neurons/mm3. It continues to decrease until about 4 months postnatally, when it reaches values of about 40,000 neurons/mm3. Thereafter neuronal density remains more or less stable and the mean value for young adults is about 35,000 neurons/mm3. Values for supragranular, granular and infragranular layers follow a similar temporal sequence and also stabilize a few months postnatally. However, until 31 weeks of gestation, the granular layer IVc has a slightly lower neuronal density than that of the supragranular zone including layers II, III, IVa and b. Around birth, the neuronal density of layer IVc is about double that in supragranular layers and remains relatively high in the adult. With aging the cortical neuronal density again increases slightly, reaching a mean of 44,000 neurons/mm3 for five cases aged over 80 years. The number of neurons under one square millimeter of cerebral cortex also undergoes a very steep decrease until birth, stabilizes a few months after birth and seems to remain stable in adult and old age. We find no conclusive evidence for neuronal loss with aging.

Adolescent↗
PubMed1986

A quantitative study of neuronal and glial numerical density in the visual cortex of the bottlenose dolphin: evidence for a specialized subarea and changes with age.

Neuronal and glial numerical densities were measured in the lateral gyrus of the cerebral hemisphere of dolphins (Tursiops truncatus) from the neonatal period to adulthood. The cortex studied is the area known to be visually excitable in evoked potential studies. Two distinct parts of the adult lateral gyrus are identifiable, one relatively anterior, in which neuronal density is 23,000/mm3, the other more posterior, with almost double this density. In a neonate, the neuronal density in the anterior lateral gyrus was found to be more than double that of the adult. No samples from the immature posterior area were available. Glial density varies much less than neuronal density, both with age and between areas. Soon after birth the glia/neuron ratio is 1.6 in anterior lateral gyrus, rising to around 3 in the adult anterior lateral area, and rather less in the posterior region, where neuronal density is high. We speculate that the existence of a high numerical density of neurons in the posterior part of the dolphin visual cortex could perhaps indicate a specialized area corresponding to the primate primary visual cortex, also known to have high neuronal density.

Age Factors↗
PubMed1985

Morphology of axons in the human lateral geniculate nucleus: a Golgi study in prenatal and postnatal material.

A study was made of rapid Golgi preparations from the lateral geniculate nucleus in humans aged from 28 weeks gestation to 70 years in order to identify axon terminals of afferent fibre systems. We describe three main axonal types using, as far as possible, nomenclature already adopted for other species. Type I axons were found only rarely. They are relatively straight with short, stalked side-branches and may represent cortico-geniculate fibres. Type II axons have complex, ball-like arborizations with large, irregular varicosities. They are common at all ages from gestation to maturity and are probably retinal in origin. Type IV axons (Type III was not used as no unequivocally intrinsic axons, for which the term has been used in the past, were identified) are branched, meandering and characterized by many, regular varicosities. Their origin is unclear, but may be related to non-specific brainstem sources. The basic morphology of Type II axons varies little between late gestation and adulthood, but Types I and IV seem to evolve during the perinatal period, perhaps from primitive forms that have similar morphological features. We conclude that the morphology of afferent axons to the human lateral geniculate nucleus is basically similar to that of lower mammalian species.

Adolescent↗
PubMed1984

Orientation of dendrites in the lateral geniculate nucleus of the monkey.

Quantitative analysis of dendritic orientation in rapid Golgi sections of the lateral geniculate nucleus of Old World monkeys was performed with the help of a computer-microscope and a tree-analysing program. The orientation of intermediate and terminal dendritic segments of parvocellular and magnocellular multipolar neurons was measured at different ages in relationship to a reference line defined by the major direction of afferent fibres visualized in Golgi preparations and by silver staining. The direction of fibre bundles crossing the nucleus is approximately perpendicular to the layers near their apex, but more oblique laterally and medially. There is a clear tendency for terminal dendritic segments of both parvocellular and magnocellular neurons to be oriented preferentially along these fibres and fewer are perpendicular to them. The orientation of intermediate segments is much less clear, showing a more random orientation with regard to the fibres. There is no obvious influence of the order of branching or of the age of the animal (between late gestation and maturity) on the orientation of terminal and intermediate dendritic segments. A parallel study (Leuba and Garey 1984) suggests that there is greater plasticity in the terminal part of the dendritic tree, and it is possible that the maturation of afferent fibres causes these terminal segments to orient along them very early during normal development.

Age Factors↗
PubMed1984

Development of dendritic patterns in the lateral geniculate nucleus of monkey: a quantitative Golgi study.

Quantitative analysis of dendritic branching patterns was performed in rapid Golgi sections of the lateral geniculate nucleus of Old World monkeys at several ages, using a computer-microscope and a tree-analysing program. In parvocellular and magnocellular multipolar neurons the dendrites were analysed in centrifugal order and according to whether they were intermediate or terminal segments. Between late gestation and birth there is an increase in the mean length of dendrites, and in the total length of dendrites per neuron, more pronounced in magnocellular layers; there follows a progressive decrease in their length until adulthood. However, only terminal dendritic segments are involved in these changes in length. Intermediate segments are shorter and show a more or less constant length throughout life. The final length of a segment seems more determined by it being terminal or intermediate than by its order of branching and there is greater plasticity in the terminal part of the dendritic tree. Magnocellular neurons are characterized by a greater number of both intermediate and terminal segments than parvocellular neurons but not by a greater length of individual segments. This accounts for the greater dendritic length in magnocellular neurons and may offer them a larger surface for synaptic connectivity.

Animals↗