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Biomedical subjects

L Hansen

Publications and source records attributed to L Hansen.

At least 145 records · Page 8Linked to original sources
PubMed1993

Differing patterns of aberrant neuronal sprouting in Alzheimer's disease with and without Lewy bodies.

About one quarter of Alzheimer's disease patients have been found to have concomitant subcortical and neocortical Lewy bodies (LBs). We compared the aberrant neuronal sprouting and the extent of neuritic and synaptic damage in these Lewy body variants of Alzheimer's disease (LBV), with the same pathologic alterations in Alzheimer's disease without LBs (AD). More of the thioflavine-S-positive senile plaques of the LBVs contained growth associated protein 43 (GAP-43), a marker of neuritic growth and sprouting. Compared to AD, the LBVs had 39% more GAP-43-positive plaques in the frontal cortex, and 53% more in the hippocampus. These neuritic alterations were accompanied by an accumulation of amyloid precursor protein and phosphorylated neurofilaments. Synapse loss was the same in LBV and AD. These results suggest more extensive aberrant neuronal sprouting in LBV than in AD.

Aged↗
PubMed1993

Sex differences and estrous cycle-variations in the AF64A-induced cholinergic deficit in the rat hippocampus.

The influence of gender and stage of the estrous cycle on the levels of acetylcholine, serotonin, and noradrenaline in the hippocampus and on the susceptibility of the cholinergic septo-hippocampal pathway to the neurotoxic effect of ethylcholine aziridinium (AF64A) was investigated in the rat. Levels of acetylcholine and serotonin were consistently higher in female rats during the stage of diestrus and proestrus than in age-matched male rats (p < 0.05). Across the estrous cycle the highest levels of acetylcholine and serotonin, coinciding with the lowest levels of noradrenaline, were measured on proestrus. Eight to 10 days after the bilateral intracerebroventricular injection of a submaximal dose of AF64A (1 nmol/ventricle) the decrease of acetylcholine in hippocampus was larger in females than in male rats. The reduction of acetylcholine was most pronounced in female rats that had received submaximal doses of AF64A on proestrus (42.7 +/- 3.4%), whereas in male rats, the corresponding decrease was 25.9 +/- 5.1% (p < 0.05). At a maximal dose of AF64A (2 nmole/ventricle), the sex-specific or cycle-dependent difference in the cholinotoxicity of AF64A vanished. The dose-dependent loss of acetylcholine was associated with a secondary dose-dependent decrease in the levels of serotonin and noradrenaline, but significant differences between male and female rats or stages of estrous cycle were not apparent. The present data provide evidence that adult female rats in general, and particularly females on proestrus, are more susceptible to the neurotoxic action of submaximal doses of AF64A than age-matched male rats.

Animals↗
PubMed1993

Neurotransmitters in basal ganglia and cortex of Alzheimer's disease with and without Lewy bodies.

We measured the concentrations of the monoamines, their precursors, and their metabolites, and the activity of choline acetyltransferase (ChAT) in basal ganglia and cortical regions of postmortem brains from cases with histologically verified pure Alzheimer's disease (AD), AD with diffusely distributed Lewy bodies (Lewy body variant [LBV]), and normal controls. Dopamine and homovanillic acid (HVA) were severely depleted in basal ganglia of the LBV cases but were not significantly altered in pure AD cases; tyrosine hydroxylase levels in putamen were also significantly reduced in LBV but not AD cases. These reductions in basal ganglia dopamine and HVA suggest that LBV cases have a level of dopamine depletion similar to Parkinson's disease (PD). Additionally, ChAT activity in caudate and norepinephrine concentration in putamen were significantly reduced in the LBV group, which may have contributed to the absence of resting tremor and the milder presentation of parkinsonian features in this group compared with classic PD. In frontal, parietal, and temporal cortex, activity of ChAT in the LBV group was significantly reduced compared with controls and lower than in pure AD.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1993

Quantitative synaptic alterations in the human neocortex during normal aging.

We quantified the synaptic population density in the frontal cortex of 25 individuals without dementia 16 to 98 years old, using sections double-immunolabeled for beta/A4 amyloid and for synaptophysin, and found a significant inverse correlation between the presynaptic terminal (PT) counts and age (r = -0.7, p < 0.001). Individuals older than 60 years had an average 20% decrease in PT density compared with individuals younger than 60 years. There were no significant correlations between the age and the number of beta/A4 amyloid-positive plaques or between synaptic density and the number of amyloid plaques. Further analysis of the digitized serial optical images showed focal areas of synapse loss and distended synaptophysin-containing boutons in the mature plaques of the normal aged cases. However, we found no microscopic changes in the synaptic content inside and outside the diffuse plaques. We suggest that a loss of synaptic input in the neocortex is an age-dependent factor that contributes to the overall synaptic loss in Alzheimer's disease, but that this might be largely independent of the beta/A4-amyloid deposition.

Adolescent↗
PubMed1993

An antibody against phosphorylated neurofilaments identifies a subset of damaged association axons in Alzheimer's disease.

We studied axonal damage in Alzheimer's disease frontal cortex and hippocampus with a novel monoclonal antibody (SMI 312) against phosphorylated neurofilaments. This antibody immunolabeled, with great detail, the neuropil axonal network. In aged normal cases only a few pyramidal cell perikarya were immunostained. In Alzheimer's disease there was a two- to four-fold increase in neuronal SMI 312 immunolabeling, and neuropil neuritic processes were severely disrupted. Double-immunolabeling analysis showed that 88% of SMI 312-immunolabeled abnormal neuritic clusters were associated with amyloid, whereas the remaining 12% were not. Serial section analysis and 3-D reconstructions suggested that dystrophic neurites of classical plaques were derived from long axons. These abnormal neurites were also growth-associated protein 43 positive and occasionally tau positive. The present study supports the contention that a subpopulation of aberrantly sprouting axons in the neuritic plaque is derived from cortico-cortico fibers. This disruption of the neocortical association fibers and neuritic microcircuitry could underlie the cognitive impairment of Alzheimer's disease.

Aged↗
PubMed1992

[Can Doppler ultrasound replace strain gauge in the measurement of ankle blood pressure?].

Traditionally, strain gauge technique is used in Denmark to measure ankle blood pressure, a method requiring both time and well-trained personnel. In a study involving 90 limbs in 45 patients, this method was compared with ultrasonic technique using a portable 5 MHz Doppler. The reproducibility of Doppler ankle pressure measurement was similar to that found in strain gauge based studies. Two consecutive measurements may differ by 20 mmHg or in terms of ankle-brachial index by 0.15 before this is considered significant. No systematic variation was found between the two methods. Increasing difficulties were encountered with the Doppler technique at pressures below 50 mmHg. It is concluded that Doppler is a good alternative to strain gauge for measurement of ankle blood pressure.

Aged↗
PubMed1992

The gamma-aminobutyric acid (GABA) uptake inhibitor, tiagabine, increases extracellular brain levels of GABA in awake rats.

The effect of systemic administration of the gamma-aminobutyric acid (GABA) uptake inhibitor, R(-)N-(4,4-di(3-methyl-thien-2-yl)-but-3-enyl) nipecotic acid, hydrochloride (tiagabine) (previously NO-328), on extracellular GABA levels in the globus pallidus, ventral pallidum and substantia nigra of awake Sprague-Dawley rats was investigated using in vivo microdialysis. Tiagabine was administered in doses of 11.5 or 21.0 mg/kg i.p. (ED50 and ED85 doses, respectively, for inhibiting pentylenetetrazole-induced tonic seizures). Tiagabine increased the extracellular concentrations of GABA in globus pallidus with peak values 310% of basal level (after 21 mg/kg) and 240% of basal level (after 11.5 mg/kg). A significant increase in extracellular GABA levels was also found in the ventral pallidum (280% increase after 11.5 mg/kg and 350% increase after 21 mg/kg) and in the substantia nigra where the ED85 dose of tiagabine (21 mg/kg) produced a peak value of 200% compared to the basal level. Thus, tiagabine acts as a GABA uptake inhibitor in vivo also.

Analysis of Variance↗
PubMed1992

Localization of amyloid precursor protein in GAP43-immunoreactive aberrant sprouting neurites in Alzheimer's disease.

Previous in vitro studies have suggested that amyloid precursor protein (APP) could be involved in cell surface adhesion, neuritic growth and survival of hippocampal neurons. In the present study, involvement of APP in aberrant sprouting in Alzheimer's disease (AD) was studied by comparing immunolabeling patterns of anti-APP and anti-growth-associated protein 43 (anti-GAP43). Confocal laser imaging of frontal cortex sections double-immunolabeled for APP and GAP43 showed an increase, in AD, of presynaptic boutons immunostained with anti-GAP43 that contained anti-APP immunoreactivity. The neuritic plaques in AD cases presented intense anti-GAP43 immunoreactive abnormal neurites colocalized with anti-APP. Three-dimensional reconstruction of the plaques showed that anti-APP was colocalized with anti-GAP43 in 57.5% of the aberrant sprouting neurites. We conclude that co-expression of APP with GAP43 in the plaque might be involved in the aberrant sprouting response observed in AD.

Aged↗
PubMed1992

Switching from differentiation to growth in hepatocytes: control by extracellular matrix.

Studies were carried out to analyze how different extracellular matrix (ECM) molecules regulate hepatocyte growth and differentiation. Freshly isolated rat hepatocytes were cultured on non-adhesive plastic dishes that were pre-coated with defined densities of either laminin, fibronectin, type I collagen, or type IV collagen. Sparse cell plating densities were used to minimize cell-cell contact formation and all studies were carried out in chemically defined medium that contained a saturating amount of soluble growth factors. Dishes coated with a low ECM density (1 ng/cm2) supported hepatocyte attachment, but did not promote cell spreading or growth. Computerized image analysis confirmed that over 80% of cells remained free of contact with other cells under these conditions. Yet, these round cells maintained high levels of albumin gene expression as well as elevated secretion rates for multiple liver-specific proteins (albumin, transferrin, and fibrinogen), regardless of the type of ECM molecule used for cell attachment. When ECM coating densities were raised from 1 to 1,000 ng/cm2, cell spreading, expression of histone mRNA, DNA synthesis, and cell proliferation all increased in parallel. Activation of growth by high ECM densities was also accompanied by a concomitant down-regulation of differentiated functions and again, dishes coated with all four types of ECM molecules produced similar effects. Thus, the ability to switch hepatocytes from differentiation to growth (i.e., between different genetic programs) is not limited to a single ECM molecule, a distinct three dimensional ECM geometry, or due to alteration of cell-cell interactions. Rather, the regulatory signals conveyed by immobilized ECM molecules depend on the density at which they are presented and thus, on their ability to either prohibit or support cell spreading.

Animals↗
PubMed1992

Three-dimensional analysis of the relationship between synaptic pathology and neuropil threads in Alzheimer disease.

Recent studies have shown that the Alzheimer disease (AD) neocortex is characterized by a loss of large neurons, the presence of dilated terminal axons, widespread loss of synapses, and a disruption of the dendritic cytoskeleton which is manifested as Tau immunoreactive threads. In the present study we have investigated the relationship between synaptic and dendritic abnormalities in the neocortex of Alzheimer patients and examined the extent to which these structural alterations correlate with the severity of cognitive impairment in AD. Quantitative neuroanatomical data were obtained from immunofluorescence-labeled specimens using a laser-scanning confocal microscope, computer-assisted image processing and serial section reconstruction techniques. We found that the AD cases showed a 34% loss in the number of presynaptic terminals per 100 square (sq) microns, many of which showed structural abnormalities. The AD neuropil had an average of 10 +/- 7 dendritic threads per 1,000 sq microns, with the average thread measuring 2 sq microns. Severe AD cases had thicker threads compared with mild to moderate AD cases. Three-dimensional analysis showed clustering of synapses around threads, as well as presynaptic boutons apposed to dendritic neuropil threads. Statistical analysis showed that the strongest correlation was between synapse density and Blessed score of cognitive impairment. Thread counts did not correlate with either but were correlated with tangle counts. Stepwise multiple regression analysis showed that tangle counts, but not threads, strengthened the correlation between Blessed score and synapses. We conclude that synaptic damage may precede dendritic thread and tangle formation, and that threads do not necessarily induce synaptic pathology. Instead, dendrite sprouting in the denervated regions could be associated with increased accumulation of cytoskeletal proteins observed in the dendritic threads.

Aged↗
PubMed1992

Normal human synovial fluid and articular cartilage contain similar intact proteoglycans.

This work, directed to characterization of proteoglycans present in normal human synovial fluid by Western blotting techniques, revealed an intimate relationship of these proteoglycans to those of articular cartilage. Analyses were performed on samples subjected to digestion with chondroitinase ABC, in the presence or absence of keratanase, yielding products containing core proteins with glycosaminoglycan side chain stubs. The proteoglycan core proteins contained epitopes reactive with monoclonal antibodies that distinguish between chondroitin sulfate-4 and chondroitin sulfate-6. Additionally, these products reacted with monoclonal antibody to keratan sulfate when keratanase was omitted from the digestion. The analysis of synovial fluid revealed that the proteoglycan core proteins expressed predominantly the chondroitin sulfate-6 epitope, with expression of the chondroitin sulfate-4 epitope demonstrable only in prepubertal individuals. There was coexpression of both chondroitin sulfate epitopes in all proteoglycan core proteins of prepubertal individuals. Coexpression of chondroitin sulfate and keratan sulfate epitopes occurred in all proteoglycan core proteins. Proteoglycan core proteins had M(r) similar to those obtained from articular cartilage. Hence, in individuals free of joint disease, most proteoglycans seem to be transferred from articular cartilage to the synovial fluid without major alteration in the apparent size of the proteoglycan core protein. Only a minor set of proteoglycan core proteins had no direct articular cartilage equivalent. As this set also contained keratan sulfate, it is likely to be of articular cartilage origin, but probably modified by proteolysis.

Adolescent↗
PubMed1992

Clozapine and D1/D2 antagonism in extrapyramidal functions.

One of the main advantages of clozapine is that it rarely produces extrapyramidal syndromes and tardive dyskinesia. This advantage is linked to the atypical biochemical profile of clozapine, especially its combined and low blockade of D1 and D2 receptors. The level of D2 receptor blockade is too low to induce extrapyramidal side-effects, and D1 antagonists have a lower extrapyramidal side-effect potential than traditional D2 neuroleptics, especially with respect to dystonia. The combined and balanced D1/D2 receptor blockade may prevent the development of a dysbalance between D1/D2 receptor function (in favour of D1) which otherwise might lead to tardive dyskinesia.

Animals↗
PubMed1992

Casein kinase II alteration precedes tau accumulation in tangle formation.

Previous studies have shown altered casein kinase II (CK-II) in Alzheimer's disease (AD). For the present study, the authors analyzed CK-II immunoreactivity at various stages of tangle formation using quantitative laser confocal microscopy and immunoelectron microscopy. AD hippocampal pyramidal cells without neurofibrillary tangles (NFTs) displayed 15% more anti-tau immunoreactivity (P less than 0.01) and 43% more anti-CKII immunolabeling than controls (P less than 0.001). In AD, tangle-bearing hippocampal neurons with strong anti-tau immunoreactivity (threefold increase from controls) showed a significant 22% increase in anti-CKII immunolabeling (P less than 0.01), compared with those without NFTs. Neurons with early neurofibrillary changes showed diffuse anti-CKII immunostaining in their cytoplasm and cell processes. In tangle-bearing neurons, in which a higher level of tau immunoreactivity was detected, anti-CKII immunolabeling was distributed along a fibrillar meshwork in cell bodies and processes. Linear regression analysis of anti-CKII and anti-tau immunoreactivity in AD showed a positive correlation (r = 0.53, P less than 0.001). At the ultrastructural level, anti-CKII was immunolocalized to the paired helical filaments (PHF) of the tangle-bearing neurons, as well as to PHF in neuropil threads and some dystrophic neurites in plaques. These results suggest a possible role for CK-II in tangle formation.

Aged↗