bluuebunny/crossref_metadata_2025 huggingface dataset:
Blood Levels of Alpha-1-Antichymotrypsin and Risk Factors for Alzheimer’s Disease: Effects of Gender and Apolipoprotein E Genotype
Authors: Licastro Federico , Masliah Eliezer , Pedrini Steve , Thal Leon J.
Published: April 2003

Concentrations of α1-antichymotrypsin (ACT) were measured in serum or plasma samples from 137 patients with late-onset probable Alzheimer’s disease (AD) and 89 controls. Levels of ACT from sera or plasma from both AD or controls were different, being highest in serum samples. Increased levels of serum or plasma ACT and normal levels of C-reactive protein (CRP) were found in AD. Differences in serum ACT levels between AD and controls were statistically significant, while those in plasma ACT were not. ACT serum levels were higher in women with AD that in female and male controls. Apolipoprotein E (APOE) genotypes did not independently affect blood ACT levels in both AD and controls; although, among AD patients, female AD patients with APOE 4,4 showed the highest level of serum ACT. The gender effect appeared to be prominent, since female AD patients with APOE 3,3 had similar ACT levels to those of female AD patients with APOE 4,4.
A Study of Remote Memory Impairment in Alzheimer’s Disease by Using the Family Line Test
Authors: Kazui Hiroaki , Hashimoto Mamoru , Hirono Nobutsugu , Imamura Toru , Tanimukai Satoshi , Hanihara Tokiji , Ikeda Manabu , Komori Kenjiro , Ikejiri Yoshitaka , Mori Etsuro
Published: April 2003

We evaluated remote autobiographical memory impairment in 25 patients with probable Alzheimer’s disease (AD) and 25 sex-, age- and education-matched healthy subjects by using a newly developed, highly effective assessment tool for remote memory, the Family Line Test (FLT). The FLT yields a total score, scores for 3 lifetime periods and the duration of remote memory impairment. In the patients with AD, the total score was significantly lower and the duration of remote memory impairment was significantly longer than in the healthy controls. A prominent temporal gradient in remote memory impairment was documented in the patients with AD. The total FLT score and duration of remote memory impairment correlated with recent memory and general cognitive dysfunctions.
Absorption of Aluminium-26 in Alzheimer’s Disease, Measured Using Accelerator Mass Spectrometry
Authors: Moore P. Brian , Day J. Philip , Taylor Geoffrey A. , Ferrier I. Nicol , Fifield L. Keith , Edwardson James A.
Published: April 2003

Although chromosomal abnormalities underpin some early onset cases of familial Alzheimer’s disease (AD), most cases are sporadic and not associated with such abnormalities. Aluminium (Al) is a significant but controversial risk factor for sporadic AD, and studies have reported associations between Al and the principal pathological features of AD, senile plaques and neurofibrillary tangles. The present study measured gastrointestinal (GI) absorption of Al under normal dietary conditions using 26Al tracer and accelerator mass spectrometry (AMS). Following overnight fast, 13 AD patients (aged 63–76 years) and 13 age-matched controls (aged 62–76 years) ingested a fruit drink containing 27 ng 26Al. Plasma samples were obtained before and 1 h after the drink and from these the fraction of 26Al absorbed across the GI tract was estimated. The GI tract rigorously excludes Al with only 0.06–0.1% of the ingested Al being absorbed. The mean fraction absorbed by AD subjects exceeded controls by a factor of 1.64 (p≤0.05, Anova). AMS is capable of determining <10–16 g of 26Al with many orders of magnitude more sensitivity than other techniques. Using this sensitivity, we have shown, under normal physiological conditions, that the ability of the GI tract to exclude Al is reduced in AD, possibly leading to greater systemic exposure to Al. Public health measures to limit Al dietary uptake or bioavailability may decrease the prevalence of AD in the community and should be considered.
Medial Temporal Lobe Width on CT Scanning in Alzheimer’s Disease: Comparison with Vascular Dementia, Depression and Dementia with Lewy Bodies
Authors: O’Brien J.T. , Metcalfe S. , Swann A. , Hobson J. , Jobst K. , Ballard C. , McKeith I. , Gholkar A.
Published: April 2003

A simple linear measurement of the minimum width of the medial temporal lobe (MTL) on angled CT scans has been suggested as an accurate ante-mortem marker for Alzheimer’s disease (AD). To determine the clinical utility and specificity of this finding, we performed angled CT scans with 5-mm slices in 116 subjects referred to a geographically based Old Age Psychiatry service in Newcastle. Diagnoses were of NINCDS/ADRDA AD (n = 69, 36 probable and 33 possible). NINDS/AIREN vascular dementia (VaD, n = 25), consensus criteria for dementia with Lewy bodies (DLB, n = 9) and DSM-IV criteria for major depression (n = 13). Subjects were well matched for age. Minimum MTL width was significantly greater in depressed subjects (13.7 mm) compared to those with dementia, though no differences were seen within the dementia groups (AD 10.8, VaD 10.4, and DLB 10.9 mm). An MTL width below 11.5 mm had a sensitivity of 54% (56/103) and a specificity of 77% (10/13) for distinguishing dementia from depression. We conclude that a single cross-sectional measurement of MTL width on CT does not help differentiate between different types of dementia, though it may provide some supportive evidence when distinguishing depression from dementia.
Estrogen Receptor Gene Polymorphisms in Patients with Alzheimer’s Disease, Vascular Dementia and Alcohol-Associated Dementia
Authors: Ji Y. , Urakami K. , Wada-Isoe K. , Adachi Y. , Nakashima K.
Published: April 2003

The association between the estrogen receptor (ER-α) gene and dementia was examined in 223 patients with Alzheimer’s disease (AD), 66 with vascular dementia (VD), 17 with alcohol-associated dementia (ALD) and 134 healthy elderly control subjects. The PvuII and XbaI restriction fragment length polymorphisms of the ER-α gene were represented as Pp (PvuII) and Xx (XbaI), with capital letters signifying the absence of restriction sites and small letters the presence of restriction sites. We found that the frequency of the ER-α gene P allele and X allele in the late-onset AD (LOAD) group (P allele was 0.51, X allele was 0.30) was significantly higher than that in controls (P 0.38, p < 0.01; X 0.20, p < 0.01), and that the frequency of the ER-α gene P allele and PP genotype was significantly different between apolipoprotein E ε4 carriers and noncarriers in LOAD. These findings suggest that the genotype of the ER-α gene may be specific in LOAD, and that the ER-α gene was an additional risk for LOAD.
A Longitudinal Population Study of the Mini-Mental State Examination in the Very Old: Relation to Dementia and Education
Authors: Aevarsson Ólafur , Skoog Ingmar
Published: April 2003

We examined the Mini-Mental State Examination (MMSE) in relation to the prevalence and incidence of dementia in a representative population sample (n = 494), followed from age 85 to 88. The study included a neuropsychiatric examination (including the MMSE) and a key informant interview conducted by a psychiatrist. Dementia was defined according to the DSM-III-R. Among non-demented 85-year-olds, 75% of those who scored below the cut-off score of 23/24 and 37% of those scoring 24–25 became demented during the follow-up. Non-demented 85-year-olds who did not develop dementia during the following 3 years had a mean decline in MMSE score of 0.6 per year, while those who became demented decreased by 2.3 points per year. A decrease of 4 or more points during the 3 years had a sensitivity of 83% and a specificity of 80% for a diagnosis of dementia. High and low MMSE score at base-line was related to a smaller decrease in MMSE score between age 85 and 88. Higher education was related to higher scores on MMSE at age 85 and to a smaller decline in scores between age 85 and 88. Change in MMSE score in non-demented individuals is small especially among individuals with high education. Non-demented individuals scoring below 26 should receive close attention, as a high proportion are at risk of developing dementia.
Cholesterol Modulates the Membrane- Disordering Effects of Beta-Amyloid Peptides in the Hippocampus: Specific Changes in Alzheimer’s Disease
Authors: Eckert G.P. , Cairns N.J. , Maras A. , Gattaz W.F. , Müller W.E.
Published: April 2003

Cholesterol represents an important determinant of the physical state of biological membranes. In Alzheimer’s disease (AD) brains, specific changes in the distribution of cholesterol and its membrane-ordering effects take place. In the present study, membrane fluidity was investigated at the level of the hydrocarbon core and of the heads of the phospholipid bilayers using two different fluorescent probes. Hippocampal membranes of AD brains showed a reduced fluidity in the hydrocarbon core region only. Fluidity was correlated with the cholesterol content in AD and control membranes. Aggregated β-amyloid peptides (Aβ) disrupted brain membrane structure in AD patients and controls in the same fashion. However, this effect was correlated with the cholesterol content in AD membranes only. It is suggested that in AD the brain becomes specifically sensitive for the modulation by membrane-bound cholesterol of the membrane-disturbing and ultimately neurotoxic properties of Aβ.
The Expression of Presenilin 1 mRNA in Skin Fibroblasts and Brains from Sporadic Alzheimer’s Disease
Authors: Ikeda Kazuyuki , Urakami Katsuya , Arai Hiroyuki , Wada Kenji , Wakutani Yosuke , Ji Yong , Adachi Yoshiki , Okada Akitsugu , Kowa Hisanori , Sasaki Hidetada , Ohno Kousaku , Ohtsuka Yuzuru , Ishikawa Yukihiro , Nakashima Kenji
Published: April 2003

We examined the expression of presenilin 1 (PS-1) mRNA in cultured skin fibroblasts taken from living patients with Alzheimer’s disease (AD) and human brains taken postmortem from AD patients by RT-PCR analysis. The donors of fibroblasts consisted of 28 cases with AD and 19 neurological patient without dementia (CTL). The brains came from 17 cases with AD and 23 cases with CTL. We found that PS-1 mRNA levels in skin fibroblasts of AD patients were significantly higher than those of CTL patients (p < 0.0001). Moreover, we found that PS-1 mRNA levels in human brains with AD were significantly higher than in those with CTL (p < 0.0001). These findings suggest that high levels of PS-1 mRNA in AD may play an important role in developing AD and that the examination of PS-1 mRNA in skin fibroblasts may be helpful for the diagnosis of AD.
Frontotemporal Dementia Can Be Distinguished from Alzheimer’s Disease and Subcortical White Matter Dementia by an Anterior-to-Posterior rCBF-SPET Ratio
Authors: Sjögren Magnus , Gustafson Lars , Wikkelsö Carsten , Wallin Anders
Published: April 2003

Sixteen patients with frontotemporal dementia (FTD), 27 with early-onset Alzheimer’s disease, 25 with late-onset Alzheimer’s disease, 19 with subcortical white matter dementia (SWD) and 28 normal controls underwent semiquantitative regional cerebral blood flow measurement (rCBF) using single-photon emission tomography (SPET; 99mTc-HMPAO) and either computerized tomography (CT) or magnetic resonance imaging (MRI) of the brain. An anterior-to-posterior rCBF-SPET ratio (mesial superior frontal gyrus/medial temporal lobes) was calculated, which significantly separated the FTD group from the other dementia groups and controls with a sensitivity of 87.5% and a specificity of at least 78.6%. CT/MRI was found to be helpful in the differential diagnosis between FTD and SWD. In FTD patients, the mesial superior frontal gyrus, near the polus frontalis, was found to be the region with the most reduced rCBF values.
Impaired Processing of Famous Faces in Alzheimer’s Disease Is Related to Neurofibrillary Tangle Densities in the Prefrontal and Anterior Cingulate Cortex
Authors: Giannakopoulos Panteleimon , Gold Gabriel , Duc Myriam , Michel Jean-Pierre , Hof Patrick R. , Bouras Constantin
Published: April 2003

To examine the neuroanatomical correlates of impaired processing of famous faces in Alzheimer’s disease (AD), we performed an anterograde clinicopathological study of 25 patients with clinically and neuropathologically confirmed AD. Famous face recognition, identification and naming was assessed using the Famous Face Test. The assessment of neurofibrillary tangle (NFT) and senile plaque (SP) densities was performed in ten cortical areas in both hemispheres, and statistical analysis was made using forward stepwise logistic regression models. A statistically significant relationship was found between NFT densities in Brodmann’s areas 9 and 24 in both hemispheres and impaired famous face naming and identification. SP counts did not correlate with any of the neuropsychological parameters. These data suggest that NFT formation in prefrontal and anterior cingulate cortex, two areas involved in semantic memory processes, is a key event in famous face naming and identification deficits. In agreement with previous studies, they also indicate that SP densities are not a good pathological correlate of neuropsychological deficits in AD.
Temporospatial Relationships between Macroglia and Microglia during in vitro Differentiation of Murine Stem Cells
Authors: Angelov D.N. , Arnhold S. , Andressen C. , Grabsch H. , Puschmann M. , Hescheler J. , Addicks K.
Published: April 2003

Embryonic stem (ES) cells of the permanent line BLC6 derived from a 129/Sv Gat mouse blastocyst were differentiated as spheroid aggregates (embryoid bodies, EBs) in the presence of retionic acid. After 2 days in suspension, EBs were plated on gelatine-coated glass coverslips and cultivated for 5, 9, and 16 days post plating (DPP) in normal medium. In this study we investigated whether the well-known retinoic acid-induced differentiation of ES cells into neurons (identified by immunostaining for neuron-specific enolase and synaptophysin) was accompanied by cells expressing astroglial (GFAP), oligodendroglial (O4), and microglial (5C6, galectin-3) markers. Whereas differentiation of neurons was closely related to their centrifugal migration towards the periphery of the EBs, the maturation of neuroglia followed a strict time-dependent manner. At 5 DPP, only neurons but no cells expressing glia-specific markers, were observed. At 9 DPP, GFAP-positive and O4-positive macroglial cells appeared. At 16 DPP, microglial cells (5C6-positive and galectin-3-positive) occurred. The established dynamic of relationships between neuronal and nonneuronal cells shows that the model of EBs is similar to the sequence differentiation of the nervous tissue. Thus, enabling in vivo observation of neurons, astrocytes, oligodendrocytes, and microglia, the model of EBs provides a basis for further investigations on the relationships between neurons and neuroglia under various experimental conditions.
Dopaminergic and Glutamatergic Interactions in the Expression of Self-Injurious Behavior
Authors: King Bryan H. , Cromwell Howard C. , Lee Hoa T. , Behrstock Soshana P. , Schmanke Troy , Maidment Nigel T.
Published: April 2003

Self-injurious behavior occurring in persons with severe mental retardation is a clinically significant and poorly understood problem. Multiple neurotransmitter systems have been implicated in the pathogenesis of this behavior, particularly dopaminergic, opioidergic, and serotonergic systems. Pemoline, a central stimulant, administered systemically at high doses reliably produces self-biting behavior in the rat. The systemic bolus of pemoline produces sustained neostriatal levels of pemoline for over 24 h in a continuous infusion paradigm. Studies of the effect of cortical lesions on pemoline-mediated behaviors reveal that cortical damage, as is common in profound mental retardation, lowers the threshold for pemoline-induced self-biting behavior. Data from the corticostriatal slice suggests that sustained exposure to pemoline produces a shift in N-methyl-D-aspartate receptor-mediated responses rendering them more susceptible to dopaminergic enhancement. Thus, dopaminergic and glutamatergic interactions appear to play an important role in the development and expression of self-biting in the pemoline model.
Landmarks in the Application of 13C-Magnetic Resonance Spectroscopy to Studies of Neuronal/Glial Relationships
Authors: Bachelard H.
Published: April 2003

The development of the use of carbon isotopes as metabolic tracers is briefly described. 13C-labelled precursors (13CO2, 13CH4) first became available in 1940 and were studied in microorganisms, but their use was limited by very low enrichments and lack of suitable analytical equipment. More success was achieved with 11C and especially 14C, as these radioactive tracers did not need to be highly enriched. Although the stable 13C isotope can be used at a low percentage enrichment in mass spectrometry, its application to magnetic resonance spectroscopy (MRS) requires very highly enriched precursors, due to its low natural abundance and low sensitivity. Despite such limitations, however, the great advantage of 13C-MRS lies in its exquisite chemical specificity, in that labelling of different carbon atoms can be distinguished within the same molecule. Effective exploitation became feasible in the early 1970s with the advent of stable instruments, Fourier transform 13C-MRS, and the availability of highly enriched precursors. Reports of its use in brain research began to appear in the mid-1980s. The applications of 13C isotopomer analysis to research on neuronal/glial relationships are reviewed. The presence of neighbouring 13C-labelled atoms affects the appearance of the resonances (splitting due to C–C coupling), and so allows for unique quantification of rates through different and possibly competing pathways. Isotopomer patterns in resonances labelled from a combination of [1-13C]glucose and [1,2-13C2]acetate have revealed aspects of neuronal/glial metabolic trafficking on depolarization and under hypoxic conditions in vitro. This approach has now been applied to in vivo studies on inhibition of glial metabolism using fluoroacetate. The results confirm the glial specificity of the toxin and demonstrate that it does not affect entry of acetate. When the glial TCA cycle is inhibited, the ability of the glia to participate in the glutamate/glutamine cycle remains unimpaired, in that labelling of glutamine, which can only be derived from neuronal metabolism of glucose, persists. The results also confirmed earlier evidence that part of the GABA transmitter pool is derived from glial glutamine.
Evidence Supporting the Existence of an Activity-Dependent Astrocyte-Neuron Lactate Shuttle
Authors: Pellerin Luc , Pellegri Giovanni , Bittar Philippe G. , Charnay Yves , Bouras Constantin , Martin Jean-Luc , Stella Nephi , Magistretti Pierre J.
Published: April 2003

Mounting evidence from in vitro experiments indicates that lactate is an efficient energy substrate for neurons and that it may significantly contribute to maintain synaptic transmission, particularly during periods of intense activity. Since lactate does not cross the blood-brain barrier easily, blood-borne lactate cannot be a significant source. In vitro studies by several laboratories indicate that astrocytes release large amounts of lactate. In 1994, we proposed a mechanism whereby lactate could be produced by astrocytes in an activity-dependent, glutamate-mediated manner. Over the last 2 years we have obtained further evidence supporting the notion that a transfer of lactate from astrocytes to neurons might indeed take place. In this article, we first review data showing the presence of mRNA encoding for two monocarboxylate transporters, MCT1 and MCT2, in the adult mouse brain. Second, by using monoclonal antibodies selectively directed against the two distinct lactate dehydrogenase isoforms, LDH1 and LDH5, a specific cellular distribution between neurons and astrocytes is revealed which suggests that a population of astrocytes is a lactate ‘source’ while neurons may be a lactate ‘sink’. Third, we provide biochemical evidence that lactate is interchangeable with glucose to support oxidative metabolism in cortical neurons. This set of data is consistent with the existence of an activity-dependent astrocyte-neuron lactate shuttle for the supply of energy substrates to neurons.
Ketone Bodies and Brain Glutamate and GABA Metabolism
Authors: Daikhin Yevgeny , Yudkoff Marc
Published: April 2003

The effects of ketone bodies on brain metabolism of glutamate and GABA were studied in three different systems: synaptosomes, cultured astrocytes and the whole animal. In synaptosomes the addition of either acetoacetate or 3-OH-butyrate was associated with diminished consumption of glutamate via transamination to aspartate and increased formation of labelled GABA from either L-[2H5-2,3,3,4,4]glutamine or L-[15N]glutamine. There was no effect of ketone bodies on synaptosomal GABA transamination. An increase of total forebrain GABA and a diminution of aspartate was noted when mice were injected intraperitoneally with 3-OH-butyrate. In cultured astrocytes the addition of acetoacetate to the medium was associated with a significantly enhanced rate of citrate production and with a diminution in the rate of conversion of [15N]glutamate to [15N]aspartate. These data are consistent with the hypothesis that the metabolism of ketone bodies to acetyl-CoA results in a diminution of the pool of brain oxaloacetate, which is consumed in the citrate synthetase reaction (oxaloacetate + acetyl-CoA → citrate). As less oxaloacetate is available to the aspartate aminotransferase reaction, thereby lowering the rate of glutamate transamination, more glutamate becomes accessible to the glutamate decarboxylase pathway, thereby favoring the synthesis of GABA.
Excitotoxicity and Oxidative Stress during Inhibition of Energy Metabolism
Authors: Zeevalk G.D. , Bernard L.P. , Sinha C. , Ehrhart J. , Nicklas W.J.
Published: April 2003

Glutamate receptor involvement and oxidative stress have both been implicated in damage to neurons due to impairment of energy metabolism. Using two different neuronal in vitro model systems, an ex vivo chick retinal preparation and dopamine neurons in mesencephalic culture, the involvement and interaction of these events as early occurring contributors to irreversible neuronal damage have been examined. Consistent with previous reports, the early acute changes in the retinal preparation, as well as irreversible loss of dopamine neurons due to inhibition of metabolism, can be prevented by blocking NMDA receptors during the time of energy inhibition. Oxidative stress was suggested to be a downstream consequence and contributor to neuronal cell loss due to either glutamate receptor overstimulation or metabolic inhibition since trapping of free radicals with the cyclic nitrone spin-trapping agent MDL 102,832 (1 mM) attenuated acute excitotoxicity in the retinal preparation or loss of mesencephalic dopamine neurons due to either metabolic inhibition by the succinate dehydrogenase inhibitor, malonate, or exposure to excitotoxins. In mesencephalic culture, malonate caused an enhanced efflux of both oxidized and reduced glutathione into the medium, a significant reduction in total reduced glutathione and a significant increase in total oxidized glutathione at time points that preceded those necessary to cause toxicity. These findings provide direct evidence for early oxidative events occurring following malonate exposure and suggest that the glutathione system is important for protecting neurons during inhibition of energy metabolism. Consistent with this, lowering of glutathione by buthionine sulfoxamine (BSO) pretreatment greatly potentiated malonate toxicity in the mesencephalic dopamine population. In contrast, BSO pretreatment did not potentiate glutamate toxicity. This latter finding indicates dissimilarities in the type of oxidative stress that is generated by the two insults and suggests that the oxidative challenge during energy inhibition is not solely a downstream consequence of glutamate receptor overstimulation.
Motoneurones That Innervate the Rat Soleus Muscle Mature Later than Those to the Tibialis anterior and Extensor digitorum longus Muscles
Authors: Sanusi Junedah , Greensmith Linda , Lowrie Margaret B. , Vrbová Gerta
Published: April 2003

The response of motoneurones that innervate either the soleus or tibialis anterior (TA) and extensor digitorum longus (EDL) muscles to increased locomotor activity or to nerve injury at different stages after birth was examined. Inceased locomotor activity of rat pups was induced by daily treatment with L-dopa during the first 12 days after birth, and the number of surviving motoneurones to the soleus or TA/EDL muscles was established by retrograde labelling. Treatment with L-dopa resulted in the loss of a significant number of motoneurones within the soleus motor pool but had no effect on the survival of those motoneurones innervating the TA/EDL. Furthermore, following nerve injury during the first few days postnatally, more motoneurones within the soleus motor pool die than in the TA/EDL pool. These results indicate that motoneurones to the soleus muscle mature later than those to the TA/EDL muscles.
Postnatal Development of Dopamine D1-Like Receptors in Rat Cortical and Striatolimbic Brain Regions: An Autoradiographic Study
Authors: Tarazi Frank I. , Tomasini Eric C. , Baldessarini RossJ.
Published: April 2003

Postnatal development of dopamine D1-like (D1/D5) receptors in rat caudate-putamen (CPu), nucleus accumbens (NAc), hippocampus, frontal and entorhinal cerebral cortex was assessed between postnatal days (PD) 7–60 by in vitro receptor autoradiography. Density of [3H]SCH-23390 binding to D1-like receptors increased from PD-7 to a peak at PD-28 in CPu (11-fold) and NAc (23-fold), then declined by 20–40% in both regions over PD-35–60, to adult levels. In hippocampus, frontal and entorhinal cortex, D1-like receptors increased by lesser amounts (3- to 4-fold) from PD-7 to stable, maximal adult levels at PD-60. Evidently, excess D1-like receptors were eliminated during maturation of CPu and NAc, but not in the other forebrain regions. Postnatal D1-like receptor development in rat forebrain paralleled that of D2- and D4-like receptors in the same regions.
Regional Age-Dependent Effects of Hemineodecortication upon Contralateral Neocortical Thickness: Comparison with Other Measures of Cortical Size
Authors: Schmanke Troy D. , Villablanca Jaime R.
Published: April 2003

This study investigated age-dependent changes in regional neocortical thickness after hemineodecortication in cats and compared the results to previously reported volumetric and cross-sectional data. Subjects sustained hemineodecortication on postnatal days (P) P10, P30, P60 or in adulthood. Neocortical thickness was quantified at 115 sites along 20 stereotaxic coronal anterior-posterior (AP) planes using defined sites of the main cerebral sulci for the measurements. The analysis established significantly lower thickness values for adult-lesioned as compared to (a) P30, P60 and control groups at AP +14, (b) P30 group at 7 planes along a range of AP +9 to AP +3, and (c) P10 and P60 groups at AP +6. Both the P10 and the P30 groups presented a significantly thicker neocortex than controls at select coronal planes clustering behind AP +10 (parietal and temporal cortices). When analyzed by sulcus, results once again reflected significant advantages for the early-lesioned cats with a significantly thicker cortex found at 4 of the 8 sulci examined. Again, significant advantages were also discovered for early-lesion subjects compared with control cats (splenial, cruciate sulci). Overall, the range of significant effects (from AP +14 to AP 0) and the direction of the means suggested that there was a significant, age-dependent (P10–P60), regional sparing of neocortical thickness with a peak effect occurring at P30. We concluded that: (a) there was a regional sparing/increase of neocortical thickness suggesting that discrete cortical areas are selectively involved in the resistance to structural atrophy following hemineodecortication in young cats (P10–P60) and (b) the global loss of neocortex volume found in our previous study was not apparent using the present thickness measurement. It is suggested that both of these measurements must be taken into account when assessing morphological effects upon the neocortex either in human pathology (i.e. hemispherectomy, intractable epilepsy) or in animal models.
Chronic Epilepsy in Developing Hippocampal Neurons: Electrophysiologic and Morphologic Features
Authors: Niesen Charles E. , Ge Shundi
Published: April 2003

Despite the susceptibility of immature neurons to seizures, there are few models of epilepsy in the developing brain. By taking advantage of activity-dependent developmental changes in young neurons, we have developed a novel model of chronic epilepsy in cultured hippocampal slices. Incubating slices in tetrodotoxin (TTX) for at least 1 week produced significant changes in the electrical activity and appearance of CA1 pyramidal neurons. Extracellular recordings revealed multiple population spikes, and, in whole-cell recordings, evoked synaptic potentials lasting hundreds of milliseconds with many superimposed action potentials were present. Spontaneous firing with burst-like discharges was also evident. These changes were secondary to increased AMPA-receptor-mediated responses and decreased GABAA receptor events. Altered membrane properties involved increased expression of T-type Ca2+ channels which are normally down-regulated in these neurons. TTX-treated neurons also showed abnormal dendritic branching. This model of chronic epilepsy in developing hippocampal neurons demonstrated many changes at the membrane, cellular and synaptic level that may provide new insights into the nature of epileptogenesis in the young brain.
Development of a Model of Status epilepticus in Pigtailed Macaque Infant Monkeys
Authors: Gunderson Virginia M. , Dubach Mark , Szot Patricia , Born Donald E. , Wenzel H. Jurgen , Maravilla Kenneth R. , Zierath Dannielle K. , Robbins Carol A. , Schwartzkroin Philip A.
Published: April 2003

Seizures, particularly multiple episodes and/or status epilepticus (SE) are prevalent in pediatric patients. Pediatric SE is associated with brain changes that have been hypothesized to contribute to the onset of temporal lobe epilepsy (TLE). In order to gain insight into the effects of seizures on the immature brain and the risk for later TLE, we have developed a model of limbic SE in the pigtailed macaque monkey. In separate studies, bicuculline methiodide or a bicuculline ‘cocktail’ was infused into three regions of the brain (area tempestas, hippocampus, entorhinal cortex) to induce seizures. Measures included MRI, electrophysiology, behavior and morphology. Our results suggest that monkey models of SE may provide useful tools for understanding the effects of prolonged seizures during infancy and the origins of TLE in humans.
Electrophysiological Observations in Hippocampal Slices from Rats Treated with the Ketogenic Diet
Authors: Stafstrom Carl E. , Wang Carl , Jensen Frances E.
Published: April 2003

The electrophysiological effects of the high-fat, low-carbohydrate ketogenic diet (KD) were assessed in normal and epileptic [kainic-acid(KA)-treated] adult rats using hippocampal slices. In the first set of experiments, normal rats were fed the KD or a standard control diet for 6–8 weeks (beginning on postnatal day 56, P56), after which they were sacrificed for hippocampal slices. All rats on the KD became ketotic. The baseline effects of the KD were determined by comparing extracellular measures of synaptic transmission and responses to evoked stimulation, and hippocampal excitability was tested in Mg2+-free medium. There were no differences in EPSP slope, input/output relationship, responses to evoked stimulation or Mg2+-free burst frequency between slices from control and KD-fed rats. In another set of experiments, rats were made epileptic by intraperitoneal injection of kainic acid (KA) on P54, which caused status epilepticus followed by the development of spontaneous recurrent seizures (SRS) over the next few weeks. Two days after KA-induced status, rats were divided into a control-fed group and a KD-fed group. Animals on the KD had significantly fewer SRS over the ensuing 8 weeks. In hippocampal slices from KA-treated, KD-fed rats, there were fewer evoked CA1 population spikes than from slices of control-fed rats. These results suggest that the KD does not alter baseline electrophysiological parameters in normal rats. In rats made chronically epileptic by administration of KA, KD treatment was associated with fewer spontaneous seizures and reduced CA1 excitability in vitro. Therefore, at least part of the KD mechanism of action may involve long-term changes in network excitability.
Cognitive Development in Benign Focal Epilepsies of Childhood
Authors: Metz-Lutz Marie-Noëlle , Kleitz Catherine , de Saint Martin Anne , Massa Rita , Hirsch Edouard , Marescaux Christian
Published: April 2003

Benign focal epilepsy of childhood (BFEC) is the most common form of epilepsy, in children from 3 to 12 years. Its prognosis is always favourable as far as the epilepsy is concerned. Nevertheless, recent clinical data suggest that children affected by BFEC are more likely to show learning difficulties and behavioural disturbances than their peers. We report here the preliminary findings of a prospective study of 22 children affected with BFEC. Electroclinical and neuropsychological changes observed during the first 18 months of the follow-up strengthen the conclusion of recent neuropsychological studies stressing the correlation between epilepsy and cognitive performances. The cognitive deficits affecting mainly non-verbal functions were significantly correlated with the frequency of seizures and spike-wave discharges and to the lateralization of the epileptic focus in the right hemisphere, whereas frontal functions like attention control, response organization and fine motor speed, were impaired in the presence of active BFEC independently of the lateralization of the epileptic focus. Our results indicate that maturing cognitive functions subserved by a cortical area distant from the epileptic focus are susceptible to interference with epilepsy.
Hippocampal Sclerosis: Development in Adult Life
Authors: Jackson G.D. , Chambers B.R. , Berkovic S.F.
Published: April 2003

Hippocampal sclerosis (HS) is the most common pathological lesion underyling intractable temporal lobe epilepsy. It is not known whether HS exists before the onset of epilepsy or whether it is caused by seizures. Its has been proposed that childhood seizures cause HS. Optimized magnetic resonance imaging (MRI), hippocampal volumes and T2 signal quantitation were performed 2 weeks and 8 months following at tonic-clonic seizure in a 23-year-old man. MRI 14 days after the seizure showed symmetrical hippocampal volumes (ratio R/L = 1.03) with intact internal architecture bilaterally but marked signal change in the right hippocampus (T2 right = 121, T2 left = 103, normal ≤108 ms). Eight months later this hippocampus showed severe atrophy with a volume ratio of 0.65 and T2 values of 117 (right) and 109 ms (left). High-resolution imaging showed that volume loss occurred mainly in the CA1 region which showed high signal in the initial study. Characteristic MRI features of HS can develop in adults and HS cannot always be assumed to have its origins in childhood. Hypoxia in the context of seizures may be an important component in hippocampal damage. HS may be a preventable lesion and MRI signal change seen in the neuronal layers of the hippocampus may be an indication for neuroprotection.
Noggin Is a Negative Regulator of Neuronal Differentiation in Developing Neocortex
Authors: Li Weiwei , LoTurco Joseph J.
Published: April 2003

Bone morphogenetic proteins (BMPs) trigger neuronal differentiation of neocortical precursors within the ventricular zone (VZ) [Li et al. (1998): J Neurosci 18:8853–8862]. BMP-2/4 protein is concentrated at the VZ surface and BMPs rapidly promote the differentiation of neocortical precursors in both dissociated cell and explant cultures. Noggin binds to BMP-2/4 with high affinity, and prevents binding to cell surface receptors. In the present study, we used human recombinant noggin protein to determine whether endogenous BMP-2/4 triggers neuronal differentiation in dissociated cell culture. We find that noggin inhibits the differentiation of neocortical neurons: noggin decreases the number of MAP-2- and TUJ1-positive cells after 24 h of treatment, yet has no effect on either proliferation or cell survival. Noggin also significantly decreases neurite growth of MAP-2-positive cells. In addition, using Western blot analysis we show that noggin protein is present in developing cortex at E15. These results are consistent with previous results showing that endogenous BMPs trigger neuronal differentiation in the neocortical VZ and also indicate that a balance of noggin and BMP may regulate the differentiation of neocortical neurons in vivo.
Timing and Competence of Neural Crest Formation
Authors: Basch Martín L. , Selleck Mark A.J. , Bronner-Fraser Marianne
Published: April 2003

Neural crest cells can be induced by an interaction between neural plate and ectoderm. To clarify the timing and nature of these inductive interactions, we have examined the time of competence of the neural plate to become neural crest as well as the time of neural fold specification. The neural plate is competent to respond to inductive interactions with the nonneural ectoderm for a limited period, rapidly losing its responsive ability after stage 10. In contrast, nonneural ectoderm from numerous stages retains the ability to induce neural crest cells from competent neural plate. When neural folds are explanted to test their ability to produce neural crest without further tissue interactions, we find that folds derived from all rostrocaudal levels of the open neural plate are already specified to express the neural crest marker Slug. However, additional signals may be required for maintenance of Slug expression, since the transcript is later down-regulated in vitro in the absence of tissue interactions. Taken together, these results suggest that there are multiple stages of neural crest induction. The earliest induction must have occurred by the end of gastrulation, since the newly formed neural fold population is already specified to form neural crest. However, isolated neural folds eventually down-regulate Slug, suggesting a second phase that maintains neural crest formation. Thus, induction of the neural crest may involve multiple and sustained tissue interactions.
Striatal Ionotropic Glutamate Receptor Ontogeny in the Rat
Authors: Nansen Elizabeth A. , Jokel Eve S. , Lobo Mary Kay , Micevych Paul E. , Ariano Marjorie A. , Levine Michael S.
Published: April 2003

Rat striatal N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and kainate (KA) receptor staining were evaluated postnatally in the rat. Immunohistochemistry was used to detect subunit proteins of the three glutamate receptor subtypes. The glutamate receptors displayed distinct developmental expression patterns in the striatum. Morphological distributions for the NMDA R1 subunit (representative of NMDA receptors), Glu R1 and Glu R2/3 subunits (indicative of AMPA receptors), and Glu R5/6/7 subunits (demonstrating KA receptors) attained adult expression patterns and levels at different postnatal time points. The ontogenic maturation sequence of striatal glutamate receptor expression was KA, then AMPA and lastly NMDA. Staining patterns for NMDA and AMPA subunit proteins were detected initially as dense patches in the neuropil, which changed to a homogeneous stain of the striatum by the second week of life. Cellular staining for the three subtypes was intense within the highly reactive neuropil patches, but less intensely stained in neurons located outside these zones. The KA receptor subunit did not exhibit neuropil heterogeneity, but was distributed evenly at birth. All three glutamate receptor subtypes were visible within the striatal neuron populations. Populations of striatal neurons that expressed the three differential glutamate receptor subtypes overlap, exhibit different growth patterns and dendritic staining. These results support a functional emergence of different glutamate receptor activation within the striatum and provide a potential therapeutic means to isolate developmental disorders specifically associated with excitatory circuits of the basal ganglia.
Role of Mitochondria in Neuronal Apoptosis
Authors: Gorman Adrienne M. , Ceccatelli Sandra , Orrenius Sten
Published: April 2003

Apoptosis is a controlled form of cell death that participates in the demise of neuronal cells during development, neurodegenerative disorders and exposure to neurotoxic agents. In recent years, the mitochondria have emerged as being pivotal in controlling apoptosis. They house a number of apoptogenic molecules that are released into the cytoplasm at the onset of apoptosis. These include cytochrome c, apoptosis-inducing factor and various caspases. Mitochondria also play an important role in intracellular Ca2+ regulation, which is crucial to excitotoxic neurodegeneration. Alterations in energy (ATP) production by mitochondria (due to hypoxia or mutations in genes encoding mitochondrial proteins of the electron transport chain) can induce apoptosis in neurons or increase their sensitivity to apoptosis.
Oral Retinoids in the Treatment of Seborrhoea and Acne
Authors: Orfanos C.E. , Zouboulis Ch.C.
Published: April 2003

Isotretinoin is an extremely effective drug if given systemically in severe forms of seborrhoea and acne, being the only retinoid with potent sebostatic properties. Its unique activity on the sebaceous gland still remains unclear since isotretinoin barely binds to cellular retinoic-acid-binding proteins and to retinoic acid receptors. Its bioavailability is approximately 25% and can be increased by food 1.5–2 times; after 30 min, the drug is detectable in the blood and maximal concentrations are reached 2–4 h after oral intake. The major metabolites of isotretinoin in blood are 4-hydroxy- and 4-oxo-isotretinoin, while several glucuronides are detectable in the bile. 4-Oxo-isotretinoin is present in plasma in a 2- to 4-fold higher concentration 6 h after a single dose. Steady-state concentrations appear after 1 week. The half-life elimination rate of the parent compound ranges from 7 to 37 h while that of some metabolites does so from 11 to 50 h. Isotretinoin crosses the placenta and is recognized as a strong teratogenic compound. About 10–30% of the drug is metabolized via its isomer tretinoin. Excretion of isotretinoin occurs after conjugation with the faeces or after metabolization with the urine. The epidermal levels of isotretinoin are rather low and no progressive accumulation, either in serum or in the skin, is found. After discontinuation of therapy, isotretinoin disappears from serum and skin within 2–4 weeks. Isotretinoin is the most effective drug in reducing sebaceous gland size (up to 90%) by decreasing proliferation of basal sebocytes, suppressing sebum production and inhibiting sebocyte differentiation in vivo. The molecular basis for its antisebotrophic activity has not been fully elucidated. Isotretinoin also exhibits anti-inflammatory activities. Systemic isotretinoin is today the regimen of choice in severe seborrhoea, since it reduces sebocyte lipid synthesis by 75% with daily doses as low as 0.1 mg/kg after 4 weeks. Patients who have received oral isotretinoin therapy for seborrhoea do not usually experience a relapse for months or years. In severe acne, a 6- to 12-month treatment with isotretinoin 1 mg/kg/day reduced to 0.5 or 0.2 mg/kg/day according to the response is recommended (cumulative dose of >120 mg/kg). Contraception is essential during isotretinoin treatment in women of childbearing age 1 month before, during and for 3 months after discontinuation of treatment.
Other Antiandrogens
Authors: Schmidt J.B.
Published: April 2003

Various substances of steroidal or nonsteroidal structure may serve as an alternative for the antiandrogenic treatment of acne. Compounds with antiandrogenic properties like cimetidine or ketoconazole are rarely administered for acne due to their weak effects. In contrast, spironolactone is an effective antiandrogen that shows good treatment effects in hirsutism and acne. Side effects occur frequently and are dose dependent. Isotretinoin – the most effective agent in acne therapy – has been under discussion for additional antiandrogenic properties for years. At present there is additional evidence for the antiandrogenic effects of isotretinoin. Regarding substances acting on both levels, androgen receptor binding and 5α-reductase inhibition, the question is raised whether the term ‘antiandrogen’ should be amplified by including the 5α-reductase inhibitors. This would pay tribute to the biological aspect of antiandrogenicity that takes into account not only the mode of action but also the effects of the substance. Under this aspect type 1 5α-reductase inhibitors may gain attention in the future.
A New Concept of Drug Delivery for Acne
Authors: Shroot B. , Michel S. , Allec J. , Chatelus A. , Wagner N.
Published: April 2003

Adapalene is a stable naphthoic acid derivative that displays a strong retinoid agonist pharmacology. This drug controls cell proliferation and differentiation, and possesses significant anti-inflammatory action. The retinoid action of adapalene are mediated by the ligand-activated gene transcription factors retinoic acid receptors RARβ and RARγ. We describe here how an aqueous gel containing adapalene was selected for the topical treatment of acne.
Activity of 5-Alpha-Reductase and 17-Beta-Hydroxysteroid Dehydrogenase in the Infrainfundibulum of Subjects with and without Acne vulgaris
Authors: Thiboutot D. , Knaggs H. , Gilliland K. , Lin G.
Published: April 2003

Linoleic acid deficiency, interleukin 1, retinoids and androgens have been implicated as causative factors in the follicular hyperkeratinization seen in acne. The goal of this study was to test the hypothesis that more androgens are produced in follicles of acne subjects compared to subjects without acne. Thirty-four subjects (males and females with and without acne) were studied. The activity of 5α-reductase (5α-R) and 17β-hydroxysteroid dehydrogenase (17β-HSD) was determined in keratinocytes cultured from the infrainfundibulum and epidermis. Mean enzyme activities were slightly higher in the acne groups compared to the groups without acne, but differences were not statistically significant, perhaps due to limitations of this in vitro model. The activity of both 5α-R and 17β-HSD was significantly greater in infrainfundibular keratinocytes compared to epidermal keratinocytes in all subject groups. 17β-HSD activity was 2.5- to 7-fold greater than the activity of 5α-R in infrainfundibular keratinocytes. The regulation of 17β-HSD by endogenous factors may be important in determining the directional activity of 17β-HSD and hence the local concentration of testosterone within the infrainfundibulum. Additional studies of the effects of androgens on follicular keratinization are needed.
The Isolation and Characterization of Androgen-Dependent Genes in the Flank Organs of Golden Syrian Hamsters
Authors: Ideta R. , Seki T. , Adachi K. , Nakayama Y.
Published: April 2003

To elucidate the molecular action of androgens, we have isolated two androgen-dependent genes, FAR-17a and -17c, from the cDNA library of flank organs of male golden Syrian hamsters by a differential hybridization method. FAR-17a has been reported previously. Androgens regulated the expression in the flank organs, ear lobe and skin. FAR-17a protein was located in sebaceous glands. FAR-17c has a similar expression pattern to that of FAR-17a, but its response to androgen is faster than that of FAR-17a. It is expressed strongly in the liver, sebaceous glands and brain. The homology search and mRNA expression pattern suggested that it might encode a stearyl CoA desaturase (SCD) of golden Syrian hamsters. The SCD is a key enzyme in fatty acid biosynthesis and its expression is controlled by temperature, nutritional conditions and hormones. This is the first report that the mRNA expression of stearyl CoA is regulated by androgens.