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Objectives: The epsilon 4 allele of apolipoprotein E (ApoE) is a risk factor for late onset Alzheimer's disease. ApoE is present in senile plaques, neurofibrillary tangles, and cerebrovascular amyloid, and it is implicated in synaptogenesis. The effect of ApoE polymorphism on the volumes of hippocampus, amygdala, and frontal lobe was studied. The hypothesis was that the patients with Alzheimer's disease carrying the epsilon 4 allele have more pronounced atrophy. The relation of ApoE and cerebral blood flow on cortical areas was also assessed.Methods: Fifty eight patients with Alzheimer's disease at the early stage of the disease and 34 control subjects were studied. Patients with Alzheimer's disease were divided into subgroups according to the number of the epsilon 4 alleles. Volumes were measured by MRI and regional cerebral blood flow ratios referred to the cerebellum were examined by 99mTc-HMPAO SPECT. ApoE genotypes were determined by digestion of ApoE polymerase chain reaction products with the restriction enzyme Hha1.Results: patients with Alzheimer's disease had smaller volumes of hippocampi and amygdala compared with control subjects, and the patients with Alzheimer's disease homozygous for the epsilon 4 allele had the most prominent volume loss in the medial temporal lobe structures. The frontal lobe volumes did not differ significantly. All patients with Alzheimer's disease had bilateral temporoparietal hypoperfusion and the subgroups with one or no epsilon 4 alleles also had frontal hypoperfusion compared with control subjects. The occipital perfusion ratios tended to decrease with increasing number of epsilon 4 alleles.Conclusions: Patients with Alzheimer's disease homozygous for the epsilon 4 allele seem to have severe damage in the medial temporal lobe structures early in the disease process and differ from the patients with Alzheimer's disease with one or no epsilon 4 alleles. [ABSTRACT FROM AUTHOR]

Abstract The role of the α2C-adrenoceptor subtype in mediating the beneficial effect of α2-adrenoceptor agonists on spatial working memory was studied in adult mice with targeted inactivation of the α2C-receptor gene (KO) and their wild-type controls (WT). A delayed alternation task was run in a T-maze with mixed delays varying from 20 s to 120 s. Dexmedetomidine, a specific but subtype non-selective α2-adrenoceptor agonist, dose-dependently decreased the total number of errors. The effect was strongest at the dose of 5 μg/kg (s.c.), and was observed similarly in KO and WT mice. KO mice performed inferior to WT mice due to a higher number of perseverative errors. Dexmedetomidine slowed initiation of the motor response in the start phase at lower doses in WT mice than in KO mice but no such difference was observed in the return phase of the task, suggesting involvement of α2C-adrenoceptors in the cognitive aspect of response preparation or in response sequence initiation. According to these findings, enhancement of spatial working memory is best achieved with α2-adrenoceptor agonists which have neither agonistic nor antagonistic effects at the α2C-adrenoceptor subtype. [ABSTRACT FROM AUTHOR]

The present study was designed to investigate the effects of combined treatment with a serotonin (5-HT) receptor agonist, 8-hydroxy-2-(dipropylamino)-tetralin (8-OH-DPAT), and a muscarinic acetylcholine receptor antagonist, scopolamine, on water maze (WM) navigation. Treatment with either 8-OH-DPAT or scopolamine before daily behavioral training disrupted spatial navigation at medium doses and cue navigation at high doses. Pretraining treatment with a combination of subthreshold doses of 8-OH-DPAT and scopolamine impaired WM spatial and cue navigation, but did not impair the WM performance if the drugs were injected post-training. In trained rats, combined injections of subthreshold doses of 8-OH-DPAT and scopolamine given pretraining did not impair the rats' ability to find the platform in a familiar or in a novel position. The combination of 8-OH-DPAT and scopolamine also disrupted WM navigation in rats with central 5-HT depletion. A combination of a peripheral muscarinic acetylcholine receptor antagonist and 8-OH-DPAT had no effect on WM navigation. These data suggest that combined treatment with drugs blocking muscarinic acetylcholine receptors and activating 5-HT receptors greatly impairs WM learning/performance, but does not impair spatial memory per se. [ABSTRACT FROM AUTHOR]

Objective: Recent evidence indicates that the apolipoprotein E (ApoE) epsilon4 allele is a risk factor for developing Alzheimer's disease. It has also been proposed that it is associated with increased counts of amyloid plaques and neurofibrillary tangles that in turn are neuropathological hallmarks initially appearing in the medial temporal lobe structures in Alzheimer's disease. In this study, the effect of the ApoE epsilon4 allele on the volume of the entorhinal cortex was evaluated in vivo.Methods: The volume of the entorhinal cortex was measured on MR images using a recently designed histology based protocol in 16 patients with Alzheimer's disease with ApoE epsilon4 (mean age 70.4 (SD 9.9)), 11 patients with Alzheimer's disease without ApoE epsilon4 (mean age 69.1 (SD7.1)), and in 31 healthy age and sex matched normal controls (72.2 (SD 3.9)). The patients met the NINCDS-ADRDA criteria for probable Alzheimer's disease and were in mild to moderate stages of the disease. MRI was performed with a 1.5 Tesla Magnetom and a 3D technique permitting the reconstruction of 2.0 mm thick contiguous slices perpendicular to the axis of the anterior-posterior commissure.Results: The patients with Alzheimer's disease without the ApoE epsilon4 allele had atrophy in the entorhinal cortex, the volume was reduced by 27% compared with control subjects. However, the most prominent shrinkage (45%) in the entorhinal cortex was seen in patients with Alzheimer's disease with the ApoE epsilon4 allele (p=0.0001). The effect of epsilon4 on the entorhinal cortex volume was especially prominent in female patients with Alzheimer's disease compared to male patients with Alzheimer's disease (p=0.014). Additionally, patients with the ApoE epsilon4 allele had inferior performance in verbal and visual memory functions than those without the alleleConclusions: Volumetric MRI measurements disclose that ApoE epsilon4 is associated with the degree of atrophy in the entorhinal cortex in early Alzheimer's disease, this effect being especially prominent in female patients with Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Objectives: In mild Alzheimer's disease, SPECT imaging of regional cerebral blood flow has highlighted deficits in the posterior association cortex, and later in the disease process, the deficit spreads to involve the frontal cortex. The sigma4 allele of apolipoprotein E is a risk factor for Alzheimer's disease. The effect of apolipoprotein E polymorphism on cerebral perfusion was studied. The hypothesis was that those patients with Alzheimer's disease who carry the sigma4 allele would have more severe cerebral hypoperfusion.Methods: Thirty one patients with Alzheimer's disease and eight age and sex matched control subjects were examined in a three year longitudinal study. Patients with Alzheimer's disease were divided into subgroups according to their number of sigma4 alleles. Regional cerebral blood flow ratios referred to the cerebellum were examined by 99mTc-HMPAO SPECT. Apolipoprotein E genotypes were determined by digestion of polymerase chain reaction products with the restriction enzyme Hha1.Results: All patients with Alzheimer's disease had bilateral temporoparietal hypoperfusion compared with control subjects. The two sigma4 allele subgroups had the lowest ratios at the baseline assessment in the parietal and occipital cortices, and at the follow up in the temporal, parietal, and occipital cortices. They had the highest reduction in percentage terms in the temporal and occipital cortices compared with the other subgroups. However, the global clinical severity did not differ at the baseline or follow up examinations between the subgroups.Conclusion: Apolipoprotein E polymorphism is involved in the pathogenesis and heterogeneity of Alzheimer's disease as the most severe cerebral hypoperfusion was found in the sigma4 allele subgroups. This might have implications for therapeutic approaches in Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Preoperative and postoperative cognitive and memory functions, psychiatric outcome, and EEGs were evaluated in 32 epileptic patients who underwent temporal lobe surgery. The presence and location of preoperative slow wave focus in routine EEG predicted memory functions of the non-resected side after surgery. Neuropsychological tests of the function of the frontal lobes also showed improvement. Moreover, psychiatric ratings showed that seizure free patients had significantly less affective symptoms postoperatively than those who were still exhibiting seizures. After temporal lobectomies, successful outcome in postoperative memory functions can be achieved in patients with unilateral slow wave activity in preoperative EEGs. This study suggests a new role for routine EEG in preoperative evaluation of patients with temporal lobe epilepsy. [ABSTRACT FROM AUTHOR]

The antipanic effect and tolerability of alprazolam and imipramine were compared during 9 weeks in 55 inpatients with panic disorder with or without agoraphobia. Both drugs decreased significantly the frequency of panic attacks, alprazolam as early as 3 weeks of treatment. The symptoms of generalized anxiety and depression decreased similarly in both groups. The tolerability of alprazolam appeared slightly better than that of imipramine. Drug-induced anticholinergic side-effects were more frequent in the imipramine group,whereas sedation, impotency, and myoclonic jerks appeared more often in the alprazolam group. [ABSTRACT FROM AUTHOR]

Using several concentrations of eight anticonvulsant drugs in clinical use (carbamazepine, clonazepam, phenytoin, phenobarbital, ethosuximide, primidone, sodium valproate, and D,L-γ-vinyl GABA), we studied their abilities in vitro to displace (35S)t-butylbicyclophosphorothionate (35S-TBPS) from its binding site in a homogenate of rat brain. Thereafter ethosuximide (150 mg/kg), phenobarbital (30 mg/kg), clonazepam (0.3 mg/kg), or phenytoin (100 mg/kg) was injected intraperitoneally into rats for 16-20 days; and the effect of drug administration on 35S-TBPS binding was studied in the cortex and hippocampus ex vivo. Phenobarbital (100 μM, P<0.001), ethosuximide (500 μM, P<0.001), and phenytoin (40 μM, P<0.001) decreased the specific 35S-TBPS binding in vitro by 10-16%. After drug administration of phenobarbital (concentration in plasma 168 μM), the number of binding sites decreased and the binding affinity (P<0.05) in the cortex increased. Other anticonvulsants did not modulate 35S-TBPS binding in vitro at the concentration analogous to therapeutic plasma levels or ex vivo at the dose used. These results suggest that the use of phenobarbital may modulate the TBPS binding site, but the role of the present findings in the anticonvulsant action of phenobarbital needs to be further studied. [ABSTRACT FROM AUTHOR]

A neuropsychological screening battery including the Mini-Mental State Examination and four other brief cognitive tests (Russell's Adaptation of the Visual Reproduction Test, Trail Making Test, Verbal Fluency Tests on letters and category, and the Buschke Selective Reminding Test) was administered to a randomly selected population sample of 403 subjects aged 68 to 77 years to evaluate the effect of education, age, and sex on test scores. The difference in neuropsychological screening tests between various education groups (3 years or less, 4 to 6 years, 7 years or more) was statistically highly significant, even after the adjustment for the effect of age. The subscores and total scores were lowest in the minimal education group on every neuropsychological test. Education correlated more strongly than age with all neuropsychological test scores and subscores. The effect of sex on test results was seen only in some subscores of brief neuropsychological tests but not in a single item of the Mini-Mental State Examination. On the basis of our results, the effects of education, age, and sex have to be evaluated before using brief neuropsychological tests in population-based dementia screening. (J Geriatr Psychiatry Neurol 1992;5:162–171). [ABSTRACT FROM PUBLISHER]

When compared to young Fisher 344 rats, aged Fisher 344 rats were impaired in their acquisition of the water maze task as indicated by longer escape latencies and distances to find a hidden platform. In a free swim trial which was performed after the training period, young rats had a better spatial bias, since they spent more time swimming in the previous training quadrant. Tacrine 3mg/kg, an anticholinesterase, and selegiline 0.25mg/kg, a MAO-B inhibitor, partially reversed the acquisition deficit in aged rats when administered on their own, and drug-treated aged rats swam more in the previous training quadrant than vehicle-treated aged rats during the free swim trial. Aged rats also swam slower than young rats. Tacrine, but not selegiline, increased swimming speed in aged rats. Taken as a whole, these data support the proposal that tacrine may be effective at alleviating age-related learning impairment and confirm the role of cholinergic dysfunction in the spatial learning deficit in aged rats. [ABSTRACT FROM AUTHOR]

Acetylcholinesterase (AChE) activity is increased in human cerebrospinal fluid (CSF) during aging. The present study investigated whether the relative amounts of different molecular forms of CSF-AChE are also affected during aging. Thus, the CSF samples of healthy human subjects (age range 20-79 years, n=23) were analyzed for sedimentation forms of AChE activity. Five different forms of AChe activity were detected in human CSF. The relative amount of tetrameric and dimeric globular forms, which are the main forms of AChE in CSF, were not related with age. Furthermore, the relative amount of monomeric globular and asymmetric forms which are minor forms of AChE in CSF did not seem to be related to age. Since total CSF-AChE activity is increased during aging, it seems to be due to the increased amounts of the tetrameric and dimeric forms of enzyme activity. [ABSTRACT FROM AUTHOR]

We have investigated neurotransmitter-related markers of the cerebrospinal fluid (CSF) in a carefully screened series of normally aging subjects in standardized conditions in order to find out the influence of age and other confounding factors on CSF measures. The levels of 3-methoxy-4-hydroxyglycol (MHPG) and the activity of acetylcholinesterase (AChE) also increased with age, while homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5 HIAA) and immunoreactivities of somatostatin (SLI), beta-endorphin (BLI) and adrenocorticotropic hormone (ACTH) were unrelated to age. The gender of subjects had no significant effect on the levels of neurotransmitter markers, while seasonal changes, as well as height and weight of the subjects seemed to cause some variations in the levels of HVA, dopamine-Β-hydroxylase (DBH) and ACTH. The study underscores the importance of standardized conditions and matched patient groups in the CSF studies. [ABSTRACT FROM AUTHOR]

We studied the levels of excitatory and inhibitory amino acids in the cerebrospinal fluid (CSF) of 28 epileptic patients (24 with partial type seizures, 4 with primary generalized seizures) and 12 controls. The levels of aspartate were 63% (p<0.01), glutamine 129% (p<0.001), and homocarnosine 127% (p< 0.005) that of controls. The concentrations of glutamate, asparagine, total GABA, free GABA, taurine, and glycine did not differ between epileptic patients and controls. Patients with partial epilepsy had a pattern of amino acids in CSF similar to that in patients with primary generalized seizures. In the present study we did not observe increased excitation or decreased inhibition in the seizure-active brains of epileptics, as far as the CSF levels of amino acids reflect their levels in the brain. [ABSTRACT FROM AUTHOR]

In patients with probable Alzheimer's disease and in controls, acetyl- and butyrylcholinesterase activities were studied in cerebrospinal fluid (CSF) and plasma, and acetylcholinesterase activity of erythrocytes was determined. In addition, the molecular forms of acetylcholinesterase were measured in CSF. Severely demented patients had significantly lower acetylcholinesterase (p<0.01) and butyrylcholinesterase (p<0.05) activities in CSF than the controls had, but the activities of these enzymes in plasma and erythrocytes were within the same range in both groups. Acetylcholinesterase and butyrylcholinesterase activities in the CSF of mildly demented patients did not differ from control values. The ratio of the intermediate molecular form of acetylcholinesterase to the light molecular form of the enzyme did not differ significantly between patients with Alzheimer's disease and controls. According to our results, AChE levels were lower in the CSF of severely demented patients, but both light and intermediate molecular forms were affected. [ABSTRACT FROM AUTHOR]

We studied the possible role of excitatory and inhibitory amino acids and their balance during generalized convulsions. The levels of amino acids in postictal cerebrospinal fluid (CSF) were compared with amino acid concentrations in interictal CSF of ten patients with generalized tonic-clonic convulsions. Glu, Gln, Asp, Asn, Tau, Gly, total GABA (t-GABA), free GABA (f-GABA), and homocarnosine levels and Glu/Gln, Asp/Asn, t-GABA/Glu, f-GABA/Glu, f-GABA/Asp, and Glu/Asp ratios were similar in both samples (Student's paired t-test). Our results suggest that in humans possible changes in amino acids in brain tissue during the ictal stage are not reflected in the lumbar CSF. [ABSTRACT FROM AUTHOR]

Twelve MS patients were treated with L-tryptophan with or without decarboxylase inhibitor for 30 days, and the daily dose was either 1.5 g or 8 g. Tryptophan, 5-HIAA and HVA were analysed from lumbar punctures before and during tryptophan treatment. Clinical evaluation of MS symptoms was performed before, during and at the end of the tryptophan treatment period as well as after a 30-day placebo period. Tryptophan and 5-HIAA levels were found to be elevated 10 hours after the last dose of L-tryptophan. HVA concentrations remained approximately constant. A slight alleviation of changeable MS symptoms was noticed during the first month. The best response was found in symptoms like motility and bladder disturbances as well as in the mood of patients. These findings are indicative of the neural transmission changes during the rapid functional disturbances in MS. [ABSTRACT FROM AUTHOR]

1. The anticonvulsant potency of vigabatrin (gamma-vinyl GABA, GVG) was studied in an open trial in a group of 21 mentally handicapped patients with drug-resistant epilepsy. 2. With this treatment one third of these patients had more than 50% reduction in seizure frequency. The anticonvulsant effect appeared during the first month of therapy and was maintained during a 7-month study. The side effects were mild: mainly tiredness, aggressiveness, and ataxia. Other anticonvulsant drugs remained at baseline levels during GVG therapy. GVG was not found to modulate EEG recordings. 3. According to our results, GVG is effective for treating intractable epilepsy in mentally handicapped patients. [ABSTRACT FROM AUTHOR]