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According to the clinical criteria of ‘probable’ Alzheimer’s disease (AD), the diagnosis is supported by a normal pattern or nonspecific changes in the electroencephalogram (EEG) such as slow wave activity. EEG has been a traditional method in the diagnosis of dementia. Slight EEG alterations are common in normal elderly people after the age of 60 years. The main changes are slowing of the alpha rhythm, appearance of slow activity and a theta focus in left temporal region. However, the changes in EEG associated with aging are quite modest. EEG changes associated with AD consist of more slowing of the dominant occipital rhythm and more accentuation of theta and delta activity than is found in normal old people, but local slowing occurs rarely. When the EEG findings of AD patients at baseline, at the time the diagnosis was made, were compared to control values, there was a significant difference in all relative power values except beta power.

We have studied, as a possible marker of cholinergic neurons, the acetylcholinesterase (AChE) activity in cerebrospinal fluid (CSF) of 21 SDA patients and 9 controls of similar age with no neurological disease. The AChE activities were significantly lower in the SDA patients compared to the controls. The AChE activities were also lowered in the most severely demented patients compared to those who were less severely demented but the difference was not statistically significant. As a potential glia marker, beta-glucuronidase activity in CSF was studied, but no significant difference was found in the activities of the SDA patients compared to the controls. The reduced AChE activities in the CSF of the SDA patients may be related to the loss of cholinergic neurons or disturbed cholinergic metabolism in the brain.

The possibility of disturbed dopamine and serotonin metabolism in senile dementia of Alzheimer type was studied. The basal concentrations of homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF) were studied in 28 patients with senile dementia of Alzheimer type and in 13 controls of similar age with no neurological disease. The concentrations of HVA were significantly reduced in the dementia patients compared to the concentrations of the controls. The values of HVA were also significantly reduced in the most severely demented patients compared to the less severely demented ones. There was a slight but statistically significant decrease in the 5-HIAA levels in the dementia patients compared to the levels of the controls. The 5-HIAA levels were reduced in the most severely demented patients compared to the controls but not when compared with the less severely demented patients. It is concluded that in severe forms of senile dementia of Alzheimer type, there is a decrease in the levels of HVA and 5-HIAA in CSF which may reflect a decreased turnover of dopamine and serotonin. Patients diagnosed as senile dementia of Alzheimer type, but with less severe symptoms, had levels of HVA and 5-HIAA similar to controls.

Recent neurochemical studies have indicated that in Alzheimer's disease there is disturbance of the cholinergic metabolism of the brain. Defects in other transmitter systems have also been suggested. As a marker of noradrenergic metabolism of the central nervous system, we measured dopamine-beta-hydroxylase (EC. 1.14.17.1) activity in cerebrospinal fluid (CSF) from 60 Alzheimer patients and 20 controls of the same age and sex. Dopamine-beta-hydroxylase activities of the CSF from Alzheimer patients did not differ significantly from those for the controls. The dopamine-beta-hydroxylase activities were not correlated with severity of dementia. As reported previously, the activity of a cholinergic marker, acetylcholinesterase (EC 3.1.1.7), was reduced in the CSF of Alzheimer patients. Interestingly, dopamine-beta-hydroxylase activities were correlated with acetylcholinesterase activities both in Alzheimer patients and control group.

A 57-year-old man with neuromyotonia and normocalcemic tetany as probable paraneoplastic symptoms of small-cell lung cancer was examined neurophysiologically. In EMG, spontaneous action potential generation was demonstrated in peripheral motor axons. There were also time-locked high-frequency discharges after some voluntarily activated motor unit potentials. After electrical stimulation of motor axons, the M-re-sponse as well as spinal F-response or H-reflex was often followed by a sequence of oscillating potentials which could last several hundred msec. There was no evident peripheral polyneuropathy. Tetany subsided when carbamazepine therapy was started. The only striking abnormality in extensive laboratory studies was an increase in the plasma noradrenaline value.

The possibility of disturbed dopamine and serotonin metabolism in the progressive myoclonus epilepsy (PME) occurring in Finland (a type of PME without Lafora bodies) was examined. Both basal concentrations of HVA and 5-HIAA in the CSF and their increase after oral probenecid administration were studied in 19 PME patients and in 19 age- and sex-matched control patients. The control patients had grand mal epilepsy but not myoclonus or ataxia. The basal value of HVA was significantly reduced and that of 5-HIAA was also slightly reduced in the PME patients as compared to the values of the epileptic controls or to those of 26 nonepileptic controls. The concentrations of HVA and 5-HIAA also seemed to correlate with the severity of the PME. The most severely affected patients had generally the lowest values. After oral probenecid this trend was also seen when the increases of HVA and 5-HIAA were expressed per microgram CSF probenecid, i.e. the mildly affected PME group showed higher increases in response to probenecid than the most severely affected PME group. The PME patients had higher probenecid levels in the CSF than the epileptic controls.

Vigabatrin is effective as add-on therapy in about 50% of patients with partial epilepsy refractory to drugs. Furthermore, at least half of the original responders maintain the response over several years. As monotherapy, both vigabatrin and carbamazepine seem to be successful in a similar proportion of newly diagnosed patients with epilepsy, but carbamazepine monotherapy fails more often due to side-effects and vigabatrin more often due to lack of efficacy. However, vigabatrin monotherapy seems to be extremely well tolerated, particularly in relation to cognitive function.

Several early studies suggested that differences exist between antiepileptic drugs (AEDs) in terms of their propensity to cause adverse effects on cognitive functions, favouring carbamazepine over phenobarbital (phenobarbitone), phenytoin and valproic acid (sodium valproate). The combined results of recent studies in patients and healthy volunteers reveal that at therapeutic serum concentrations phenobarbital, phenytoin, carbamazepine, oxcarbazepine and valproic acid produce nearly comparable adverse effects on higher cognitive functions.The newer AEDs (with the exception of zonisamide and topiramate) appear to induced fewer cognitive adverse effects than the older agents. Furthermore, there is limited evidence that gabapentin, lamotrigine and vigabatrin may have beneficial effects on cognitive function. Some of the newer AEDs may also have neuroprotective effects that can prevent seizure-induced neuronal damage, and so reduce cognitive dysfunction. This is an important clinical consideration, as even modest differences between older and newer AEDs are relevant for patients.

1. Aged alpha2C-adrenoceptor knockout and wild type mice were used to investigate whether alpha2C-adrenoceptors are involved in mediating the beneficial effects of alpha2-adrenoceptor agonist, dexmedetomidine, on spatial working memory. 2. A win-stay task in the radial arm maze was used to dissociate the effects of dexmedetomidine on working vs. reference memory. In addition, the animals were tested in simple response habit learning in the T-maze. 3. Knockout mice made more working memory errors after the change of the baited arm in radial arm maze, but after training reached again as accurate level of performance as wild type controls. Dexmedetomidine 5 and 10 microg/kg alleviated the increase in spatial working memory errors after the change of the baited arm in knockout mice. Knockout and wild type mice performed equally well in T-maze, and dexmedetomidine had no effect on this simple response learning. 4. The present results indicate that alpha2-adrenoceptor agonists have a selective effect on spatial working memory not only in monkeys but also in mice. Further, this study confirms our earlier finding that the presence of alpha2C-adrenoceptors is not necessary for the spatial working memory enhancing effect of alpha2-adrenoceptor agonists.

We investigated the effect of pre-training on the improvement of spatial navigation performance provided by a cholinesterase inhibitor, tetrahydroaminoacridine (3 mg/kg, i.p.), and a positive modulator of NMDA receptor, d -cycloserine (10 mg/kg, i.p.), or their combination in aged rats. Pre-training consisted of spatial or non-spatial conditions and took place in either the same or a separate room. We found that any kind of pre-training was able to eliminate the enhancing effect of tetrahydroaminoacridine and d -cycloserine on spatial navigation. However, none of these pre-training conditions was able to block the age-related deficit in spatial navigation. These results indicate that tetrahydroaminoacridine and d -cycloserine, separately or in combination, do not themselves alleviate the age-related spatial memory deficit, but may enhance procedural aspects of water maze learning in aged rats.

Background: Due to the progressive nature of Alzheimer’s disease (AD), it has been proposed that serial imaging studies tracking the course of progression might improve the diagnostic accuracy of AD. Methods: Longitudinal changes in hippocampal volumes were evaluated using magnetic resonance imaging (MRI) over a period of 3 years in 27 AD patients and 8 control subjects. Results: A statistically nonsignificant trend towards accelerated volume loss in the AD group compared to control subjects was observed. During the study period, the average shrinkage of the hippocampal volume ranged from −2.2% to −5.8% in control subjects, and from −2.3% to −15.6% in AD patients. Conclusions: The observed changes at an individual level were small, and within the accuracy range of the measurements. Therefore, serial MRI of the hippocampus did not offer any advantage over a single MRI to support the diagnosis of AD in this study sample.

We investigated whether the nucleus basalis lesion induced by quisqualic acid was associated with a more severe impairment of spatial navigation in a water maze, a greater reduction in frontal choline acetyltransferase activity and decrease in the number of choline acetyltransferase-positive neurons in the nucleus basalis in apolipoprotein E-deficient mice than in control mice. We also studied the effect of ageing on water maze spatial navigation and cortical choline acetyltransferase activity in 16-month-old control and apolipoprotein E-deficient mice. We found that the lesion decreased choline acetyltransferase-positive neurons in the nucleus basalis and frontal choline acetyltransferase activity equally in control and apolipoprotein E-deficient mice. The nucleus basalis lesion had no effect on the initial acquisition in the water maze in control and apolipoprotein E-deficient mice after 25 or 106 days of recovery. However, the nucleus basalis lesion impaired the reversal learning in the water maze similarly in both strains after 25 days of recovery, but had no effect after 106 days of recovery. Finally, water maze spatial navigation and cortical choline acetyltransferase activity were similar in old control and apolipoprotein E-deficient mice. These results suggest that young and old apolipoprotein E-deficient mice do not have impairments in cholinergic activity or spatial navigation. Furthermore, apolipoprotein E deficiency does not increase the sensitivity to cholinergic and spatial navigation deficits induced by lesioning of the nucleus basalis with an excitatory amino acid and does not slow down the behavioral recovery.

Clinical features of epilepsy, especially those connected with drug therapy, were evaluated for mentally retarded adult epileptics who were admitted to the neurological out-patient unit during 1977-83. These features were re-evaluated in 1985 and compared with findings from the first visit. During follow-up, the type and frequency of seizures were determined and if possible, medical therapy was either concluded or changed. The therapeutic intervention resulted in the use of fewer and less toxic drugs, for which the serum concentrations were more often within recommended ranges. These aspects may be due to the significant decrease in seizure frequency observed. In order to provide patients with the most efficacious therapy, the therapeutic needs of mentally retarded adult epileptics should be evaluated by a neurologist familiar with epilepsy.

We investigated the effect of the noradrenergic neurotoxin, N -(2-chloroethyl)- N -ethyl-2-bromobenzylamine (DSP-4) (1 or 3×50 mg/kg, intraperitoneally), on hippocampal, cortical and cerebellar noradrenaline levels after recovery of one, five and 11 months in control and apolipoprotein E-deficient mice. Apolipoprotein E-deficient mice had lower hippocampal noradrenaline levels than control mice. DSP-4-lesioned control mice had a more extensive recovery of hippocampal and cortical noradrenaline levels than DSP-4-lesioned apoE-deficient mice after five months' survival. Futhermore, the hippocampal noradrenaline levels after five and 11 months and cortical noradrenaline levels after five months of recovery had slightly recovered in control but not in apolipoprotein E-deficient mice treated with a single dose of DSP-4 compared with mice treated with three doses of DSP-4. These results show that apolipoprotein E-deficient mice have impaired recovery capacity in their locus coeruleus neurons.

We investigated the role of overexpression of alpha2C-adrenoceptors in water maze navigation in mice transgenically manipulated to have a threefold overexpression of the alpha2C-adrenoreceptors. Alpha2C-adrenoreceptors overexpressing mice swam more in the peripheral annulus of the pool and did not find the hidden escape platform as well as the wild type control mice. A subtype-nonselective alpha2-adrenoreceptor antagonist, atipamezole (ATI, 1000 μg/kg, s.c.), fully reversed the deficit in platform finding and search strategy in overexpressing mice. Noradrenaline depletion (−95%) induced by N -(2-chloroethyl)- N -ethyl-2-bromobenzylamine (DSP-4) did not impair platform finding of wild type or overexpressing mice. The DSP-4 lesion slightly increased swimming in the peripheral annulus in wild type mice, but not in overexpressing mice. The DSP-4 lesion produced a dissociable effect on the action of atipamezole to improve platform finding and search strategy in overexpressing mice: atipamezole did not alleviate the platform finding deficit in DSP-4 lesioned overexpressing mice, but normalized their abnormal search strategy. These results suggest that the abnormal search pattern and deficit in the accuracy of platform finding are mediated by constitutive activity of overexpressed alpha2C-adrenoreceptors.

The loss of dopaminergic cells during Parkinson's disease (PD) produces "frontal"-like impairment in spatial working memory (SWM) and planning functions. This study investigated whether an alpha2-adrenergic agonist, clonidine (0.5 or 2 microg/kg, orally), improves SWM, spatial short-term or spatial recognition memory, and planning functions in PD patients. Clonidine 2 microg/kg decreased errors in SWM, but a lower dose, 0.5 microg/kg, had no effect on performance. Clonidine 0.5 and 2 microg/kg failed to improve the strategy used to solve the SWM test. Clonidine 0.5 and 2 microg/kg had no effect on accuracy of performance in the other tests. These results showed that clonidine improves performance in a test of SWM and that this is not due to improved spatial short-term or spatial recognition memory or planning functions. The authors suggest that stimulation of alpha2-adrenoceptors improves the mnemonic processing required for accurate SWM performance in PD patients.

Significantly increased glial fibrillary acidic protein (GFAP) expression was seen in postmortem brain tissue from demented patients with Alzheimer’s disease (AD) (73 cases, 61 females/12 males, mean age 84 ± 9 years) compared to controls (22 cases, 10 females/12 males, mean age 78 ± 9 years). In demented patients, the GFAP expression, counts of AD lesions, senile/neuritic plaques (SP/NP) and neurofibrillary tangles (NFT) were higher in patients carrying the apolipoprotein E (ApoE) ε4 allele compared to those without the ApoE ε4 allele. The astrogliosis correlated significantly with the counts of NFT in demented patients both with and without the ApoE ε4 allele. Furthermore, the astrogliosis correlated significantly with the counts of SP/NP, but this correlation, however, was influenced by the ApoE ε4 allele, being significant only in those cases without the ApoE ε4 allele. Our results demonstrate that not only the extent of AD lesions and GFAP expression, but also the relationship between AD lesions and the GFAP expression is influenced by the ApoE ε4 allele.

We investigated whether the local intrathalamic infusion of a muscarinic acetylcholine receptor agonist (oxotremorine) at either the reticular nucleus of thalamus (NRT) or the ventroposteromedial nucleus of thalamus (VPM) suppresses thalamocortically generated neocortical high-voltage spindles (HVSs). In addition, we studied whether the intracerebroventricular (ICV) infusion of a selective muscarinic M2 acetylcholine receptor antagonist (methoctramine) could block the suppression of HVSs induced by either systemic (IP) administration of an anticholinesterase drug [tetrahydroaminoacridine (THA)] or ICV infusion of oxotremorine in rats. Intrathalamic administration of oxotremorine at 3 and 15 microg in the NRT, and at 15 microg in the VPM suppressed HVSs. ICV oxotremorine at 30 and 100 microg and IP THA at 3 mg/kg decreased HVSs. ICV methoctramine at 100 microg increased HVSs and completely blocked the decrease in HVSs produced by oxotremorine 100 microg and THA 3 mg/kg. The results suggest that activation of muscarinic M2 acetylcholine receptors in thalamic nuclei (NRT and VPM) can suppress thalamocortical oscillations and that ICV or systemically administered drugs that activate either directly (oxotremorine and methoctramine) or indirectly (THA) the muscarinic M2 acetylcholine receptors may modulate neocortical HVSs via the thalamus.

The present study examined the efficacy of single and combined treatments with an anticholinesterase, tetrahydroaminoacridine, nicotine and a glycine-B site partial agonist, D-cycloserine, in alleviating the water maze reversal learning defect induced by a medial septal lesion. D-cycloserine (3 and 10 mg/kg) improved reversal learning. Tetrahydroaminoacridine (1 and 3 mg/kg) and nicotine (0.1 and 0.3 mg/kg) had no effect on reversal learning. A combination of tetrahydroaminoacridine 3 mg/kg or nicotine 0.3 mg/kg and D-cycloserine 10 mg/kg was not more effective than D-cycloserine 10 mg/kg alone in improving reversal learning. This suggests that stimulation of NMDA mechanisms may more effectively improve in medial septal-lesioned rats reversal learning processes than stimulation of cholinergic activity.

NIITTYKOSKI M., R. LAPPALAINEN, J. JOLKKONEN, A. HAAPALINNA, P. RIEKKINEN Sr and J. SIRVIO. Systemic administration of atipamezole, a selective antagonist of alpha-2 adrenoceptors, facilitates behavioural activity but does not influence short-term or long-term memory in trimethyltin-intoxicated and control rats . NEUROSCI BIOBEHAV REV 22 (6) 735–750, 1998.—The present study used trimethyltin (TMT)-intoxicated rats as a model for the behavioural syndrome seen after neuronal damage to the limbic system. Behavioural assessments indicated increased locomotor activity and reduced number of groomings in an open-arena task in TMT-intoxicated (6.6 mg/kg as a free base) rats, as has been found previously. A novel finding was the severe deficit in swimming to a visible platform in the water maze task, with reduced swimming speed at the beginning of the training period. During the reacquisition phase of a radial arm maze task, TMT-intoxicated rats made more short-term and long-term memory errors, and their behavioural activity was increased in comparison with controls. The administration of atipamezole (300 μg/kg), a selective antagonist of α 2 -adrenoceptors, enhanced locomotor activity compared to saline-treated rats, but these effects did not differ between the TMT group and their controls. Atipamezole did not enhance short-term or long-term memory in either TMT or control groups. Taken together, the present data indicate that TMT intoxication is a model for global dementia rather than for a specific loss of relational memory. Previous studies on the neurochemical effects of TMT and the alleviation or prevention of neurotoxicity of TMT are reviewed.

Objective—Recent evidence indicates that the apolipoprotein E (ApoE) Â4 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 eVect of the ApoE Â4 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 Â4 (mean age 70.4 (SD 9.9)), 11 patients with Alzheimer’s disease without ApoE Â4 (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 anteriorposterior commissure. Results—The patients with Alzheimer’s disease without the ApoE Â4 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 Â4 allele (p=0.0001). The eVect of  4o n 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 Â4 allele had inferior performance in verbal and visual memory functions than those without the allele Conclusions—Volumetric MRI measurements disclose that ApoE Â4 is associated with the degree of atrophy in the entorhinal cortex in early Alzheimer’s disease, this eVect being especially prominent in female patients with Alzheimer’s disease. (J Neurol Neurosurg Psychiatry 1998;65:322‐327)

Summary: We performed a subgroup analysis of the first European Stroke Prevention Study including 1,306 patients recruited in a single center, Kuopio, Finland, to investigate whether or not antiplatelet therapy is effective in the secondary prevention of stroke in hypertensive patients with transient ischemic attack (TIA) or stroke. The patients were treated with aspirin, 990 mg/day, plus dipyridamole, 225 mg/day, or placebo for 2 years. The patients with high systolic blood pressure (≥140 mm Hg; n = 1,105) or high diastolic blood pressure (≥85 mm Hg; n = 1,120) at entry, were classified into subgroups by blood pressure level. The effect of treatment was statistically significant in all subgroups with high systolic (end-point reduction, 55.2-68.2%) and diastolic blood pressure (end-point reduction, 47.3-82.1%). Risk reduction was, however, greatest in patients with the highest diastolic blood pressure. One possible explanation is that platelets are more activated in these patients, and this can be effectively prevented by antiplatelet therapy. Further studies are needed to confirm this hypothesis.

To investigate whether recurrent seizures cause hippocampal damage in temporal lobe epilepsy (TLE).Eighteen patients with newly diagnosed cryptogenic TLE, 14 patients with chronic well-controlled cryptogenic TLE, 32 patients with chronic drug-resistant cryptogenic TLE, and 25 healthy subjects were studied.Hippocampal MRI volumetry and T2 relaxometry were used.Chronic drug-resistant patients with seizure focus in the left temporal lobe had an 18% smaller left hippocampus and chronic drug-resistant patients with seizure focus in the right temporal lobe had a 14% smaller right hippocampus than did the control group (p0.05). Chronic drug-resistant patients with seizure focus on the left side had longer T2 relaxation times in the body of the left hippocampus than did the control group (p0.001) and chronic drug-resistant patients with seizure focus on the right side had longer T2 relaxation times in the body of the right hippocampus than did the control subjects (p0.01). In all patients with a left seizure focus, the left hippocampal volume correlated inversely with the estimated total number of partial (r = -0.391, p0.01) or generalized (r = -0.312, p0.05) seizures the patient had experienced. The prolongation of the left T2 relaxation time in the body of the hippocampus correlated with the total number of both partial (r = 0.670, p0.001) and generalized (r = 0.481, p0.001) seizures and with the duration of TLE symptoms (r = 0.580, p0.001).In patients with cryptogenic epilepsy, recurrent seizures may cause damage to the hippocampus throughout the lifetime of the patient.

We evaluated the cognitive effects of two moderate doses (30 mg/kg x 3 every 12 h and 20 mg/kg x 6 every 8 h, i.p.) of 1-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) in mice. The dose of 30 mg/kg x 3 caused about 60% depletion of striatal dopamine but did not reduce the levels of its metabolites. Mice treated with MPTP did not differ from controls in their motor behavior in the open field. Mice treated with MPTP were comparable to controls in T-maze delayed alternation with fixed delays but were impaired when trials with mixed 20 s and 120 s delays were presented, indicative of a spatial working memory impairment. Dexmedetomidine at 10 microg/kg (s.c.) slightly improved delayed alternation performance in all groups but also slowed initiation of the motor response. Mice treated with MPTP at the dose of 30 mg/kg x 3 were less sensitive to this adverse effect of dexmedetomidine. The impairment in spatial working memory after MPTP exposure in mice parallels the findings in monkeys, but the deficit is much less severe.

We investigated the effects of acute i.p. injections of the Ca2+-dependent K+ channel blocker, apamin, on water maze spatial navigation, Y-maze and passive avoidance behavior in intact and medial septal-lesioned mice. Apamin 0.02, 0.06 or 0.2 mg/kg (i.p.) administered 30 min before or immediately after the training did not affect the performance of intact mice. Apamin 0.02 or 0.06 mg/kg (i.p.) administered immediately after the daily training did not affect the performance of medial septal-lesioned mice. Apamin 0.02 and 0.06 mg/kg (i.p.) administered 30 min before daily training reversed the navigation failure present in medial septal-lesioned mice during the initial and reversal learning stages of the water maze task. Apamin had no effect on the cognitive performance in Y-maze or passive avoidance tests. The results indicate that blockade of Ca2+-dependent K+ channels may facilitate acquisition of spatial navigation performance, but has no effect on consolidation, inhibitory avoidance and spontaneous alternation behavior in mice.

We investigated the role dopamine and noradrenaline in the modulation of attention in Parkinson's disease (PD) patients. We observed that PD patients with mild and moderate motor disability did not differ in their attentional accuracy in easy tests, but the severe PD group was slightly disrupted in a more arduous test of attention. Attentional accuracy was not affected by withdrawal of dopaminergic drugs in mild or severe PD patients. The movements of severe PD patients were slower, and withdrawal of dopaminergic drugs aggravated motor slowing more in severe PD patients. Clonidine (0.5 and 2 microg/kg) retarded accuracy of performance in the most difficult attention test in mild PD patients, but had no effect in the severe PD group. Clonidine had no effect on movement times. These data suggest that a defect in noradrenaline release may contribute to the impaired accuracy of attention in severe PD patients and that dopamine may be important for maintaining rapid motor responding.

The present study investigated the role of 5-HT1A and 5-HT2 receptors in the execution of a working memory task (delayed non-matching to position, DNMTP) by assessing the influence of 8-OH-DPAT (5-HT1A receptor agonist) and DOI (5-HT 2 receptor agonist) on the performance of rats lesioned with 5,7-dihydroxytryptamine (5,7-DHT) and their controls. Post-mortem neurochemical analysis revealed that serotonin and 5-hydroxyindoleacetic acid levels were reduced in examined brain areas (especially in the hippocampus where there was a 90 percent reduction). Noradrenaline concentrations were also decreased (mostly on the same side of the injection) by about 20 percent. 5,7-DHT lesioned rats did not significantly differ from their controls in performance in the DNMTP task. At the 30 μg/kg dose, 8-OH-DPAT did not affect the DNMTP-performance of rats, but at the higher dose (100 μg/kg) it reduced the probability of responding to the sample lever. DOI (100 and 300 μg/kg) also interfered with the non-cognitive performance of rats. Since neither of these agonists affected significantly the choice accuracy, they do not appear to influence the working memory per se. The 5,7-DHT lesioned rats did not differ from their controls in response to these agonists. These results suggest that the combination of 5-HT1A receptor stimulation by 8-OH-DPAT and 5-HT2 receptor stimulation by DOI can interfere with the non-cognitive performance of rats in the DNMTP task. The results further indicate that the effect of 8-OH-DPAT may be mediated through post-synaptic rather than pre-synaptic 5-HT1A receptors.

The ideal biomarker for Alzheimer's disease (AD) should detect a fundamental feature of neuropathology and be validated in neuropathologically-confirmed cases: it should have a sensitivity >80% for detecting AD and a specificity of >80% for distinguishing other dementias: it should be reliable, reproducible non-invasive, simple to perform, and inexpensive. Recommended steps to establish a biomarker include confirmation by at least two independent studies conducted by qualified investigators with the results published in peer-reviewed journals. Our review of current candidate markers indicates that for suspected early-onset familial AD. it is appropriate to search for mutations in the presenilin 1, presenilin 2, and amyloid precursor protein genes. Individuals with these mutations typically have increased levels of the amyloid Aβ 42 peptide in plasma and decreased levels of APPs in cerebrospinal fluid. In late-onset and sporadic AD. these measures are not useful. but detecting an apolipoprotein E e4 allele can add confidence to the clinical diagnosis. Among the other proposed molecular and biochemical markers for sporadic AD. cerebrospinal fluid assays showing low levels of Aβ 42 and high levels of tau come closest to fulfilling criteria for a useful biomarker.

OBJECTIVE To study cognitive function in an elderly population with persistent impaired glucose tolerance (IGT). RESEARCH DESIGN AND METHODS Fasting and postload 2-h plasma glucose and insulin levels were determined at baseline in a population-based sample of 1,300 people and repeated an average of 3.5 years later in 980 subjects. At follow-up, cognitive function was evaluated in subjects with persistent normal glucose tolerance (NGT; n = 506) and IGT (n = 80) with a brief neuropsychological test battery. RESULTS Subjects with persistent IGT scored lower in the Mini-Mental State Examination (MMSE) and in the Buschke Selective Reminding Test long-term memory scores. Multiple linear regression analysis revealed that age, education, and insulin levels (either fasting or 2-h value) were associated with the MMSE score in subjects with persistent IGT. Other potential risk factors for impaired cognitive function were not significantly associated with the MMSE score. CONCLUSIONS Our study showed that persistent IGT in the elderly is associated with mildly impaired cognitive function, and hyperinsulinemia may account for this association.

Antiplatelet treatment is well established in the secondary prevention of ischemic cerebrovascular events. The reasons for the occurrence of stroke, even though the patient receives drug treatment, have remained unclear. We performed a subgroup analysis of the European Stroke Prevention Study (ESPS 1) to investigate the efficacy of treatment in patients with different cardiovascular risk factors. The ESPS 1 recruited 1306 patients with TIA, RIND or stroke in one single center of Kuopio in Finland. The patients were treated with aspirin 990 mg/day+dipyridamole 225 mg/day or placebo for 2 years or until an endpoint. The endpoints were stroke or death from any cause. The risk factors for endpoints were analyzed by Cox univariate regression analyses. The effect of a single risk factor on the efficacy of antiplatelet therapy was analyzed by Cox proportional hazards model in subgroups according to the significant risk factors found in the univariate analysis. The efficacy of treatment was statistically significant in all subgroups except diabetics and current smokers for the stroke endpoint. When the combined endpoint of stroke or death was used, the treatment failed also to show statistical significance in patients with coronary heart disease. This lack of efficacy might be due to the small sample size. The efficacy of treatment was significantly better in TIA patients than in stroke patients when analyzed with stroke as an end point. This study provides strong evidence that the effectiveness of antiplatelet treatment in ischemic stroke and TIA patients is independent of most cardiovascular risk factors. Furthermore, all patients with TIA and ischemic stroke should receive secondary prevention regardless of whether or not there are risk factors.

The present experiments were designed to examine the effects of alpha-1 adrenergic stimulation and inhibition on memory encoding and to investigate whether the alpha-1 adrenergic and muscarinic cholinergic systems interact in the regulation of spatial navigation behavior in the Morris water maze test and we also studied the effects of D-cycloserine, a partial agonist at the glycine binding site on the N-methyl-D-aspartate (NMDA) receptor complex, on the performance of scopolamine-treated rats in this task. Pre-training subcutaneous administration of St-587 (a putative alpha-1 agonist) at 1000 micrograms kg-1 or 1500 micrograms kg-1 improved water maze navigation to a hidden platform. Prazosin (an alpha-1 antagonist), 300-2000 micrograms kg-1, did not significantly impair the spatial navigation performance. Pre-training administration of prazosin 1000 micrograms kg-1, but not 300 micrograms kg-1, slightly potentiated the deficit in water maze navigation seen after scopolamine (200 micrograms kg-1, pre-training intraperitoneal injection). Pre-training administration of St-587 at a dose 1500 micrograms kg-1, but not 500 micrograms kg-1, slightly ameliorated the scopolamine-induced (200 micrograms kg-1) impairment in performance of rats. Pre-training administration of prazosin at doses 300 or 1000 micrograms kg-1 or St-587 at doses 500 micrograms kg-1 or 1500 micrograms kg-1 did not have any significant influence on the scopolamine-induced (200 micrograms kg-1) increase of swimming speed. Furthermore, D-cycloserine at the dose of 300 micrograms kg-1 but not 1000 or 3000 micrograms kg-1 reversed the scopolamine (200 micrograms kg-1)-induced deficit in acquisition of the water maze task but not the increase in motor output (increased swimming speed). These results indicate that the stimulation of alpha-1 adrenoceptors may facilitate the encoding of new information. These findings suggest that alpha-1 adrenergic mechanisms do not participate or at least are not the most critical part of the noradrenergic system in the interaction between noradrenaline and muscarinic receptors in the modulation of learning and memory. In addition, these results suggest that D-cycloserine may be effective in alleviating states of central cholinergic hypofunction.

In this study, magnetic resonance imaging (MRI) of the hippocampus for the diagnosis of early Alzheimer's disease (AD) is evaluated. We measured hippocampal volumes and the area of the medial hippocampus with a 1.5 T MR imager in 160 subjects: 55 patients with probable AD according to the NINCDS-ADRDA criteria, 43 subjects fulfilling the NIMH criteria of age-associated memory impairment (AAMI), 42 cognitively normal elderly controls, and 20 controls younger than 50 years. Three methods for normalization were compared. The hippocampi were atrophied in the AD patients, but not in the AAMI subjects or the elderly controls. There was no significant correlation between hippocampal volumes and age in the nondemented subjects. The discrimination based on volumetry resulted in an overall correct classification of 92% of AD patients vs. nondemented elderly subjects, whereas discrimination based on hippocampal area was less accurate, producing a correct classification in 80% of the subjects. We conclude that the hippocampus as assessed by MRI volumetry is atrophied early in AD, and spared by aging or AAMI. A brief critical review of previous studies is in concordance with the presented data: all the previous studies that have used volumetry, have similarly ended up with a good classification, whereas simpler or subjective measurements, subject to various sources of bias, have produced most variable results.

In a previous study, we reported that Alzheimer disease (AD) patients with an apolipoprotein E (APOE) epsilon 4 allele (+ APOE4) show more severe loss of nucleus basalis (NB) cholinergic cells than patients without epsilon 4 alleles (-APOE4). The present study investigates the effects of a single oral administration of THA 25 or 50 mg on cortical spectral EEG activity in + (five APOE4/4, six APOE4/3) and -APOE4 (eight APOE3/3) AD patients. THA 25 mg had no significant effect on EEG activity in any AD patients. However, THA 50 mg increased alpha activity and alpha/theta ratio in -APOE4 patients. In contrast, THA 50 mg had no effect on EEG activity in + APOE4 patients. This result tentatively suggests that in AD patients APOE genotype may affect the response of cortical electrical arousal to cholinergic therapy that enhances the efficacy of presynaptic NB axons.

We investigated if activation of the muscarinic or nicotinic acetylcholine receptors and serotonin (5-hydroxytryptamine; 5-HT) subtype 2 receptors would have additive or synergistic effects on the suppression of thalamocortically generated rhythmic neocortical high-voltage spindles (HVSs) in aged rats. The 5-HT2 receptor antagonist, ketanserin, at a moderate dose (5 mg/kg) prevented the ability of a muscarinic acetylcholine receptor agonist, (oxotremorine 0.1 mg/kg), and a nicotinic acetylcholine receptor agonist (nicotine 0.1 mg/kg), to decrease HVSs. At a higher dose (20 mg/kg), ketanserin completely blocked the decrease in HVSs produced by moderate doses of muscarinic acetylcholine receptor agonists (pilocarpine 1 mg/kg and oxotremorine 0.1 mg/kg), and by a high dose of nicotine (0.3 mg/kg), though not that produced by high doses of pilocarpine (3 mg/kg) and oxotremorine (0.9 mg/kg). The ability of a 5-HT2 receptor agonist, (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) (0.1-1.0 mg/kg), to suppress HVSs was non-significantly modulated by the nicotinic acetylcholine receptor antagonist, mecamylamine (1-15 mg/kg), and the muscarinic acetylcholine receptor antagonist, scopolamine (0.03-0.3 mg/kg). The effects of the drugs on behavioral activity could be separated from their effects on HVSs. The results suggest that activation of the muscarinic or nicotinic acetylcholine receptors plus 5-HT2 receptors has additive effects in the suppression of thalamocortical oscillations in aged rats.

17 patients with vascular dementia (VaD) representing moderate to severe stage of the disease and 11 age-matched control subjects were examined with spectral analysis of EEG and a neuropsychological test battery comprising visual, praxic, verbal and memory functions as well as Mini-Mental Status test. VaD patients did not have less activity in the alpha band than control subjects, but the alpha amplitude ratio between eyes closed (EC) and eyes open (EO) situations (EC/EO ratio) was decreased in VaD patients, compared to controls. In VaD the variables of the awake background EEG with eyes closed (amplitude of alpha, beta, theta and delta activity; mean frequency) had only a few correlations to neuropsychological test scores. However, the (EC)/(EO) alpha ratio showed significant correlations with several neuropsychological variables in the temporo-occipital and centro-parietal derivations and some of these correlations were lateralized to the left or right hemisphere. Frontal EEG derivations with less alpha activity did not reveal any correlations to neuropsychological variables. We conclude that the dynamic EC/EO alpha ratio variable may be even more sensitive in the assessment of brain dysfunction in VaD than the background EEG variables.

Little is known about the appearance and severity of amygdaloid damage in temporal lobe epilepsy, particularly in its early stages. In the present magnetic resonance imaging study, we measured amygdaloid volumes and T2 relaxation times in 29 patients with newly diagnosed and in 54 patients with chronic temporal lobe epilepsy. The control population included 25 normal subjects. In the newly diagnosed patients, the mean amygdaloid volume did not differ from that in controls. Also, in the chronic patients the mean amygdaloid volume did not differ from that in controls or in newly diagnosed patients. However, in 19% of the chronic patients the amygdaloid volume was reduced by at least 20%. Moreover, in all of the epilepsy patients, both chronic and newly diagnosed, we found an inverse correlation between the number of epileptic seizures the patient had experienced and the amygdaloid volume on the focal side (focus on the left, r = -0.371, P0.01; focus on the right, r = -0.348, P0.05). The mean T2 relaxation time in newly diagnosed or chronic patients did not differ from each other or from control values. However, the T2 relaxation time of the left amygdala wasor = 111 msec (i.e.,or = 2 S.D. over the mean T2 time of the left amygdala in control subjects) in seven (10%) patients, one of which was newly diagnosed and six were chronic. The T2 time of the right amygdala was prolonged in eight (12%) patients, three of which were newly diagnosed and five were chronic. We did not find any clear asymmetries in amygdaloid volumes or T2 relaxation times between the ipsilateral and contralateral sides relative to seizure focus. According to the present findings, signs of amygdaloid damage were observed in approximately 20% of patients with temporal lobe epilepsy, most of which had chronic epilepsy.

Nitric oxide has been postulated as a retrograde intercellular messenger for long-term potentiation, a form of synaptic plasticity that is associated with learning and memory processes. [8] In the present study we investigated whether the loss or survival of nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase-containing neurons, which are known to synthesize nitric oxide, [19] would be an useful indicator for evaluating the structural and functional state of the rat hippocampus after status epilepticus that is induced by intraperitoneal injection of kainic acid. Besides NADPH diaphorase histochemistry, two other histological parameters were studied: the grade of cell damage evaluated from silver-impregnated sections, and the number of somatostatin-containing neurons in different hippocampal subfields. We found that the number of NADPH diaphorase-containing neurons in the hilus and granule cell layer correlated well with spatial learning and memory performance as assessed by the Morris water-maze test. The extent of cell damage in the CA1 subfield analysed in silver-impregnated sections and the number of hilar somatostatin-containing neurons also significantly correlated with latencies in the water-maze test. Furthermore, linear regression analysis revealed that the number of somatostatin-containing neurons in the hilus explains about 50% of the variation in water-maze learning. These findings emphasize that although general structural preservation is of crucial importance for the function of the hippocampus also interneurons, such as somatostatin- and NADPH diaphorase-containing neurons, may play an important role during the acquisition phase and processing of information in hippocampal circuitry. Therefore, in addition to evaluating general cell damage, analysis of the cell loss that occurs in the interneuron subpopulations will be beneficial in verifying structural and functional deficits of the hippocampus after status epilepticus.

The effects of three different serotonin (5-HT) receptor antagonists (ketanserin, methysegide, methiothepin) in the modulation of attention, working memory and behavioural activity were investigated in this study by assessing the performance of rats in two separate cognitive models; the 5-choice serial reaction time (5-CSRT) task, which measures attention, and the delayed non-matching to position (DNMTP) task, which measures working memory. Methysergide and methiothepin bind at the 5-HT1 and 5-HT2 as well as the 5-HT5–7 receptors, with varying degrees of selectivity, and ketanserin binds at the 5-HT2A receptors rather selectively. None of these agents bind to any significant extent to 5-HT3 or 5-HT4 receptors. In the 5-CSRT task, neither methiothepin (0.15 mg/kg) nor ketanserin (1.0 and 3.0 mg/kg) impaired the choice accuracy of rats, although they induced sedation. The low doses of methysergide (1.5 and 3.0 mg/kg) slightly increased the behavioural activity of rats, whereas the high dose of methysergide (15.0 mg/kg) reduced behavioural activity and slightly reduced choice accuracy of the rats in the attentional task (monitoring of visual stimuli) under the baseline conditions or curtailed stimulus duration. This effect was not augmented at the reduced stimulus intensity. These findings suggest that the high dose of methysergide did not interfere with the visual discrimination of rats. Furthermore, methysergide did not reduce motivation for this task, since it did not increase food collection latencies. In the DNMTP task, methiothepin (0.15 mg/kg) induced a delay non-dependent deficit in choice accuracy. This could be due to an impaired alternation ability or akinesia, which increases an actual delay between sample and choice. Methiothepin (0.15 mg/kg) also interfered with behavioural activity of rats. Interestingly, ketanserin (1.0 mg/kg and 3.0 mg/kg) and methysergide (3.0–15.0 mg/kg) neither impaired the choice accuracy nor reduced the behavioural activity of rats in the DNMTP task. These results suggest that the blockade of 5-HT2A receptors does not interfere with attention and working memory per se. However, all three serotonin receptor antagonists interfered with behavioural activity of rats in the 5-CSRT task more severely than in the DNMTP task. The possible role of serotonin and non-serotonin receptors underlying the influence of these antagonists on behavioural activity will be discussed.

The role of serotonin (5-HT) and its interaction with the muscarinic or nicotinic receptor-mediated mechanisms in the modulation of working memory and motor activity was investigated by assessing the effects of 5-HT lesion and cholinergic receptor blockade on the performance of rats in a working memory (delayed non-matching to position, DNMTP) task. A global serotonergic lesion was induced by the intracerebroventricular administration of 5,7-dihydroxytryptamine (5,7-DHT). Post-mortem neurochemical analysis revealed that serotonin and 5-hydroxyindoleacetic acid (5-HIAA) levels were reduced in frontal and parieto-occipital cortices and in hippocampi of 5,7-DHT lesioned rats. 5-HIAA levels were also reduced in striatum. 5,7-DHT lesion slightly impaired choice accuracy of rats in the DNMTP task and also transiently reduced motor activity in rats. Even the lower dose of scopolamine (0.075 mg/kg), a muscarinic receptor antagonist, impaired the choice accuracy already at the shortest delay (i.e. not indicative of a working memory impairment per se), and caused a marked disruption of motor activity (lengthened response latencies, increased probability of omissions and decreased trials completed). Furthermore, the quaternary analogue, N-methylscopolamine (0.150 mg/kg), affected the motor activity of rats to the same extent as scopolamine. Mecamylamine (1.0; 3.0 mg/kg) also interfered with motor activity and it slightly decreased the choice accuracy, which was not dependent on the delay. Although mecamylamine disrupted the performance of rats in the DNMTP task, the disruption was not as severe as that seen with scopolamine. Moreover, both scopolamine and mecamylamine augmented the slight impairment on the choice accuracy of 5,7-DHT lesioned rats, but this was non-mnemonic in character. We conclude that there is no evidence for any major interaction between the serotonergic system and muscarinic or nicotinic cholinergic mechanisms in working memory per se, but muscarinic and nicotinic receptor antagonists may act additively with the 5,7-DHT lesion to disrupt the choice accuracy of rats.

The present study investigated whether combined stimulation of the cholinergic system and 5-hydroxytryptamine (5-HT) subtype 2 receptors can suppress neocortical high-voltage spindles (HVSs) reflecting thalamocortical oscillations in aged rats. Cholinesterase inhibitors-tetrahydro-aminoacridine (THA: 1.0 and 3.0 mg/kg i.p.) and physostigmine (0.36 mg/kg i.p.)- and a 5-HT2 receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI; 0.3 and 1.0 mg/kg SC)-suppressed HVSs in aged rats. A combination of subthreshold doses of THA (0.3 mg/kg i.p.) and DOI (0.1 mg/kg s.c.) suppressed HVSs more effectively than either drug alone. Furthermore, a 5-HT2 receptor antagonist, ketanserin (5.0 and 20.0 mg/kg s.c.), reduced the efficacy of THA (1.0 and 3.0 mg/kg i.p.) and physostigmine (0.12 and 0.36 mg/kg i.p.) in decreasing HVSs. THA and ketanserin slightly decreased, physostigmine tended to increase, and DOI significantly increased behavioral activity of the rats, demonstrating that the effects of the drugs on behavioral activity may be separated from their effects on generation of thalamocortical oscillations. The results suggest that activation of the cholinergic system and 5-HT2 receptors has additive effects in the suppression of thalamocortical oscillations in aged rats.

We investigated the effects of acute oral pretraining treatment with an indirect acetylcholinesterase inhibitor, metrifonate, on water maze spatial navigation in medial septum-lesioned rats. We observed that metrifonate (30 mg/kg, orally) (1) does not alter the pattern of exploration of lesioned rats at the water maze pool or retrieval of spatial memory, (2) effectively reverses the acquisition defect, (3) enhances reversal learning, and (4) improves acquisition of water maze navigation by facilitating the encoding of the spatial representation of a specific environment. These results indicate that metrifonate does not improve escape performance to the hidden platform by modulating exploration strategy, but that metrifonate enhances the speed and accuracy of development and durability of spatial memory engrams, and facilitates learning capacity that depends on activity of the septo-hippocampal projection.

WE investigated the effect of nicotine, a nicotinic agonist, and D-cycloserine (DCS, a partial glycine-B agonist of the N-methyl-D-aspartate (NMDA) receptor complex) on aging-induced defects of water maze (WM) spatial navigation in rats. Nicotine (0.3 mg kg -1 , s.c.) or DCS (10 mg kg -1 , i.p.) enhanced acquisition of the WM task. A combination of subthreshold doses of nicotine (0.1 mg kg -1 ) and DCS (3 mg kg -1 ) improved WM acquisition. A subthreshold dose of a competitive NMDA antagonist, CPP (1 mg kg -1 ), blocked the effect of nicotine (0.3 mg kg -1 ) on WM acquisition. A nicotine antagonist, mecamylamine (10 mg kg -1 ), impaired WM acquisition and had no effect on retention, but did not bock the effect of DCS to mg kg -1 . The results suggest that nicotine and DCS synergistically enhance spatial navigation in aged rats.

A five-choice serial reaction time (5-CSRT) task was used to assess attention in rats. In this behavioral paradigm, the rats are required to spatially discriminate a short visual stimulus that will occur randomly in one of five locations while maintaining a sufficient activity level. The ability of a rat to maintain attention on the task can be measured by counting the choice accuracy (percent correct responses), whereas the probability of premature responses indicates the level of impulsivity. According to previous results [24], rats performing poorly in the task have a lower choice accuracy and make more premature responses than normally behaving individuals, i.e., a clear, inverse correlation was observed between choice accuracy and impulsiveness of rats. Methylphenidate, a psychostimulant that has been shown to alleviate the symptoms in attention deficit-hyperactivity disorder (ADHD), improved the choice accuracy of poor performing rats in this task [24]. The present results show that the correlation between choice accuracy and impulsivity exists also when the rats are tested using a reduced stimulus intensity or curtailed stimulus duration. The results of a pharmacological experiment suggested that atipamezole (30, 300, or 1000 micrograms/kg), a potent and specific alpha-2 antagonist that is known to increase the activity of monoaminergic systems in the brain, did not affect the percent correct responses in poor performers or in controls tested either at the baseline conditions or at a curtailed stimulus duration (which impaired their choice accuracy). At the doses of 300 and 1000 micrograms/kg, however, atipamezole slightly increased the probability of premature responses in all group of rats. The results of an electrophysiological study indicated that the poor choice accuracy or impulsiveness of rats is not related to the amount of cortically recorded spike-wave discharges/high voltage spindle (HVS) activity, which reflect thalamo-cortical oscillation. Atipamezole dose-dependently reduced the incidence and duration of HVSs. The present data, therefore, indicate that (a) alpha-2 antagonist treatment is not superior to methylphenidate treatment when investigated using acute administrations of the agents in poor performers of the 5-CSRT task, and (b) thalamic oscillations are not the reason for the attention deficit of rats in this model of ADHD. The relationship between choice accuracy and impulsivity is discussed.

The aim of the present study was to investigate whether the activation of alpha-1 adrenergic receptors can influence intermediate-term memory. Therefore, the effects of ST 587 (30 or 100 micrograms/kg), a putative alpha-1 agonist, on the retention of the radial arm task using non-matching to sample with a 4-h delay were investigated in rats. The results indicated that the administration of ST 587 (100 micrograms/kg) before a sampling phase increased the time to complete the sampling phase which was due to an increased number of errors of repetition (regarded as working memory errors) and a reduced number of arms visited in a given time (regarded as behavioral activity). However, this treatment increased the number of correct choices before the first error during the retention phase in this task. Since we were also interested in investigating the role of NMDA receptors in memory encoding, we investigated whether NMDA receptor modulation by d-cycloserine (1 or 10 mg/kg), a partial agonist of the glycine site on the NMDA receptor, had any influence on the performance of rats in this task. The results indicated that d-cycloserine (10 mg/kg) given before the sampling phase did not influence the performance of rats during the sampling phase, but it did improve their choice accuracy during the retention phase of this task. These data suggest that the systemic administration of either an alpha-1 agonist or an indirect agonist of NMDA receptors can facilitate intermediate-term retention of spatial information.

The present study investigated if short-term treatment with an L-type Ca2+-channel inhibitor, nimodipine, can stimulate cognitive functioning and cortical electroencephalograph (EEG) arousal, and potentiate the effect of a cholinesterase inhibitor, metrifonate. Pretraining administration of nimodipine (3, 10 and 30 mg/kg, p.o.) had no effect on water maze and passive avoidance behavior of young neurologically intact controls, or water maze and passive avoidance performance failure induced by scopolamine pretreatment (i.p.; 0.4 mg/kg during the water maze and 2.0 mg/kg during the passive avoidance study), medial septal lesioning, or aging. Furthermore, nimodipine (3, 10 and 30 mg/kg, p.o.) had no effect on the improvement by metrifonate (10 mg/kg, p.o.) of the water maze and passive avoidance failure induced by scopolamine pretreatment or medial septal lesioning, nor did it affect the potential of metrifonate (30 mg/kg. p.o.) to improve the water maze or passive avoidance behavior of aged rats. Finally, nimodipine (3, 10 and 30 mg/kg, p.o.) had no effect on spontaneously occurring thalamically generated neocortical high-voltage spindles or spectral EEG activity of young controls, nor did it alleviate the spectral EEG abnormality induced by scopolamine (0.2 mg/kg, i.p.) administration. Also, the combination of nimodipine 3 or 10 mg/kg and a subthreshold dose of metrifonate 10 mg/kg could not suppress high-voltage spindles or scopolamine treatment-induced spectral EEG activity abnormalities. According to the present results, short-term treatment with nimodipine does not stimulate cognitive functions or increase cortical EEG arousal, and does not block or potentiate the propensity of metrifonate to improve cognitive performance of rats.

A new anti-epileptic drug, tiagabine, is a potent inhibitor of GABA uptake into neurons and glia. Tiagabine has shown promising efficacy and safety profiles as add-on treatment for partial seizures. We evaluated the long-term effects of tiagabine on cognition and EEG in 37 patients with partial epilepsy. The study protocol consisted of a randomized, double-blind, placebo-controlled, parallel-group add-on study and an open-label extension study. During the 3 month double-blind phase at low doses (30 mg/day) tiagabine treatment did not cause any cognitive or EEG changes as compared with placebo. Tiagabine treatment did not cause deterioration in cognitive performance or produce any rhythmic slow-wave activity or other constant, new abnormalities on EEG during longer follow-up with successful treatment on higher doses after 6-12 months (mean 65.7 mg/day, range 30-80 mg/day) and after 18-24 months (mean dose 67.6 mg/day, range 24-80 mg/day). The daily dosages in the long-term follow-up of the present study are higher than in the previous reports.

Our preliminary results showed that mossy fibres do not undergo sprouting after global ischaemia in gerbils, although the pattern of hippocampal cell damage resembled that seen in ischaemic and epileptic rats, where mossy fibre sprouting is known to occur. In order to investigate whether the observed differences in the appearance of mossy fibre sprouting are related to the animal model or species used, this study was undertaken to compare the neuropathological changes induced in gerbils by systemic injection of kainate or by occlusion of carotid arteries with the changes induced in rats by injection of kainate. The pattern of pyramidal cell damage was very similar in each group. Mossy fibre sprouting was present in epileptic rats but not in ischaemic or epileptic gerbils. The number of somatostatin-immunoreactive neurons was decreased in the hilus of epileptic rats and ischaemic gerbils, but not in epileptic gerbils. The analysis of calretinin immunoreactivity in the dentate gyrus revealed differences between the rat and gerbil. The most striking difference between these species was that the mossy cells contained calretinin in gerbils but not in rats. Cell counting showed that the calretinin-containing mossy cells had survived both in epileptic and ischaemic gerbils. Therefore, since the mossy cells are known to be highly susceptible to excitotoxic insult in rats and degeneration of these cells is thought to be a key element in the induction of mossy fibre sprouting, we propose that the absence of mossy fibre sprouting in gerbils is related to the survival of the mossy cells.

The present experiments were designed to investigate whether the alpha-1 adrenergic and muscarinic cholinergic systems interact in the regulation of spatial navigation behavior in the Morris water maze test and passive avoidance performance. Pretraining administration of scopolamine, a muscarinic antagonist, markedly impaired the acquisition of water maze task (a hidden platform version) as well as retention of this task. The drug also impaired slightly navigation to a visible platform. Pretraining subcutaneous administration of St-587 (alpha-1 agonist) at 2000 micrograms/kg slightly improved the water maze navigation to a hidden platform in control rats, but its effect was not augmented in scopolamine-treated rats. Pretraining administration of prazosin (alpha-1 antagonist) 1000 micrograms/kg or 2000 micrograms/kg did not significantly potentiate the scopolamine (muscarinic cholinergic antagonist)-induced (doses 200 micrograms/kg and 100 micrograms/kg, pretraining intraperitoneal injection) deficit in water maze navigation. Pretraining administration of prazosin at doses 1000 micrograms/kg and 2000 micrograms/kg or St-587 at doses 1000 micrograms/kg and 2000 micrograms/kg did not have any significant influence on scopolamine-induced (200 micrograms/kg or 400 micrograms/kg) disruption in passive avoidance performance. These findings suggest that alpha-1 adrenergic mechanisms do not participate or are not the most important component of the noradrenergic system in the interaction between noradrenaline and muscarinic receptors in the modulation of learning and memory. The analysis of results indicates that activation of alpha-1 adrenoceptors might facilitate the acquisition of water maze task in its initial phase, for instance, switching from wall hugging strategy to an active exploration strategy. Furthermore, the present data suggest that muscarinic cholinergic blockade may affect both mnemonic and nonmnemonic processes in rats.

A prolonged MR T 2 relaxation time was proposed to mark the presence and severity of Alzheimer's disease (AD). We studied the value of T 2 relaxometry in diagnosing early AD. T 2 was measured from 54 patients with AD, 25 subjects with age-associated memory impairment (AAMI), 18 elderly and 16 young controls. The AD patients had longer T 2 in the right hippocampal head (104 ± 11 ms) and tail (98 ± 10 ms) than age-matched controls (95 ± 5 and 92 ± 9 ms, respectively). This prolongation was not related to age. In the AD group, the T 2 of the left hippocampal head also correlated with the clinical severity. The T 2 of the amygdala did not differ across the groups. Increased T 2 in the temporal and parietal white matter and the thalamus related to increasing age rather than to the diagnostic category. The AAMI subjects had T 2 comparable with those of age-matched controls. Despite the prolongation of T 2 in the AD group the possible diagnostic value was compromized by a substantial overlap between the study groups. We, thus, conclude that the T 2 relaxometry is not a reliable method for diagnosing early AD.