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We have used in situ hybridization with biotinylated oligonucleotide (antisense) probes and streptavidin-biotinylated alkaline phosphatase method to detect the amount of amyloid β-protein mRNA in the paraffin-embedded and formalin-fixed brain samples of patients affected by Alzheimer's disease and those of non-affected controls. Instead of the expected specific binding to neuronal cytoplasm, the probes did constantly bind to neuritic senile plaques, the strongest binding being found in the hippocampus and the cerebral cortex. We have been able to constantly repeat this peculiar phenomenon with other (30-mer) oligonucleotide probes, e.g. the sense probes for β-amyloid protein and those specific for human papillomavirus (HPV) 18- and c-erb B-2 mRNAs. Replacing the probe with water as a negative control lead to abolishment of the colour reaction, thus excluding the possibility of the non-specific staining being due to the detection system. This confirms that the oligonucleotide probe is essential for this binding phenomenon.

Quisqualic acid NBM lesions had no effect on water maze performance, but slightly impaired passive avoidance acquisition. GammavinylGABA treatment alone had no effect on the passive avoidance and water maze performance, but aggravated acquisition deficit in rats subjected to NBM lesioning. However, gammavinylGABA-treated NBM-lesioned rats reached control level of performance.

Cerebrospinal fluid (CSF) acetylcholinesterase (AChE) was determined for 11 chronic schizophrenic patients with dementia, 9 patients with dementia associated with alcoholism and 8 age-equivalent control subjects. The AChE levels in both patient groups were unrelated to the degree of cognitive decline and they were in the same range as in the control group. In schizophrenic patients no relationship was found between CSF AChE and the severity of psychotic symptoms. Our results suggest that dementia may occur in these patient groups without CSF AChE involvement.

The present study evaluated the ability of tetrahydroaminoacridine (THA) to reverse the age-related increase in high voltage spindles (HVS). THA was injected either 15 or 90 min before EEG recordings were made. A THA dose of 3 mg/kg IP decreased the incidence of HVS, but was ineffective at doses of 0.03 and 1 mg/kg. The HVS suppressing effect of THA (3 mg/kg) declined during a 10-day treatment period. After 10 days chronic THA treatment, a challenge dose of 6 mg/kg of THA reinstated HVS suppressing effect of THA. Our results suggests that (1) THA reverses the age-related deficit of thalamo-cortical activation (2) tolerance develops to THA-induced HVS suppression (3) anti-cholinesterase activity may be important for the efficacy of THA in decreasing HVS because pilocarpine, a muscarinic agonist, also decreased HVS.

Cerebrospinal fluid beta-endorphin-like immunoreactivity (CSF BLI) was determined for 11 chronic schizophrenic patients with moderate cognitive impairment, for 9 patients with dementia associated with alcoholism, and for 8 age-matched control subjects. The CSF BLI was moderately reduced (20%) in schizophrenic patients and in the alcoholics with dementia (17%) as compared with the control subjects. Our results suggest that CSF beta-endorphin levels are affected in cognitively impaired schizophrenic patients and in patients with dementia associated with alcoholism.

Dementia of the Alzheimer type (AD) is clinically characterized by a progressive deterioration of intellect, memory, judgment, and abstract thinking. It is incurable, and causal therapy is not yet available. For the development of therapeutic drugs, valid animal models are needed that mimic the pathophysiological change in brain functions and the concomitant behavioural deterioration seen in AD patients. This article provides an overview of the animal models that are used most often to study the substrates and mechanisms of the pathological changes underlying AD and to identify, characterize and develop putative neuroprotective, antidegenerative, revalidation-supporting and/or cognition-enhancing compounds or treatments. The first generation of agents for the symptomatic treatment of the disease has been developed on the basis of results obtained with these models. These drugs are presently undergoing clinical testing or are already used therapeutically. There is, however, no single animal model that can mimic the full range of pathophysiological alterations and key symptoms of AD. New, genetically engineered mouse models that mimic at least some of the key pathological changes of AD are expected to provide tools that will facilitate the development of symptomatic and preventive drug therapies.

The present study investigates the effects of ageing on the number of choline acetyltransferase (ChAT)-positive neurons in the nucleus basalis (NB) and the correlation between the number of ChAT-positive neurons and passive avoidance (PA) retention in young (3-month-old) and aged (26-month-old) rats. The results indicate that the number of ChAT-positive neurons is decreased in aged rats and that the degree of loss of NB neurons is related to the degree of PA retention deficit in aged rats.

The present experiments were carried out in order to study the interaction between alpha 2-noradrenergic and muscarinic systems in regulating high voltage spindle (HVS) activity in neocortex. Alpha 2-antagonist (atipamezole 1 and 10 mg/kg) blocked HVS activity. Atipamezole at 0.1 mg/kg dose had no effect on HVS activity. Alpha 2-agonist (guanfacine 0.004, 0.02 and 0.1 mg/kg) increased dose dependently HVSs. Guanfacine-induced HVSs were blocked by nucleus reticularis (NRT) lesions and by stimulation of either noradrenergic or cholinergic (pilocarpine) systems. Moreover, combined injections of atipamezole 1 mg/kg and pilocarpine 3 mg blocked HVSs more effectively than either of the drugs alone. Our results suggest that the NRT is jointly modulated by the noradrenergic and cholinergic afferents.

Lepola U, Mervaala E, Nousiainen U, Riekkinen P, Rimon R. Panic disorder in the differential diagnosis of temporal lobe epilepsy.Panic disorder has received little attention in the differential diagnosis of episodic behavioural symptoms. We report four patients with panic disorder previously diagnosed and treated as having intractable temporal lobe epilepsy. Comprehensive neurologic, neuro-physiologic, and neuropsychiatric evaluation resulted in appropriate drug treatment and favourable outcome of the illness.

Several experimental models of epilepsy have used kainic acid in animals to induce seizures and neuropathological changes which mimic those observed in human temporal lobe epilepsy. These models differ in the location and manner in which kainic acid is applied. In the present study, we characterized the seizure activity and neuropathological changes that occur in awake rats after kainic acid (25 ng/250 nl) is injected into the entorhinal cortex of freely moving rats. In 91% of the animals, this induced generalized motor seizures. Moreover, all of the animals survived status epilepticus. Animals were perfused two weeks after the injection for neuropathological examination. Silver-impregnation revealed that kainic acid caused pyramidal cell damage which was most severe in the CA1 subfield and to a lesser degree in the CA3c area. A loss of NADPH diaphorase-containing neurons in the hilus and the CA1 area was also consistently seen and, in most cases, a population of somatostatin-immunoreactive neurons was diminished. Our findings show that a minute amount of kainic acid delivered directly to the entorhinal cortex on unanesthetized animals reliably produces generalized seizures as well as a consistent pattern of cell damage in the hippocampus. Therefore, this model may be suitable for investigating the mechanisms underlying temporal lobe epilepsy, and may prove useful in assessing different treatment strategies for preventing seizure-induced structural damage.

The duration of formic acid (FA) pretreatment clearly influences the extent of beta-amyloid immunoreactivity in brain tissue and consequently also the results of quantitative analysis. All of the parameters studied (area fraction, density, and mean size of beta-amyloid deposits) significantly increased with pretreatment of up to 6 h with beta-amyloid antibody obtained from Dako. Longer exposure to FA only marginally increased the mean size of the single deposits, whereas the area fraction and the density of beta-amyloid deposits slightly decreased. Optimal 6-h pretreatment (or even longer) did not reveal any beta-amyloid aggregates in those cases where none was seen with shorter durations of FA pretreatment. Similar results were obtained with beta-amyloid antibody 4G8 obtained from Senetek, whereas beta-amyloid antibody 6E10 was shown to be less dependent upon FA pretreatment. In conclusion, we recommend that the FA pretreatment time should be studied and optimized for each antibody used and always be described when the quantitative analysis of beta-amyloid load is reported.

Drugs acting via alpha2-adrenoceptors modulate cognitive functions mediated via frontostriatothalamic feedback loops. The alpha2C-adrenoceptor subtype is expressed in the basal ganglia, hippocampus, and neocortex, areas that are involved in memory and other cognitive functions. alpha2C-Overexpressing (OE) mice were impaired in spatial or nonspatial water maze (WM) tests, and alpha2 antagonist treatment fully reversed the WM escape defect in OE mice. However, alpha2C-overexpression did not influence open field and passive avoidance behaviors or cortical EEG arousal or the actions of alpha2 agonist or antagonist drugs on these functions. Our results suggest that alpha2C-adrenoceptors can modulate navigation to a hidden or visible escape platform, whereas many other actions of alpha2-adrenergic agents, such as sedation, are not mediated via alpha2C-adrenoceptors. Therefore, alpha2-agonists lacking alpha2C-AR affinity or alpha2C-AR subtype-selective alpha2 antagonists could modulate functioning of frontostriatothalamic feedback loops more effectively than the current subtype-nonselective drugs.

Examination of the allelic frequency of the butyrylcholinesterase K (BChE-K) variant gene revealed no increase among Finnish late-onset Alzheimer's disease (AD) patients either as a whole or among a subset of AD patients carrying the epsilon4 allele of apolipoprotein E (ApoE4). In contrast, BChE-K allele frequency was significantly reduced in the Finnish AD patient group under 75 years of age carrying the ApoE4 allele when compared to the non-demented controls (chi2, P < 0.05). The proportion of subjects with both BChE-K and ApoE4 alleles was 14% and 41% in AD and control groups, respectively (chi2, P < 0.01; odds-ratio 0.22, 95% CI 0.07-0.71). These results are in contrast to a previous study on English AD patients, in which the genes for BChE-K and ApoE4 were suggested to act in synergy.

Levels of soluble amyloid beta protein (sAbeta), amyloid beta precursor protein (APP) and apolipoprotein E (apoE) were examined in cerebrospinal fluid (CSF) obtained twice, at baseline and after 3-year follow-up, from 25 patients with probable Alzheimer's disease (AD). Levels of sAbeta and apoE from patients with the apoE4 allele decreased with time, whereas the levels were similar in patients without apoE4 allele. Changes of sAbeta and apoE concentrations correlated significantly with those of mini-mental state examination (MMSE) scores. Levels of sAbeta did not change with time in patients with mild dementia, whereas they decreased significantly in patients with moderate dementia. ApoE concentrations decreased in both groups whereas APP levels were similar. We conclude that measurements of CSF sAbeta and apoE levels may be helpful in monitoring progression of the disease.

The present study was designed to investigate the effects of infusions into reticular nucleus of thalamus (NRT) or intracerebroventricular (i.c.v.) infusions of muscarinic M1 and M2 receptor subtype selective drugs on thalamocortically generated neocortical high voltage spindles (HVSs) in awake immobile rats. NRT administration of 2.0 and 20.0 microg McN-A-343, a muscarinic M1 agonist, and 20.0 microg methoctramine, a muscarinic M2 antagonist, suppressed HVSs. The results suggest that the blockade of presynaptic M2 receptors and activation of postsynaptic M1 receptors in the NRT suppress thalamocortical oscillations and increase neocortical electrical arousal.

WE investigated the neuropsychological correlates of hippocampal atrophy in Parkinson's disease (PD) patients. The memory impaired PD patients had smaller hippocampi than other PD patients. The performance of PD patients in spatial working memory and attentional set-shifting correlated with the severity of motor defect, and not with hippocampal atrophy. Our results suggests that failure of verbal/visual memory may be related to hippocampal atrophy in Parkinson's disease. On the contrast, the defect in spatial working memory and attentional set-shifting may be sensitive to dysfunction of ‘fronto-striatal’ systems in PD patients.

THE present study examines the efficacy of single and combined treatments with an antiocholinesterase, tetrahydroaminoacridine (THA, i.p.), and a glycine-B site partial agonist, D -cycloserine (DCS, i.p.) to alleviate water maze (WM) spatial navigation defect induced by medial septal (MS) lesion. THA 3 and DCS at 3 or 10 mg/kg improved acquisition of the WM test, but only DCS improved spatial bias. These drugs had no effect on consolidation. A combination of THA 3 and DCS 10 mg/kg enhanced WM acquisition more effectively than either of the treatments on their own. This suggests that combined modulation of acetylcholine and NMDA mechanisms may have greater therapeutic effect to stimulate cognitive dysfunctions.

We investigated the effect of tetrahydroaminoacridine, a cholinesterase inhibitor and D-cycloserine (a partial glycine-B agonist of the NMDA receptor complex) on the defect of water maze spatial navigation in rats induced by aging. Tetrahydroaminoacridine (3 mg/kg, i.p.) or D-cycloserine (10 mg/kg, i.p.) enhanced acquisition of the water maze task. A combination of subthreshold doses of tetrahydroaminoacridine (1 mg/kg) and D-cycloserine (3 mg/kg) improved water maze acquisition, but a combination of lower subthreshold doses (tetrahydroaminoacridine 0.3 mg/kg + D-cycloserine 1 mg/kg) was ineffective. Consolidation in water maze test was not improved by tetrahydroaminoacridine (3 mg/kg) and/or D-cycloserine (10 mg/kg). The results suggest that tetrahydroaminoacridine and D-cycloserine synergistically enhance acquisition of spatial navigation in aged rats.

Aspartyglucosaminuria (AGU) is a lysosomal storage disease with autosomal recessive inheritance that is caused by deficient activity of aspartylglucosaminidase (AGA), a lysosomal enzyme belonging to the newly described enzyme family of N-terminal hydrolases. An AGU mouse model was generated by targeted disruption of the AGA gene designed to mimic closely one human disease mutation. These homozygous mutant mice have no detectable AGA activity and excrete aspartylglucosamine in their urine. Analogously to the human disease, the affected homozygous animals showed storage in lysosomes in all analyzed tissues, including the brain, liver, kidney and skin, and lysosomal storage was already detected in fetuses at 19 days gestation. Electron microscopic studies of brain tissue samples demonstrated lysosomal storage vacuoles in the neurons and glia of the neocortical and cortical regions. Magnetic resonance images (MRI) facilitating monitoring of the brains of living animals indicated cerebral atrophy and hypointensity of the deep gray matter structures of brain-findings similar to those observed in human patients. AGU mice are fertile, and up to 11 months of age their movement and behavior do not differ from their age-matched littermates. However, in the Morris water maze test, a slow worsening of performance could be seen with age. The phenotype mimics well AGU in humans, the patients characteristically showing only slowly progressive mental retardation and relatively mild skeletal abnormalities.

We measured tau concentrations in cerebrospinal fluid (CSF) samples taken during the lifetime of 43 patients with Alzheimer's disease (AD) and correlated these values with neurofibrillary tangle (NFT) scores as well as glial fibrillary acidic protein (GFAP) expression as a marker of astrocytosis in the brain post-mortem. The CSF tau values showed a positive correlation with neocortical NFT scores (r = 0.44, p < 0.005), while GFAP immmunoreactivity did not correlate with CSF tau. This study reveals a high variation in CSF tau values in patients with neuropathologically confirmed AD (range 194-1539 pg/ml) and indicates that high CSF tau values in the late phase of Alzheimer's disease predict severe neurodegeneration as evidenced by increased NFT scores.

The study compared the efficacy of acute versus chronic metrifonate treatment to improve initial and reversal learning of the water maze spatial navigation task in medial septal-lesioned rats. Acute oral administration of 30 mg/kg metrifonate at 30 min, but not at 150 or 360 min, before training improved the initial acquisition of the water maze task. In contrast, improvement of initial learning performance of medial septal-lesioned rats pretreated for 21 days with metrifonate was observed irrespective of the timing of metrifonate treatment relative to behavioral testing. Reversal learning was assessed after a four-day wash-out period. No drug treatment was administered during this part of the study. All the medial septal-lesioned rats that had received only acute treatment with metrifonate during the initial learning stage were now as impaired as vehicle treated medial septal-lesioned rats. However, the group subchronically pretreated with metrifonate performed better than the vehicle-treated medial septal-lesioned controls. These results indicate that both acute and subchronic treatment with metrifonate can facilitate spatial learning in medial septal-lesioned rats and the transient nature of this beneficial effect after single acute administration is transformed into a long-lasting improvement by subchronic treatment.

OBJECTIVE: To determine the association between features of the insulin resistance syndrome and Alzheimer's disease. DESIGN: Cross sectional population based study. SUBJECTS: 980 people aged 69 to 78 (349 men, 631 women). SETTING: Population of Kuopio, eastern Finland. MAIN OUTCOME MEASURES: Presence of features of the insulin resistance syndrome and diagnosis of Alzheimer's disease by detailed neurological and neuropsychological evaluation. RESULTS: 46 (4.7%) subjects were classified as having probable or possible Alzheimer's disease. In univariate analyses, apolipoprotein E4 phenotype (odds ratio; 95% confidence interval 3.24: 1.77 to 5.92), age (1.16; 1.05 to 1.29), low level of education (0.82; 0.72 to 0.93), low total cholesterol concentration (0.77; 0.59 to 1.00), high systolic blood pressure (1.01; 1.00 to 1.03), high fasting and 2 hour plasma glucose concentrations (1.11; 1.01 to 1.23 and 1.08; 1.03 to 1.13, respectively), high fasting and 2 hour insulin concentrations (1.05; 1.02 to 1.08 and 1.003; 1.00 to 1.01, respectively), and abnormal glucose tolerance (1.86; 1.23 to 2.80) were significantly associated with Alzheimer's disease. In multivariate analysis including apolipoprotein E4 phenotype, age, education, systolic blood pressure, total cholesterol concentration, fasting glucose concentration, and insulin concentration, apolipoprotein E4 phenotype, age, education, total cholesterol, and insulin were significantly associated with Alzheimer's disease. In 532 non-diabetic subjects without the e4 allele hyperinsulinaemia was associated with an increased risk for Alzheimer's disease (prevalence of disease 7.5% v 1.4% in normoinsulinaemic subjects, P = 0.0004). In contrast, in the 228 with the e4 allele hyperinsulinaemia had no effect on the risk of disease (7.0% v 7.1%, respectively). CONCLUSION: Features of the insulin resistance syndrome are associated with Alzheimer's disease independently of apolipoprotein E4 phenotype.

The present study was designed to investigate the effect of i.c.v. administration of various muscarinic receptor antagonists in rats on memory performance in delayed non-matching to position test. The drugs chosen were the non-selective antagonist scopolamine (3 and 10 micrograms), the muscarinic M1 receptor-selective antagonist pirenzepine (10 and 30 micrograms) and the muscarinic M2 receptor-selective antagonist methoctramine (2, 5 and 20 micrograms). Scopolamine delay-independently decreased % correct choices and reduced motor activity. Pirenzepine also delay-independently decreased % correct choices. In contrast, methoctramine 2 micrograms, but not at 5 or 20 micrograms, improved slightly, but significantly, % correct performance delay-dependently. The present data suggests that the decrease in activation of inhibitory muscarinic M2 autoreceptors induced by methoctramine produces a specific improvement of short-term memory at long forgetting delays.

Background Cerebral ischemia induces a massive release of norepinephrine associated with neuronal death in the brain. It has been demonstrated that alpha2-adrenoceptor agonists decrease the release and turnover of noradrenaline, and this might prove advantageous in counteracting the neurodegeneration in ischemic brain. Therefore, in the present study, the authors tested whether dexmedetomidine, a selective alpha2-receptor agonist, has neuroprotective effects in a gerbil transient global ischemia model. Methods Ischemia was induced by bilateral carotid occlusion for 5 min in diethylether-anesthetized normothermic gerbils. Dexmedetomidine was administered subcutaneously in four different treatment paradigms (6-8 animals/group): 3 or 30 microg/kg 30 min before and thereafter at 3, 12, 24, and 48 h after the occlusion, or 3 or 30 microg/kg at 3, 12, 24, and 48 h after the occlusion. Control animals were subjected to forebrain ischemia but received only saline injections. One week after occlusion, animals were transcardially perfused for histochemistry. Neuronal death in the CA1 and CA3 regions of the hippocampus and in the hilus of the dentate gyrus was evaluated in silver-stained 60-microm coronal sections. Results Compared with saline-treated ischemic animals, dexmedetomidine at a dose of 3 microg/kg given before and continued after the induction of ischemia reduced the number of damaged neurons in the CA3 area (2 +/- 3 vs. 17 +/- 20 degenerated neurons/mm2; P < 0.05). Also in the dentate hilus, the number of damaged neurons was reduced by dexmedetomidine (3 microg/kg) given before and continued after ischemia (5 +/- 7 vs. 56 +/- 42 degenerated neurons/mm2; P < 0.01). Conclusions The present data demonstrate that dexmedetomidine effectively prevents delayed neuronal death in CA3 area and in the dentate hilus in gerbil hippocampus when the management is started before the onset of ischemia and continued for 48 h after reperfusion. Inhibition of ischemia-induced norepinephrine release may be associated with neuroprotection by dexmedetomidine.

Apolipoprotein E (APOE) has been identified as a major susceptibility marker for Alzheimer's disease (AD) and it has been proposed that a common polymorphism in the alpha1-antichymotrypsin (ACT) gene increases the risk of developing AD, when the combination of ACT/AA genotype and APOE epsilon4 allele segregate together. The ACT polymorphism was analysed in 218 sporadic late-onset AD patients and 101 healthy control subjects from Eastern Finland. Samples of the ACT polymorphism were divided into three subgroups according to their APOE genotypes and the genotyping of samples was done using the polymerase chain reaction (PCR) method. Any association between the AD group and the controls was tested with the chi2 test. Our data failed to detect any effect of polymorphism in the ACT genotypes associated with the APOE alleles, suggesting that in this population ACT does not increase the risk of AD.

We evaluated the effect of a single dose of a cholinesterase inhibitor, tetrahydroaminoacridine (THA; 25 and 50 mg, orally), on attention in patients with Alzheimer's disease (AD). THA 50 mg improved performance in attentional measures (Trail Making Test, Big/Little Circle, Simple and Choice Reaction Time) in nine of 28 patients with AD. We analysed retention of 99mTc-labelled ethylene dicysteinate (ECD) in the cortical areas using single photon emission computed tomography. Those patients who benefited from THA treatment had bilaterally higher frontal and prefrontal ECD retention values. We suggest that THA may improve attention in patients with AD, but a severe frontal dysfunction may block the therapeutic effect of THA.

The present study was designed to investigate the efficacy of stimulation of alpha1-adrenoceptors and the strychnine insensitive glycine-B binding sites of the N-methyl-D-aspartate (NMDA) receptor complex to alleviate the age-related defect in water maze (WM) spatial (hidden platform) navigation. We found that daily pretraining IP treatment with 2-(2-chloro-5-trifluoromethylphenylamino) imidazole nitrate (ST 587), an alpha1-adrenoceptor agonist, at 3000 micrograms/kg, but not at 1000 micrograms/kg, facilitated acquisition of water maze spatial navigation in aged rats. However, ST 587 3000 micrograms/kg (IP) did not stimulate WM spatial reversal learning or cue navigation to a visible platform in aged rats. A partial strychnine insensitive glycine-B binding site agonist, D-cycloserine (DCS) at 10000 micrograms/kg stimulated acquisition of WM navigation, but had no effect on reversal learning or cue navigation. DCS at 1000 or 3000 micrograms/kg (IP) had no marked effect on WM spatial navigation, and did not enhance the WM performance improving effect of ST 587 in aged rats. A subthreshold dose of ST 587 1000 micrograms/kg did not enhance the therapeutic effect of DCS 1000 micrograms/kg. The present results indicate that activation of alpha1-adrenoceptors and glycine binding sites of NMDA receptor may to some extent alleviate the age-related defect in spatial navigation. DCS treatment does not enhance the therapeutic effects of ST 587 and vice versa.

We studied cognitive function in normoglycaemic elderly subjects at different risk levels for developing non-insulin-dependent diabetes mellitus (NIDDM) and in patients with NIDDM. Risk for NIDDM was considered increased if both 2 h glucose and insulin values on oral glucose tolerance testing were higher than the median in normoglycaemic subjects, and low if the respective values were lower than the median. The increased risk group showed impairment on tests of immediate and delayed memory, attention, visuomotor speed and verbal fluency. Moreover, the increased risk group did not differ from patients with NIDDM on any cognitive tests. Our results suggest that increased risk for NIDDM is associated with widely affected cognitive function in the normoglycaemic elderly, highlighting the importance of healthy living habits.

The present experiment was designed to elucidate whether chronic dietary treatment with nimodipine (3 months, 1000 ppm) enhances water maze spatial navigation, passive avoidance behavior and locomotor activity, and whether such a treatment with nimodipine would interact with the therapeutic effect of acute metrifonate treatment. In young medial septum-lesioned rats, nimodipine had no effect by its own on cognitive or motor behavior, and did not enhance the water maze and passive avoidance behavior improving action of metrifonate (3 and 10 mg/kg, p.o.). Nimodipine treatment of aged rats did not markedly affect the deficit in motor performance. Single and combined nimodipine and metrifonate (3 and 10 mg/kg, p.o.) treatment of aged rats resulted in shorter escape distance values to the hidden water maze escape platform compared to those of control aged rats. The passive avoidance performance of aged rats was more effectively facilitated by a combined nimodipine and metrifonate treatment than by either of the drugs on their own. Following a washout period of 2.5 months the rats that were treated previously with nimodipine no longer performed better than aged controls in the water maze test. Furthermore, after the washout period metrifonate 10 mg/kg was no longer effective in improving the water maze behavior of the now 26-month-old rats irrespective of their chronic pretreatment. Taken together, these findings indicate that chronic nimodipine and acute metrifonate treatment may more effectively stimulate cognitive functioning than either of the treatments on their own.

The present study investigated the effects of bilateral dorsal hippocampal infusions with muscarinic acetylcholine (scopolamine; 3 and 10 micrograms per hemisphere) and N-methyl-D-aspartate (NMDA) (CPP; 0.01 and 0.03 microgram per hemisphere) antagonists on acquisition (drug delivered before daily training), consolidation (drug delivered after daily training) and retrieval (drug delivered only before spatial bias test) performance in a water maze (WM) spatial navigation test. Scopolamine 10 micrograms disrupted acquisition, but had no effect on consolidation or retrieval. CPP 0.03 microgram disrupted acquisition and retrieval behaviour. A combination of subthreshold doses of CPP (0.01 microgram) and scopolamine (3 micrograms) disrupted acquisition performance. The treatments did not disrupt navigation to a clearly visible escape platform. The present data indicate that dorsal hippocampal NMDA and muscarinic acetylcholine receptors are important for spatial navigation behaviour.

To assess frontal lobe functions of subjects with age-associated memory impairment (AAMI) and to examine whether performance on neuropsychological tests is correlated with the volume of the frontal lobes in magnetic resonance imaging.Cross-sectional two-group comparison.The Memory Research Clinic of Kuopio University and the Magnetic Resonance Imaging Center of Kuopio University Hospital.Ninety subjects (mean age, 70.5 years), 43 with AAMI diagnosed according to National Institute of Mental Health criteria and 47 age-matched healthy controls.Four neuropsychological tests were used to assess frontal lobe function: Verbal Fluency Test (VFT), Modified Wisconsin Card Sorting Test (WCST), Trail Making Test (TMT), and Stroop Test (ST). A 1.5-T magnetic resonance imager was used for volume measurements.The AAMI subjects scored significantly worse on the WCST, ST, and TMT compared with controls (ANCOVA, adjusted for age and education, p0.05). The frontal lobe volumes did not differ between AAMI subjects and controls.AAMI subjects appear to be impaired not only in tests assessing memory but also in tests of executive functions. This finding agrees with previous reports suggesting a central role for frontal dysfunction in memory loss of elderly people.

We studied the effect of nimodipine (1000 ppm mixed in food), an L-type calcium-channel antagonist, administered for 4 months, on the cortical EEG activity in young and aged rats. Nimodipine treatment decreased cortical high voltage spindles (HVSs) in aged rats, but did not prevent the diminution of spontaneous locomotor activity. The threshold dose of metrifonate, a cholinesterase inhibitor, for suppression of HVSs was lower in nimodipine compared to placebo treated aged rats (30 mg/kg versus 60 mg/kg; p.o.). In young rats, nimodipine did not decrease HVSs, protect from scopolamine (0.1 or 0.8 mg/kg, i.p.) induced EEG slowing or augment the effect of metrifonate to suppress slow waves induced by scopolamine. The present results suggest that a chronic nimodipine treatment modulates thalamocortical arousal and thereby adds to the therapeutic effects of metrifonate to restore normal cortical electrical arousal in aged rats.

Locus coeruleus (LC) noradrenaline (NA) neurons innervate forebrain structures, such as hippocampus, thalamus and cortex, that are important for the regulation of cognitive processes (Foote, 1987). Dysfunction of LC NA cells has been associated with the cognitive decline observed in Parkinson’s disease (PD) and in some patients with Alzheimer disease (AD). Indeed, the number of LC cells may be severely depleted in the brains of AD and PD patients.

We investigated the effect of apolipoprotein E (apoE) genotype on amyloid load in the frontal and cerebellar cortices of 24 patients with definite Alzheimer disease (AD) and 19 controls. Amyloid load was examined by using two methods: 1) acid-extractable amyloid beta-protein (A beta) and insoluble A beta levels of frontal and cerebellar cortices were measured by using enzyme-linked immunosorbent assay, and 2) all types of amyloid plaques and neurofibrillary tangles (NFT) in the frontal cortices were counted after silver staining. Acid-extractable A beta and insoluble A beta levels were higher in AD brains than controls, although there was an overlap between the groups. Acid-extractable A beta and insoluble A beta levels were higher from AD and controls with the apoE epsilon 4 alleles than those without such alleles. However, the differences did not reach statistical significance in AD group. There was no correlation between acid-extractable A beta or insoluble A3 levels and the number of amyloid plaques in AD and control brains. However, insoluble A beta levels correlated positively with the number of NFT in AD brains. Our results show that although apoE epsilon 4 influences the accumulation of A beta, multiple processes may be involved in deposition of A beta in the brain.

To investigate the roles of the cholinergic system and 5-HT2 receptors in the modulation of thalamocortical oscillations, we studied the effects of systemic (s.c.) administration of anticholinesterases (physostigmine, tetrahydroaminoacridine) and muscarinic acetylcholine receptor agonists (pilocarpine, oxotremorine) on spontaneous thalamically generated rhythmic neocortical high-voltage spindles in adult rats pretreated with either saline or ketanserin, a 5-HT2 receptor antagonist. Ketanserin at 20.0 mg/kg increased the number of high-voltage spindles. In saline-treated rats, tetrahydroaminoacridine 3.0 and 9.0 mg/kg was able to decrease high-voltage spindles, whereas in ketanserin 20.0 mg/kg-treated rats only the highest dose of tetrahydroaminoacridine (9.0 mg/kg) decreased high-voltage spindles. Both doses of physostigmine, 0.12 and 0.36 mg/kg, decreased high-voltage spindles in both saline and ketanserin 20.0 mg/kg-treated rats. Lower doses of tetrahydroaminoacridine (1.0 mg/kg) and physostigmine (0.06 mg/kg) were ineffective in both saline- and ketanserin 20.0 mg/kg-treated rats. Pilocarpine 3.0 mg/kg and oxotremorine 0.1 and 0.9 mg/kg decreased high-voltage spindles in saline-treated rats. However, in rats treated with ketanserin 20.0 mg/kg, only the lower doses of pilocarpine (0.3 and 1.0 mg/kg) and oxotremorine (0.03 mg/kg) were able to decrease the high-voltage spindles. The results suggest that activation of the cholinergic system and activation of 5-HT2 receptors have additive effects in the suppression of thalamocortical oscillations and related neocortical high-voltage spindles in rats, thus maintaining effective information processing in thalamocortical networks.

We compared auditory event-related potentials (ERPs) and neuropsychological test scores in nine patients with non-insulin-dependent diabetes mellitus (NIDDM) and in nine control subjects. The measures of automatic stimulus processing, habituation of auditory N100 and mismatch negativity (MMN) were impaired in patients. No differences were observed in the N2b and P3 components, which presumably reflect conscious cognitive analysis of the stimuli. A trend towards impaired performance in the Digit Span backward was found in diabetic subjects, but in the tests of secondary or long-term memory the groups were comparable. Patients with NIDDM may have defects in arousal and in the automatic ability to redirect attention, which can affect their cognitive performance.

Introduction - Down's syndrome patients express a neurodegenerative disorder and mental retardation. We studied the reactivity of EEG and its correlation with neuropsychological test score in Down's syndrome. Material and methods - We studied 32 patients with Down's syndrome and 31 controls for blocking of occipital EEG activity. The temporo-occipital EEG with eyes open (EO) was compared with resting EEG with eyes closed (EC), (EC/EO ratio). Results - Both Down patients and controls showed significant diminution of alpha, beta and theta activity and decrease of EEG frequency with EO. However, there was a significant impairment in Down patients in the EC/EO ratio in alpha band, compared to controls. The controls had no correlation of the alpha EC/EO ratio with age or gender. The Down patients showed a significant correlation of this variable with age which is in accordance with a gradually progressing disease. They had also significant correlations of the alpha EC/EO ratio and neuropsychological test scores which indicates that this ratio may be a more general measure of cerebral or hemispherical dysfunction than a mere impairment of visual activation. Down patients also showed significant differences in resting EEG variables, compared to the controls, even if the conventional EEG showed normal or mildly slowed dominant occipital rhythm in most of the patients. The correlation analysis between resting EEG and EC/EO ratio variables pointed out that they are relatively independent, representing different factors in the regulation of EEG. Conclusions - We believe that the alpha EC/EO ratio of EEG add a new domain in the assessment of cerebral dysfunction in Down's syndrome.

Childhood hyperactivity (attention deficit hyperactivity disorder, ADHD) is a common behavior disorder among grade-school children. The characteristic symptoms are attentional problems and hyperkinesia. A number of animal models for ADHD syndrome have been developed, but very few of these models are truly representative in that they rarely describe both hyperactivity and attentional problems. Frequently the disorder has been induced in animals by pharmacological manipulations or exogenous brain lesions which are distinct from the disturbances in normal developmental processes which ultimately lead to ADHD. The main purpose of the present research was to develop a new animal model of ADHD, such that it would include an attention deficit, hyperactivity and alleviation by treatment with a psychostimulant. We used rats trained for a 5-choice serial reaction time task which assessed sustained attention. In this behavioral paradigm, rats are required to discriminate spatially a short visual stimulus that will occur randomly in one of five locations and have to maintain an adequate activity level. The ability of a rat to maintain its attention on the task can be measured by counting choice accuracy (percent correct responses), whereas percentage of premature responses indicates the level of motoric activity. According to the present results, rats performing poorly in the task have poorer choice accuracy and they make more premature responses than well performing individuals, i.e., a clear correlation was observed between these parameters (r = -0.59, p.001). Interestingly, choice accuracy of poorly performing rats was found to be better at the beginning of testing, but it became impaired toward the end of testing session. It was also found that the deficiency was not due to impaired visual discrimination, since a reduction in the intensity of the visual stimulus impaired to a similar extent the performance of normal and poorly performing subjects. Equally, no relationship was observed between choice accuracy and the latencies to collect earned food pellets after the correct responses, indicating that motivational factors do not underlie the attention deficit or excessive activity of poorly performers. Furthermore, methylphenidate hydrochloride at doses of 100 and 1000 micrograms/kg slightly improved the attentional performance of poorly performing animals. At the dose 100 micrograms/kg, methylphenidate slightly decreased the probability of premature responses (impulsivity) in these rats, but 1000 micrograms/kg methylphenidate increased the impulsivity of both normal and poorly performing rats. However, methylphenidate did not affect the choice accuracy of normal animals tested at the baseline conditions or with the reduced stimulus duration which impaired their performance. The present data indicate that rats showing poor performance when trained and tested in a 5-choice serial reaction time task may be a model for ADHD.

We investigated the effects of acute p.o. pretraining treatment with an indirect acetylcholinesterase inhibitor, metrifonate, on water maze spatial navigation and passive avoidance behavior. Metrifonate (10-100 mg/kg, orally, p.o.) did not improve the water maze or passive avoidance performance of young intact rats. However, in young rats metrifonate over a broad dosage range (10-100 mg/kg, p.o.) was able to alleviate the adverse effects of scopolamine (a muscarinic acetylcholine receptor antagonist; 0.4 and 2.0 mg/kg in water maze and passive avoidance study, respectively) and medial septum-lesioning on spatial reference and working memory and passive avoidance performance. In old (23-month-old) rats, a defect of water maze and passive avoidance behavior was observed. In old rats, metrifonate improved spatial reference memory function in the water maze and also passive avoidance at 10-30 mg/kg, but the 3 mg/kg dose was ineffective. Very old (27-month-old) rats had a more severe impairment of water maze performance than old rats, and metrifonate 3-30 mg/kg did not improve their spatial navigation. These results show that metrifonate may over a wide range of doses stimulate cognitive functioning, but during advanced aging neurobiological defects develop that may mask some of the therapeutic effects of metrifonate in rats.

The present study investigates the effects of nicotine (0.1 and 0.3 mg/kg) and tetrahydroaminoacridine (3 mg/kg) treatment on spatial navigation in aged control and p-chlorophenylalanine (a serotonin (5-hydroxytryptamine, 5-HT) synthesis inhibitor, 400 mg/kg on 3 successive days, i.p.)-treated rats. p-Chlorophenylalanine did not aggravate the water maze failure of aged rats. Nicotine (0.3 mg/kg) was more effective than tetrahydroaminoacridine (3 mg/kg) in promoting water maze navigation by aged control rats. p-Chlorophenylalanine blocked the therapeutic effect of nicotine (0.3 mg/kg), but did not decrease the effect of tetrahydroaminoacridine (3 mg/kg) in aged rats. Frontal cortex dopamine levels and choline acetyltransferase activity were lower in aged rats, but 5-HT and noradrenaline levels were unaltered. p-Chlorophenylalanine decreased selectively 5-HT levels in young rats, but in aged rats 5-HT, dopamine and noradrenaline levels were decreased. These results suggest that aged rats are neurochemically more sensitive to p-chlorophenylalanine treatment and that tetrahydroaminoacridine may more effectively than nicotine stimulate spatial learning if 5-HT, dopamine and noradrenaline systems are severely affected.

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.

Summary Different diagnostic definitions have been proposed for use in the characterization of mild cognitive disorders associated with ageing. Previously, we reported a high (38.4%) prevalence of age-associated memory impairment (AAMI) using the National Institute of Mental Health criteria in an elderly population. Recently, a work group of the International Psychogeriatric Association proposed criteria for 'ageing-associated cognitive decline' (AACD). The objective of this study was to evaluate the prevalence of AACD in an elderly population. We examined 403 randomly selected subjects (68-78 years of age) with tests of memory, cognitive processing, attention, verbal and visuoconstructive functions and with a structured questionnaire for health status and subjective complaints of cognitive decline. In all, 26.6% of the subjects (24.4% of women, 30.1% of men) fulfilled the AACD criteria. The prevalence was slightly related to age and education. The rate was lowest in the oldest age group of 75-78 years (20.5%) and highest in the age group of 71-74 years (30.5%). Subjects with less than 4 years of education had the lowest (14.3%) and subjects with more than 6 years of education had the highest rate (29.4%) for AACD. However, the differences between these subgroups were not statistically significant. These results suggest that the prevalence of AACD is lower than that of AAMI. As AAMI tends to identify a very heterogeneous subject group, the AACD diagnosis, which takes into account age and education specific norms in its inclusion criteria, might prove superior to AAMI in differentiating a meaningful subgroup from an elderly population both for research purposes and in clinical settings.