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Apolipoprotein E (ApoE) is associated with Alzheimer's disease (AD) neurofibrillary tangles and beta-amyloid protein in senile plaques. There are three common alleles of ApoE, designated epsilon 2, epsilon 3 and epsilon 4. We studied Finnish patients with neurodegenerative disorders: AD, vascular dementia (VAD), Parkinson's disease (PD), PD+dementia (PDD), Lewy body variant of AD (LB), frontal dementia (FD), and Down's syndrome (DS), as well as control individuals (C). The ApoE genotypes and corresponding allele frequencies of 188 patients and 60 controls were determined by digestion of ApoE polymerase chain reaction products with the restriction enzyme Hha I. The ApoE epsilon 4 allele frequency was 0.17 for C, 0.44 for AD, 0.35 for VAD, 0.10 for PD, 0.38 for PDD, 0.28 for LB, 0.39 for FD, and 0.17 for DS. We found significant differences in genotype frequency between AD/C, AD/PD and AD/DS. Our results suggest that, beside AD, an increased frequency of epsilon 4 may also be involved in other dementing neurological disorders.

We measured the activities of choline acetyltransferase (ChAT) in the post mortem frontal cortex in 32 Alzheimer's disease (AD) patients with different apolipoprotein E (apoE) genotypes. The ChAT values were significantly lower for the AD patients with 2 epsilon 4 alleles than for those with 0 epsilon 4 (ANOVA, P0.05). The ChAT activities of AD patients carrying 2 or 1 epsilon 4 alleles and those without the epsilon 4 allele also differed significantly: 16.3 +/- 15.2 versus 30.5 +/- 20.6 pmol/mg protein per min, ANOVA, P0.05. However, the AD patients carrying the epsilon 4 allele were significantly younger than those with 0 epsilon 4 allele. The study indicates that AD patients carrying the epsilon 4 allele have a more severe cholinergic deficit than the AD patients without the epsilon 4 allele.

The results of the present study indicate that D-cycloserine, a partial agonist at the glycine binding site, which is a positive modulation site of the N-methyl-D-aspartate receptor, could improve dose dependently the acquisition of a water maze task in rats treated with scopolamine, a muscarinic antagonist. The low to moderate doses of D-cycloserine which improved learning did not affect swimming speed in scopolamine-treated rats. The higher dose did not improve learning, but it increased swimming speed in scopolamine-treated rats. These results show a dissociation between impaired acquisition and abnormal behavioral activity in scopolamine-treated rats in the water maze task. Furthermore, the present results suggest that D-cycloserine can act as a cognitive enhancer at the appropriate doses.

The thalamus is involved in the regulation of the neocortical rhythmicity reflected in EEG as the alpha rhythm. Recent evidence suggests that the thalamus is affected in Alzheimer's disease (AD). We studied the relationship between the dominant occipital rhythm of the lifetime EEG and the choline acetyltransferase activity (ChAT) and monoamine concentrations in the postmortem thalamus of 20 histologically verified AD patients. The AD patients were divided into 3 groups (5–6 Hz, 7 Hz and 8–9 Hz) according to the frequency of the dominant occipital rhythm (FOC). Noradrenaline (NA) concentrations were significantly lower for the 5–6 Hz and 7 Hz subgroups as compared to the 8–9 Hz subgroup. The NA content of the thalamus correlated significantly with the FOC (r=0.46, P=0.04). The ChAT activity or concentra-tions of dopamine or serotonin did not correlate with the FOC or differ across the AD subgroups. The result suggests that the noradrenergic deficit of the thalamus may contribute to slowing of the dominant occipital rhythm in AD.

In this study, we screened for the amyloid beta precursor protein (APP) 665 (glutamic acid to aspartic acid), 670/671 (lysine to asparagine and methionine to leucine) and 717 (valine to isoleucine) mutations in 34 persons affected with familial Alzheimer's disease (AD) and 139 with sporadic AD, originating from eastern Finland, using polymerase chain reaction amplification and restriction enzyme digestion. We did not find any of these mutations in the APP gene in our study. We conclude that these mutations in the APP gene may be a very rare cause of AD in Eastern Finland and thus most Finnish familial AD will likely be due to other gene defects.

Apolipoprotein E is a polymorphic protein defined by three alleles, epsilon 2, epsilon 3 and epsilon 4. An increased frequency of the epsilon 4 allele is associated with late-onset familial and sporadic Alzheimer's disease (AD). We studied 202 Finnish AD patients and 55 age- and sex-matched controls. AD patients were divided into four subgroups; sporadic early-onset, sporadic late-onset, familial early-onset and familial late-onset disease. We found no significant differences in the epsilon 4 allele frequency between the subgroups. However, all the subgroups differed in the frequency of epsilon 4 allele detection from the controls (P < 0.0001). In the late-onset patients, the age at onset decreased from 76 to 69 as the number of epsilon 4 alleles increased from 0 to 2.

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.

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.

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.

The apolipoprotein E epsilon4 allele is the most common risk factor for Alzheimer's disease (AD). The epsilon2 allele may play a protective role in AD. Our previous cross-sectional study showed that in non-demented elderly subjects the epsilon2 allele is associated with better learning ability than other alleles. We wished to investigate the influence of different apolipoprotein E (apoE) phenotypes on cognitive functions in a 3-year follow-up study starting with a random sample of 917 non demented elderly subjects. Episodic memory was examined with the List Learning Test (Buschke's selective reminding method), as well as with immediate and delayed recall of figures. Retrieval from semantic memory was assessed with the Category and Verbal Fluency tests. Constructional abilities were examined by copying figures. Attention functions were examined with the Trail Making A and B tests. A total of 632 subjects completed the 3-year follow-up study. The subjects with apoE phenotypes E2/2 or E2/3 were able to maintain their verbal learning performance, while the learning ability of the subjects with other apoE phenotypes deteriorated. We suggest that successful mental aging may be at least in part associated with genetic factors.

We studied the neuroprotective effect of vigabatrin (gamma-vinyl GABA, VGB) in the rat hippocampus after status epilepticus (SE) induced by kainic acid (KA). Rats were treated with VGB (500 or 1000 mg/kg, i.p.) 24 h before KA injection (9 mg/kg, i.p.). The lower dose of VGB had no effect on the generation or severity of convulsions. However, VGB decreased neuronal damage in the CA3a (P < 0.05) and CA1 (P < 0.01) subfields of the hippocampus. The higher dose of VGB attenuated the severity of convulsions (P < 0.05) but had no effect on the development or generalization of convulsions. This finding may have clinical implications in the prevention of neuronal damage induced by drug refractory seizures or SE.

The present study investigated if acute treatment with tetrahydroaminoacridine (THA) (25 or 75 mg, p.o.) affects technetium-99m labelled ethylene dicysteinate (ECD) retention abnormalities in patients with mild to moderate Alzheimer's disease (AD; mean age 69 years). THA (75 mg) increased temporal, prefrontal and occipital ECD retention (normalized to cerebellum) in mildly demented AD patients, but 25 mg of THA had no effect on ECD retention. After 75 mg THA, prefrontal and temporal ECD retention correlated with improved executive and memory functioning, respectively. THA (25 or 75 mg) had no measurable effect on ECD retention of moderately demented patients.

Several studies have shown an association between the apolipoprotein epsilon 4 allele and Alzheimer's disease (AD). The allele epsilon 2 has been associated with survival and longevity. We wanted to examine whether the relationship between cognitive efficiency and apolipoprotein E polymorphism (APOE) exists in a random sample of 916 non-demented elderly subjects. Episodic memory was examined with the list learning test, and with immediate and delayed recall of the figures. Semantic memory was examined with the Category and Verbal Fluency Tests. Constructional abilities were examined by copying the figures. Attention functions were examined with Trail Making A and B tests. We found that subjects with APOE E2/2 and 2/3 phenotypes showed better learning ability than those subjects with the APOE E2/4, 3/4 or 4/4 phenotypes. Impaired memory was not related to the excess of cardiovascular diseases in the subjects with APOE E2/4, 3/4, 4/4 phenotypes. Thus they may be associated, at least partly, with genetic factors.

We report the results of our study suggesting that a single dose pharmaco-EEG may predict treatment response to tetrahydroaminoacridine (THA) in Alzheimer's disease (AD). 14 AD patients and 7 age-matched neurologically healthy controls were selected for the study. AD patients had 7 weeks' THA treatment. 6 patients were regarded as responders and 8 patients as nonresponders, respectively. AD patients as well as controls had a baseline EEG recording and next day another recording 90 minutes after a peroral single dose of 50 mg THA. The relative change from the baseline in the alpha-theta ratio was the most sensitive discriminator of responders and nonresponders (P = 0.004, ANOVA).

Choline acetyltransferase (ChAT) activity in the cerebral cortex and the different solubility fractions of acetylcholinesterase (AChE) in the cerebral cortex and cerebellum were investigated in rats of different ages. ChAT activity was not decreased markedly in the cerebral cortex of 24- to 25-month-old rats compared to 3- to 4-month-old rats. The activity of detergent-soluble (DS) AChE in the cerebral cortex and cerebellum was lower in the older rats (24–25 months) rats than in younger (3–4 months) ones. The activity of DS-AChE in the cerebral cortex and cerebellum did not differ between 10- to 11-month-old and 24- to 25-month-old rats. The activity of low salt soluble (LSS) AChE in the cerebral cortex and cerebellum did not differ between older and younger rats.

The activity of 2′,3′-cyclic nucleotide-3′-phosphodiesterase (CNPase) was determined as an index of myelin in the post-mortem brain samples of 16 patients with Alzheimer's disease (AD) and of 14 controls. The CNPase activity was mildly increased in the temporal, hippocampal and parietal cortex in AD subjects pointing to a relative sparing of myelin as compared to the neuron loss within cortex in AD. In the hippocampus the CNPase activity was decreased in AD patients indicating loss of myelin and thus myelinated axons in this area in AD.

The circadian rhythm and dehydration-induced response of vasopressin (AVP) levels in rat cerebrospinal fluid (CSF) were studied after lesions had been made in the paraventricular (PVN) and suprachiasmatic (SCN) nuclei. The rhythmic fluctuation of AVP levels in CSF was abolished after SCN lesions, whereas lesions of the PVN had no effect. Dehydration seems to increase AVP levels in CSF of both sham-operated and lesioned animals. These data further suggest that the circadian rhythm of AVP in CSF is preferentially generated by SCN. In contrast, several areas of the brain may contribute to the overall AVP levels in CSF, both under normal physiological conditions and under osmotic stress.

Somatostatin levels of the cerebrospinal fluid (CSF) were correlated with variables of quantitative EEG and with neuropsychological performance in patients with probable Alzheimer's disease. Low somatostatin levels of CSF correlated with decreased beta activity and with decreased mean frequency in the combined alpha and theta EEG range. In the subgroup of mild Alzheimer cases CSF somatostatin correlated positively also with alpha power, and the peak and the mean frequency, and negatively with theta power but not with delta activity. Furthermore, low somatostatin of the CSF correlated with neuropsychological tests assessing temporoparietal dysfunction. To our knowledge, this is the first study to indicate the correlation between spectral analysis results of the EEG and CSF somatostatin suggesting that the relationship between somatostatin and EEG variables is worthy of further studies.

The effect of desglycinamide-arginine-vasopressin (DGAVP) on monoaminergic neurotransmission was studied in human subjects. Samples of cerebrospinal fluid (CSF) were collected during 240 min after DGAVP (2 mg) had been administered intranasally, and monoamine metabolites in CSF were measured with HPLC using electrochemical detection. Levels of homovanillic acid and 5-hydroxyindoleacetic acid increased (P less than 0.05) 150 min after DGAVP administration, whereas levels of 3-methoxy-4-hydroxyphenylglycol were stable during the time monitored. These results suggest that in human subjects the mechanism of action of DGAVP may involve dopaminergic and serotonergic systems.

To study free brain amino acids and their relation to dementia, the levels of glutamate, glutamate, asparagine, aspartate, glycine, taurine, homocarnosine and gamma-aminobutyric acid were determined in the temporal cortex and caudate nucleus in demented and non-demented patients with Parkinson's disease. In the temporal cortex, the levels of aspartate and asparagine were significantly increased in non-demented parkinsonian patients as compared both to demented patients and to controls. In the caudate nucleus no significant changes in amino acid levels were seen. Thus, the cortical and striatal glutamate/aspartate systems seem to be preserved in dementia in Parkinson's disease.