Analysis of SNAP25 mRNA expression and promoter DNA methylation in brain areas of Alzheimer's Disease patients.

Alzheimer's Disease (AD) is the most common cause of dementia in elderly people. The presynaptic terminal is an important site of pathological changes in AD, leading to synaptic loss in specific brain regions, such as in the cortex and hippocampus. In this study, we investigated synaptosomal-associated protein, 25-kDa (SNAP25) mRNA levels and promoter DNA methylation in post mortem brain tissues (entorhinal and auditory cortices and hippocampus) from healthy elderly and AD subjects as well as in peripheral blood leukocytes of young, healthy elderly and AD patients. mRNA quantification was performed by quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR) using the ΔΔC(T) method and promoter DNA methylation was quantified by mass spectrometry using the Sequenom EpiTYPER platform. We observed a significant decrease in SNAP25 expression in AD across all the three brain regions in relation to the healthy elderly subjects, suggesting impairment in synaptic function. The changes in the auditory cortex reflected those observed in the hippocampus and entorhinal cortex, the primary areas affected in AD. However, no AD-associated differences in SNAP25 promoter DNA methylation were observed suggesting that other mechanisms may be involved in mediating the observed gene expression changes.

Clinical correlates of olfactory dysfunction in spinocerebellar ataxia type 3.

Olfactory dysfunction is a very common and early sign in neurodegenerative disorders, but few data are already available in hereditary ataxias. Our aim was to evaluate the sense of smell in patients with molecular-proven spinocerebellar ataxia type 3 (SCA3). Forty-one patients with SCA3 and 46 control subjects were studied. The sense of smell was tested using the Sniffin's Sticks (SS-16). We also evaluated Mini-Mental State Examination (MMSE) and non-cerebellar symptoms, such as parkinsonism, dystonia, and restless legs syndrome (RLS). The SCA3 group had significantly lower SS-16 scores than controls (11.5 ± 2.4 vs 12.8 ± 1.5, p = 0.003). Multiple linear regression analyses, controlling for age, sex, education, cigarette smoking, and MMSE scores, showed that SCA3 (p = 0.021), sex (p = 0.003) and MMSE scores (p = 0.002) had significant regression coefficients. All the variables taken together were significantly associated with the SS-16 scores (p ≤ 0.001). Although MMSE scores and female sex were stronger predictors of the SS-16 scores than SCA3, subjects with SCA3 had lower scores on the SS-16, regardless of sex or MMSE scores. Additionally, MMSE scores, sex and presence of RLS were the best predictors of SS-16 scores. Overall, our results strengthen that the sense of smell is significantly reduced in patients with SCA3 and that sex, MMSE scores and RLS also influence the SS-16 scores.

Memory with emotional content, brain amygdala and Alzheimer's disease.

OBJECTIVES: A highly adaptive aspect of human memory is the enhancement of explicit, consciously accessible memory by emotional stimuli. We studied the performance of Alzheimer's disease (AD) patients and elderly controls using a memory battery with emotional content, and we correlated these results with the amygdala and hippocampus volume. METHODS: Twenty controls and 20 early AD patients were subjected to the International Affective Picture System (IAPS) and to magnetic resonance imaging-based volumetric measurements of the medial temporal lobe structures. RESULTS: The results show that excluding control group subjects with 5 or more years of schooling, both groups showed improvement with pleasant or unpleasant figures for the IAPS in an immediate free recall test. Likewise, in a delayed free recall test, both the controls and the AD group showed improvement for pleasant pictures, when education factor was not controlled. The AD group showed improvement in the immediate and delayed free recall test proportional to the medial temporal lobe structures, with no significant clinical correlation between affective valence and amygdala volume. CONCLUSION: AD patients can correctly identify emotions, at least at this early stage, but this does not improve their memory performance.

Recognition memory for emotional pictures in Alzheimer's patients.

OBJECTIVE: The purpose of the present study was to examine whether Alzheimer's Disease (AD) patients can benefit from the emotional content of visual stimuli in a picture recognition test. METHODS: Sixteen patients with AD and 19 normal controls matched for age and years of education, were studied. Sixteen pictures (with varying emotional contents) were presented to each participant. Thirty minutes later, a recognition test was applied with the target-pictures mixed among 34 others of similar content. The subjects were instructed to rate them as pleasant, unpleasant or indifferent. RESULTS: The total of pictures correctly recognized by the AD patients (75.4% of the target-pictures) was smaller than that of the controls (96.4%). Controls recognized more emotional pictures than indifferent pictures. CONCLUSION: Emotional content enhanced recognition of pictures in normal subjects, whereas for the Alzheimer's subjects the emotional significance attached to the pictures was of no benefit to enhance recognition.

The cognitive subscale of the "Alzheimer's Disease Assessment Scale" in a Brazilian sample.

The cognitive subscale of the "Alzheimer's Disease Assessment Scale" (ADAS-Cog) is widely used for the evaluation of dementia and is very popular in dementia drug trials because of the characteristics of the scale. The objective of the present study was to adapt the ADAS-Cog for use for the Brazilian population. A major problem is that education is variable, a fact that may influence performance in cognitive evaluation. This study was conducted on a control group (CG) of 96 subjects (25 males and 71 females aged 68 +/- 8.6 years) and on 44 Alzheimer's disease (AD) patients (19 males and 25 females aged 72 +/- 6.4 years) with mild dementia (Clinical Dementia Rating score 1). For statistical analysis groups were divided into three educational levels: I, 0-4 years of schooling (65 CG/20 AD); II, 5-11 years of schooling (19 CG/7 AD), and III, 12 or more years of schooling (12 CG/17 AD). The battery was applied according to original instructions. Total mean score for CG and AD was 10.9 and 22.9 for level I, 7.8 and 22.4 for level II, and 6.2 and 15.4 for level III, respectively. These results indicate that our version of the ADAS-Cog is useful to identify mild dementia, though there may be an overlapping when comparing high education demented with low education non-demented subjects.

Applicability of the CERAD neuropsychological battery to Brazilian elderly.

There is a limited choice of psychometric tests for Portuguese speaking people which have been evaluated in well defined groups. A Portuguese version of CERAD neuropsychological battery was applied to a control group of healthy elderly (CG) (mean age 75.1 years/ education 7.9 years), 31 Alzheimer disease (AD) patients classified by clinical dementia rating (CDR) as CDR1 (71.4/ 9.0) and 12 AD patients CDR 2 (74.1/ 9.3). Cut-off points were: verbal fluency-11; modified Boston naming-12; Mini-mental State Examination (MMSE) -26; word list memory-13; constructional praxis-9; word recall-3, word recognition-7; praxis recall-4. There was a significant difference between CG and AD-CDR1 (p<0.0001) for all tests. There was a less significant difference for constructional praxis and no difference for Boston naming. Comparison between AD-CDR1 and AD-CDR2 showed difference only for MMSE, verbal fluency, and Boston naming. The performance of CG was similar to that of a US control sample with comparable education level. These results indicate that this adaptation may be useful for the diagnosis of mild dementia but further studies are needed to define cut-offs for illiterates/low education people.

The cognitive subscale of the "Alzheimer's Disease Assessment Scale" in a Brazilian sample

The cognitive subscale of the "Alzheimer's Disease Assessment Scale" (ADAS-Cog) is widely used for the evaluation of dementia and is very popular in dementia drug trials because of the characteristics of the scale. The objective of the present study was to adapt the ADAS-Cog for use for the Brazilian population. A major problem is that education is variable, a fact that may influence performance in cognitive evaluation. This study was conducted on a control group (CG) of 96 subjects (25 males and 71 females aged 68 + or - 8.6 years) and on 44 Alzheimer's disease (AD) patients (19 males and 25 females aged 72 + or - 6.4 years) with mild dementia (Clinical Dementia Rating score 1). For statistical analysis groups were divided into three educational levels: I, 0-4 years of schooling (65 CG/20 AD); II, 5-11 years of schooling (19 CG/7 AD), and III, 12 or more years of schooling (12 CG/17 AD). The battery was applied according to original instructions. Total mean score for CG and AD was 10.9 and 22.9 for level I, 7.8 and 22.4 for level II, and 6.2 and 15.4 for level III, respectively. These results indicate that our version of the ADAS-Cog is useful to identify mild dementia, though there may be an overlapping when comparing high education demented with low education non-demented subjects

[Generalized anxiety disorder in a population aged 80 years and older]. / Transtorno de ansiedade generalizada em idosos com oitenta anos ou mais.

OBJECTIVE: To describe the prevalence of generalized anxiety disorder (GAD) in a community-dwelling population aged 80 years and older. Also to compare sleep patterns, cognitive function and prevalence of other psychiatric conditions between healthy controls and GAD subjects. METHODS: DSM-IV criteria were used to diagnose GAD. A representative random sample of 77 community-dwelling subjects (35%), aged 80 years or more from the rural southern county of Veranopolis, Brazil, was selected. Sleep patterns were assessed using the Pittsburgh Sleep Quality Index and a 2-week sleep/wake diary. Five neuropsychological tests (Buschke-Fuld Selective Reminding Test, CERAD word list, verbal fluency test and two sub-tests of the Wechsler memory scale) were used for cognitive evaluation. RESULTS: The estimated GAD prevalence was 10.6 percent. GAD was associated with major depression, with a significant greater number of depressive symptoms as measured by the Geriatric Depression Scale and with a significant more frequent occurrence of minor depression. Sleeping patterns and cognition function among GAD subjects were not compromised. The severity of physical diseases was similar in both GAD subjects and healthy controls. GAD was associated with a significantly lower health-related quality of life. CONCLUSIONS: In comparison with previous studies, the prevalence of GAD is higher in the studied population. This disorder is frequently associated with both depressive symptoms and a lower health-related quality of life.

Quantitative evaluation of the rRNA in Alzheimer's disease.

The ribosomal RNA (rRNA) genes are located in nucleolus during active transcription and are transcribed by RNA polymerase I. This group of genes is involved in transcription and translation processes which can modulate gene expression. The association between rRNA levels and aging has been reported. In the present study, we investigated the ratio of mature rRNA 28S and 18S in peripheral blood of 15 Alzheimer's disease (AD) patients, 15 elderly healthy controls and 15 healthy young controls. Our results showed a statistically significant decrease of the mature rRNA 28S/18S ratio in AD patients when compared with the elderly and young control groups. Thus we can suggest that there is a possible change in the transcriptional or maturation process or a preferential degradation of the 28S subunit in AD.

Ribosomal RNA in Alzheimer's disease and aging.

Ribosomal RNA genes are involved in cell transcription and translation processes and can modulate gene expression. In an earlier cytogenetic study, (Payão, S.L.M., Smith, M.de A.C., Kormann-Bortolotto, M.H., Toniolo, J., 1994 (Investigation of the nucleolar organizer regions in Alzheimer's disease. Gerontology 40, 13-17), reported a decreased activity of ribosomal genes in Alzheimer's disease (AD). We studied the ratio of mature rRNA 28S and 18S in peripheral blood samples derived from eight patients with AD, eight healthy elderly sisters of these patients (SA), eight healthy elderly (EC) and eight healthy young (YC) controls, all female. Our results showed a statistically significant decrease of mature rRNA 28S and 18S ratio in the elderly groups (AD, SA, EC) in relation to the young one, probably by fragmentation of 28S rRNA. The Alzheimer's patient group had the lowest 28S/18S ratio. Thus, we can suggest that there is a possible change in the transcriptional or maturation process, or a preferential degradation of the 28S subunit with ageing.

Differential chromosome sensitivity to 5-azacytidine in Alzheimer's disease.

BACKGROUND: The methylation process in the DNA has been considered a control mechanism of gene activity, connected with genetic imprinting. 5-Azacytidine (5-AZC) is known to be a demethylation agent. OBJECTIVE: We studied the cytogenetic effect of 5-AZC in Alzheimer's disease patients and in two control groups. METHODS: Peripheral lymphocyte cultures derived from 8 patients with Alzheimer's disease and 8 elderly and 8 healthy young individuals, all female, were studied. The parameters investigated were: the undercondensation of constitutive heterochromatin of chromosomes 1, 9, and 16: the number of lesions in fragile sites 1q42 and 19q13; heterochromatin association, and the total number of induced lesions. RESULTS: Our results showed a significantly increased frequency of undercondensation of chromosomes 1, 9, and 16 in Alzheimer's disease patients when compared with elderly and young healthy groups. CONCLUSION: These results suggest that the demethylating action of 5-AZC could reveal differential gene activity in the Alzheimer group at the level of cellular division.

[Normative data on the verbal fluency test in the animal category in our milieu]. / Dados normativos para o teste de fluência verbal categoria animais em nosso meio.

OBJECTIVE: Evaluate the performance on verbal fluency (VF) in our population in a Brazilian sample checking the influence of age and literacy. METHODS: 336 people without neurological or psychiatric complaints evaluated through Mini-Mental State Examination and VF (animals). For comparison, and to determine cut-off points, 65 people with cognitive loss followed at our clinic were also evaluated. RESULTS: We found a mean of 13.8 animals in 1 minute, with the following distribution: illiterates, 11.9; up 4 years of education, 12.8; 4 to 7 years, 13.4; 8 years or more, 15.8 (p = 0.0001). In relation to age the means were: up to 64 years, 13.7; 65 years or more, 13.9. There was no difference between the two groups. The cut-off points were 9 for people under 8 years of education with a sensitivity of 75% for illiterates, 100% for low educational level (up 4 years), and 87% for middle level (4 to 7 years). The specificity was respectively 79%, 84%, and 88%. For the high educational level the mean was 13 with a sensitivity of 86% and specificity of 67%. CONCLUSIONS: In the VF (animals) there is a significant influence of schooling and different cut-off points should be used.

Neurological outcome in coronary artery surgery with and without cardiopulmonary bypass.

INTRODUCTION: The neurological complications of coronary artery surgery with cardiopulmonary bypass (CPB) have been extensively studied, but to our knowledge those without CPB (NCPB) have not been defined. PATIENTS & METHODS: We prospectively examined 81 patients, before and up to seven days after surgery, to compare the neurological morbidity between patients subjected to coronary artery bypass graft (CABG) surgery with and without CPB. We analyzed demographic variables, risk factors and neurological examination including neuropsychological (NPS) tests using chi-square and non-parametric analysis (Mann-Whitney and Kruskal-Wallis). RESULTS: Forty-eight patients (34M; median age = 62 yrs; median number of grafts = 3 and median total surgery duration = 300 min) operated with CPB and 33 without CPB (23M; median age = 64 yrs; median number of grafts = 2 and median total surgery duration = 240 min) differed only in relation to number of grafts (p = 0.0001) and surgery duration (p = 0.0001). CONCLUSION: We found no difference in early neurological outcome in patients subjected to CABG with or without CPB.

Bilateral putaminal hemorrhage related to methanol poisoning: a complication of hemodialysis? Case report.

A case of acute methanol intoxication is presented, in which bilateral putaminal hemorrhage developed after hemodialysis. Even though the patient was initially comatose and profoundly acidotic, favorable outcome was achieved, with long-term neurologic impairments essentially restricted to mild crural paraparesis, retrograde amnesia, and marked visual deficit. A comparative literature review is evaluated.

[The Mini-Mental State Examination in a general population: impact of educational status]. / O Mini-Exame do Estado Mental em uma população geral. Impacto da escolaridade.

To assess the influence of age and education on cognitive performance in our population, 530 adults were interviewed using the MMSE (Mini-Mental Status Examination). Education level, classified as illiterate, elementary and middle (< 8 years) and high (> 8 years), was a significant predictor of performance (p < 0.0001). Nevertheless, the total scores were not significantly different among the age-groups, young (< or = 50 years), middle age 51 to 64 years) and elderly (> or = 65 years). The reference cut-off values were taken from the fifth percent lowest score for each group: illiterate, 13; elementary and middle, 18; and high, 26. When compared to 94 patients with cognitive impairment, our cut-off values achieved high sensitivity (82.4% for illiterates; 75.6% for elementary and middle; 80% for high) and specificity (97.5% for illiterate; 96.6% for elementary and middle; 95.6% for high educational level). Education-specific reference values for the MMSE are necessary in interpreting individual test results in populations of low educational level, in order to reduce the false positive results.

Alternating periodic lateralized epileptiform discharges (cerebral bigeminy).

Periodic lateralized epileptiform discharges (PLEDs) are seen, as a rule, following acute brain damage. We presented a 54-year-old diabetic male with ischemic coronary disease. Following cardiopulmonary arrest, the patient had a particular EEG pattern of PLEDs, characterized by two recurrent discharges. To our knowledge, this is the fourth published case of such EEG alteration. All of the cases were related to anoxic events.

A study on the action of two calcium channel blockers (verapamil and flunarizine) upon an experimental model of tardive dyskinesia in rats.

Tardive dyskinesia (TD), a serious complications of neuroleptic chronic use, has no effective therapy yet. We performed an experiment to study the action on TD, of the calcium channel blockers (CCB) drugs, verapamil and flunarizine. We obtained the TD model in rats, administering haloperidol for a 21-day period. After this, the stereotyped movement induced by apomorphine was rated. The CCB drugs were administered in acute (in the 28th day) and chronic (for 8 days, after the 25th day) experiments. Acutely, verapamil increased the stereotyped behaviour, and promoted a reduction of it in the chronic experiment. The results suggest that CCB drugs should be tested in clinical trials of TD.

Effect of psychotropic drugs on excitatory amino acids in patients undergoing psychosurgery for depression.

Samples of ventricular CSF were taken from 52 consecutive patients admitted for psychosurgery for intractable depression. Concentrations of asparagine, aspartate, glutamine, glutamic acid, and serine were determined. Glutamate and aspartate concentrations, implicated in excitotoxic brain damage, were not affected by various types of psychotropic drug treatment. Serine, a modulator of glutamate responses, was significantly elevated in samples from subjects receiving antidepressants. These subjects responded poorly to the operation. Psychotropic drugs are unlikely to be neurotoxic. Nevertheless, antidepressants may influence excitatory neurotransmission.

Characterisation of the glycine modulatory site of the N-methyl-D-aspartate receptor-ionophore complex in human brain.

[3H]Glycine binding and glycine modulation of [3H]MK-801 binding have been used to study the glycine allosteric site associated with the N-methyl-D-aspartate receptor complex in postmortem human brain. The effect of glycine on [3H]MK-801 binding appeared sensitive to duration of terminal coma, and possibly postmortem delay. Thirty percent of the binding occurred in a subfraction of brain tissue and did not show enhancement by glycine and glutamic acid. [3H]Glycine binding to a subfraction free from this component was studied and showed high specific binding. KD and Bmax values showed considerable intersubject variability which did not appear to be due to demographic features or to tissue content of amino acids with an affinity for this site. The pharmacological characteristics of binding in this subfraction and a correlation between Bmax values and the maximal enhancement of [3H]MK-801 binding by glycine are consistent with [3H]glycine binding occurring to an N-methyl-D-aspartate receptor complex associated site. Further support for this is provided by a significantly lower Bmax value for [3H]glycine binding in subjects with Alzheimer's disease and reduced glycine enhancement of [3H]MK-801 binding. However, the effect of perimortem factors makes it difficult to confidently attribute this solely to a disease-related change in the receptor. The possible role of the glycine allosteric site in the treatment of neuropsychiatric disorders is discussed.

Terminal coma affects messenger RNA detection in post mortem human temporal cortex.

In situ hybridization histochemistry has been used to study the amount of M1 muscarinic receptor mRNA in temporal cortex from subjects with Alzheimer's disease and other neurodegenerative disorders, where the duration of terminal coma was known. Total polyadenylated mRNA and glutamate decarboxylase activity were also measured. Both muscarinic receptor mRNA and enzyme activity showed a significant decline with increasing duration of terminal coma, but were not related to diagnosis. Polyadenylated mRNA signal did not show an association with coma. These data indicate the need to consider the nature of the terminal illness in post mortem studies of mRNA as well as for neurochemical research.