The Role of Silence in Verbal Fluency Tasks - A New Approach for the Detection of Mild Cognitive Impairment.

OBJECTIVE: Most recordings of verbal fluency tasks include substantial amounts of task-irrelevant content that could provide clinically valuable information for the detection of mild cognitive impairment (MCI). We developed a method for the analysis of verbal fluency, focusing not on the task-relevant words but on the silent segments, the hesitations, and the irrelevant utterances found in the voice recordings. METHODS: Phonemic ('k', 't', 'a') and semantic (animals, food items, actions) verbal fluency data were collected from healthy control (HC; n = 25; Mage = 67.32) and MCI (n = 25; Mage = 71.72) participants. After manual annotation of the voice samples, 10 temporal parameters were computed based on the silent and the task-irrelevant segments. Traditional fluency measures, based on word count (correct words, errors, repetitions) were also employed in order to compare the outcome of the two methods. RESULTS: Two silence-based parameters (the number of silent pauses and the average length of silent pauses) and the average word transition time differed significantly between the two groups in the case of all three semantic fluency tasks. Subsequent receiver operating characteristic (ROC) analysis showed that these three temporal parameters had classification abilities similar to the traditional measure of counting correct words. CONCLUSION: In our approach for verbal fluency analysis, silence-related parameters displayed classification ability similar to the most widely used traditional fluency measure. Based on these results, an automated tool using voiced-unvoiced segmentation may be developed enabling swift and cost-effective verbal fluency-based MCI screening.

Temporal Speech Parameters Indicate Early Cognitive Decline in Elderly Patients With Type 2 Diabetes Mellitus.

INTRODUCTION: The earliest signs of cognitive decline include deficits in temporal (time-based) speech characteristics. Type 2 diabetes mellitus (T2DM) patients are more prone to mild cognitive impairment (MCI). The aim of this study was to compare the temporal speech characteristics of elderly (above 50 y) T2DM patients with age-matched nondiabetic subjects. MATERIALS AND METHODS: A total of 160 individuals were screened, 100 of whom were eligible (T2DM: n=51; nondiabetic: n=49). Participants were classified either as having healthy cognition (HC) or showing signs of MCI. Speech recordings were collected through a phone call. Based on automatic speech recognition, 15 temporal parameters were calculated. RESULTS: The HC with T2DM group showed significantly shorter utterance length, higher duration rate of silent pause and total pause, and higher average duration of silent pause and total pause compared with the HC without T2DM group. Regarding the MCI participants, parameters were similar between the T2DM and the nondiabetic subgroups. CONCLUSIONS: Temporal speech characteristics of T2DM patients showed early signs of altered cognitive functioning, whereas neuropsychological tests did not detect deterioration. This method is useful for identifying the T2DM patients most at risk for manifest MCI, and could serve as a remote cognitive screening tool.

Telltale silence: temporal speech parameters discriminate between prodromal dementia and mild Alzheimer's disease.

This study presents a novel approach for the early detection of mild cognitive impairment (MCI) and mild Alzheimer's disease (mAD) in the elderly. Participants were 25 elderly controls (C), 25 clinically diagnosed MCI and 25 mAD patients, included after a clinical diagnosis validated by CT or MRI and cognitive tests. Our linguistic protocol involved three connected speech tasks that stimulate different memory systems, which were recorded, then analyzed linguistically by using the PRAAT software. The temporal speech-related parameters successfully differentiate MCI from mAD and C, such as speech rate, number and length of pauses, the rate of pause and signal. Parameters pauses/duration and silent pauses/duration linearly decreased among the groups, in other words, the percentage of pauses in the total duration of speech continuously grows as dementia progresses. Thus, the proposed approach may be an effective tool for screening MCI and mAD.

Nilvadipine in mild to moderate Alzheimer disease: A randomised controlled trial.

BACKGROUND: This study reports the findings of the first large-scale Phase III investigator-driven clinical trial to slow the rate of cognitive decline in Alzheimer disease with a dihydropyridine (DHP) calcium channel blocker, nilvadipine. Nilvadipine, licensed to treat hypertension, reduces amyloid production, increases regional cerebral blood flow, and has demonstrated anti-inflammatory and anti-tau activity in preclinical studies, properties that could have disease-modifying effects for Alzheimer disease. We aimed to determine if nilvadipine was effective in slowing cognitive decline in subjects with mild to moderate Alzheimer disease. METHODS AND FINDINGS: NILVAD was an 18-month, randomised, placebo-controlled, double-blind trial that randomised participants between 15 May 2013 and 13 April 2015. The study was conducted at 23 academic centres in nine European countries. Of 577 participants screened, 511 were eligible and were randomised (258 to placebo, 253 to nilvadipine). Participants took a trial treatment capsule once a day after breakfast for 78 weeks. Participants were aged >50 years, meeting National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's disease Criteria (NINCDS-ADRDA) for diagnosis of probable Alzheimer disease, with a Standardised Mini-Mental State Examination (SMMSE) score of ≥12 and <27. Participants were randomly assigned to 8 mg sustained-release nilvadipine or matched placebo. The a priori defined primary outcome was progression on the Alzheimer's Disease Assessment Scale Cognitive Subscale-12 (ADAS-Cog 12) in the modified intention-to-treat (mITT) population (n = 498), with the Clinical Dementia Rating Scale sum of boxes (CDR-sb) as a gated co-primary outcome, eligible to be promoted to primary end point conditional on a significant effect on the ADAS-Cog 12. The analysis set had a mean age of 73 years and was 62% female. Baseline demographic and Alzheimer disease-specific characteristics were similar between treatment groups, with reported mean of 1.7 years since diagnosis and mean SMMSE of 20.4. The prespecified primary analyses failed to show any treatment benefit for nilvadipine on the co-primary outcome (p = 0.465). Decline from baseline in ADAS-Cog 12 on placebo was 0.79 (95% CI, -0.07-1.64) at 13 weeks, 6.41 (5.33-7.49) at 52 weeks, and 9.63 (8.33-10.93) at 78 weeks and on nilvadipine was 0.88 (0.02-1.74) at 13 weeks, 5.75 (4.66-6.85) at 52 weeks, and 9.41 (8.09-10.73) at 78 weeks. Exploratory analyses of the planned secondary outcomes showed no substantial effects, including on the CDR-sb or the Disability Assessment for Dementia. Nilvadipine appeared to be safe and well tolerated. Mortality was similar between groups (3 on nilvadipine, 4 on placebo); higher counts of adverse events (AEs) on nilvadipine (1,129 versus 1,030), and serious adverse events (SAEs; 146 versus 101), were observed. There were 14 withdrawals because of AEs. Major limitations of this study were that subjects had established dementia and the likelihood that non-Alzheimer subjects were included because of the lack of biomarker confirmation of the presence of brain amyloid. CONCLUSIONS: The results do not suggest benefit of nilvadipine as a treatment in a population spanning mild to moderate Alzheimer disease. TRIAL REGISTRATION: Clinicaltrials.gov NCT02017340, EudraCT number 2012-002764-27.

[Frailty syndrome: an old new friend]. / Esendoségszindróma: egy régi új ismeros.

Frailty syndrome is defined as extreme stress vulnerability and decreased potential to adapt. The elderly and chronically ill patients are affected mostly. This condition increases the risk of adverse health outcomes as infections, falls, delirium, institutionalization, progression of comorbidities and mortality. The pathophysiological mechanism is a complex immune and neuroendocrine dysregulation. According to the phenotype model, frailty presents when three of the followings occur: weakness, exhaustion, slowness, weight loss and decreased activity, while cumulative model counts the number of health deficits. Aging, frailty, dementia and depression are independent clinical entities; they may present separately but may also potentiate each other. Hence most of the frailty scales assess the physical, mental and social dimensions as well. Mild or moderate frailty is potentially reversible with an individualised caring plan. Given short, easy-to-use screening tools, risk groups can be identified in the primary care and referred to a specialised team for further treatment. Here the authors summarise the literature of a re-discovered, current clinical phenomena, frailty syndrome, focusing on the practical issues in primary care.

[Early Mental Test--developing a screening test for mild cognitive impairment]. / Korai Mentális Teszt: az enyhe kognitív zavar szurotesztjének fejlesztése.

BACKGROUND AND PURPOSE: Mild cognitive impairment (MCI) is a heterogenous syndrome considered as a prodromal state of dementia with clinical importance in the early detection of Alzheimer's Disease. We are currently developing an MCI screening instrument, the Early Mental Test (EMT) suitable to the needs of primary care physicians. The present study describes the validation process of the 6.2 version of the test. METHODS: Only subjects (n = 132, female 95, male 37) over the age of 55 (mean age 69.2 years (SD = 6.59)) scoring at least 20 points on Mini-Mental State Examination (MMSE), mean education 11.17 years (SD = 3.86) were included in the study. The psychometric evaluation consisted of Alzheimer's Disease Assessment Scale Cognitive subscale (ADAS-Cog) and the 6.2 version of EMT. The statistical analyses were carried out using the 17.00 version of SPSS statistical package. RESULTS: The optimalised cut-off point was found to be 3.45 points with corresponding 69% sensitivity, 69% specificity and 69% accuracy measures. The Cronbach-alpha, that describes the internal consistence of the test was 0.667, which is higher as compared with the same category in the case of the ADAS-Cog (0.446). A weak negative rank correlation was found between the total score of EMT 6.2 and the age of probands (rs = -0.25, p = 0.003). Similarly, only a weak correlation was found between the education levels and the total score of EMT 6.2 (rs = 0.31, p < 0.001). Two of the subtests, the repeated delayed short-time memory and the letter fluency test with a motorical distraction task had significantly better power to separate MCI and control groups than the other subtests of the EMT. CONCLUSION: The 6.2 version of EMT is a fast and simple detector of MCI with a similar sensitivity-specificity profile to the MMSE, but this version of the test definitely needs further development.

Restraint stress in rats alters gene transcription and protein translation in the hippocampus.

Stress is a relatively new and emerging risk factor for Alzheimer's disease (AD). Severe stress can alter brain characteristics such as neuronal plasticity, due to changes in the metabolism of cytoskeletal proteins. In this study, male Wistar rats were exposed to restraint stress (RS) for 5 h daily for different time periods. At the end of the exposure periods, the amounts of ß-actin, cofilin, amyloid precursor protein (APP) and mitogen-activated protein kinase 1 (MAPK-1) RNAs and proteins were investigated. The mRNA expressions of ß-actin, cofilin and MAPK-1 followed U-shaped time course. Acute (3 days) and chronic (21 days) RS caused a fourfold and tenfold increases, respectively, in hippocampal ß-actin mRNA expression. In the case of cofilin mRNA expression, elevations were detected in the hippocampus on days 3, 7 and 21. The APP mRNA level was increased on day 21. On protein level, chronic stress elevated the levels of ß-actin, cofilin and APP in the hippocampus. These results suggest that stress causes the induction of some genes and proteins that are also elevated in AD selectively in the hippocampal region of the rat brain.

Marking the markers of Alzheimer's: too good to diagnose, too bad to use?

One of the most important neurodegenerative diseases of our time is Alzheimer's disease, which mainly affects the elderly population. The accumulation of ß-amyloid and tau protein in the brain tissue is the most characteristic pathomechanical event of the disease, later causing neuronal cell death. Setting up an accurate diagnosis of Alzheimer's disease has essentially changed recently, since besides psychometry, neurochemical and neuroimaging examinations are also gaining greater importance in the clinical routine. Thanks to the widening of diagnostic methods, in the future the disease could be recognised even during the preclinical phase. The most remarkable source of brain-derived compounds is the cerebrospinal fluid. Although obtaining cerebrospinal fluid is greatly unpleasant, it poses a low risk and is frequently used as part of the diagnostic procedure. The assay of cerebrospinal fluid means the identification of the level of ß-amyloid(1-42), tau and phospho-tau and their ratio, but to get more specific and sensitive investigations there is intensive research work both on the utility of their combination and on finding even more specific biomarkers. This review gives a summary of the biomarkers that are being used and being researched for the diagnostic tests of both familial and sporadic forms of Alzheimer's disease. Other notable sources of neurochemical compounds are the serum and the plasma, however, the identification of their biomarkers is under preclinical examinations. Unfortunately neither the validation of these markers nor the consistent acceptance of the experimental results is possible due to the wide range of protocols in international research. The importance of biomarkers in the development of potential drug candidates is also discussed.

[Achetylcholinesterase (AChE) inhibition and serum lipokines in Alzheimer's disease: friend or foe?]. / Acetilkolin-észteráz gátlás és szérum lipokinek Alzheimer-kórban: barát vagy ellenség?

Throughout the natural progression of Alzheimer's disease (AD), the body mass index (BMI) decreases. This is believed to be brought on by the disturbance in the central lipid metabolism, but the exact mechanism is yet unknown. Adipokines (adiponectin, leptin), hormones produced by the adipose tissue, change glucose and lipid metabolism, and have an anorectic effect through increasing energy consumption in the hypothalamus. The goal of our study was to examine donepezil - an acetylcholinesterase inhibitor (AChEI) currently used in AD therapy -, and to what degree it influences the serum adipokine levels and metabolic parameters of AD patients. During the self-evaluation of 26 clinically diagnosed mild to moderate AD patients, therapy with 10 mg/day donepezil was started according to current protocols. We measured serum adiponectin, leptin, LDL, HDL, trigliceride levels, and BMI and ApoE polymorphism at the beginning of our study, and at 3 and 6-months intervals respectively. All data were analyzed with SPSS 17. In comparison with pre-donepezil therapy values, at the third month interval serum adiponectin levels showed an increasing and leptin levels a decreasing tendency. At the six month interval, adiponectin levels significantly increased (p=0.007), leptin levels decreased (p=0.013), BMI (p=0.001) and abdominal circumference (p=0.017) was significantly lower at 6 months as compared to control values. We did not observe any changes in the lipid profile, and ApoE4 allele carrying showed no association with the parameters. To our knowledge, we are the first to publish that AChEI therapy with donepezil alters lipokine levels, which positively influences the currently known pathomechanism and numerous risk factors of AD. The AChEI treatment-induced weight loss should be considered in the long-term therapy of AD patients.

[Validation of the Hungarian version of Alzheimer's Disease Assessment Scale--cognitive subscale]. / Az Alzheimer's Disease Assessment Scale kognitív alskála magyar verziójának validálása.

UNLABELLED: The cognitive subscale of the Alzheimer's Disease Assessment Scale is the most widely used test in the diagnostic and research work of Alzheimer's disease. AIMS: The aim of this study was to validate and investigate reliability of the Hungarian version of the Alzheimer's Disease Assessment Scale in patients with Alzheimer's disease and healthy control subjects. METHODS: sixty-six patients with mild and moderate Alzheimer's disease and 47 non-demented control subjects were recruited for the study. The cognitive status was established by the Hungarian version of the Alzheimer's Disease Assessment Scale and Mini Mental State Examination. Discriminative validity, the relation between age and education and Alzheimer's Disease Assessment Scale, and the sensitivity and specificity of the test were determined. RESULTS: Both the Mini Mental State Examination and the Alzheimer's Disease Assessment Scale had significant potential in differentiating between patients with mild and moderate stages of Alzheimer's disease and control subjects. A very strong negative correlation was established between the scores of the Mini Mental State Examination and the Alzheimer's Disease Assessment Scale in the Alzheimer's disease group. The Alzheimer's Disease Assessment Scale showed slightly negative relationship between education and cognitive performance, whereas a positive correlation between age and Alzheimer's Disease Assessment Scale scores was detected only in the control group. According to the analysis of the ROC curve, the values of sensitivity and specificity of the Alzheimer's Disease Assessment Scale were high. CONCLUSIONS: The Hungarian version of the Alzheimer's Disease Assessment Scale was found to be highly reliable and valid and, therefore, the application of this scale can be recommended for the establishment of the clinical stage and follow-up of patients with Alzheimer's disease. However, the current Hungarian version of the Alzheimer's Disease Assessment Scale is not sufficient; the list of words and linguistic elements should be selected according to the Hungarian standard in the future.

[The role of immobilization stress and sertindole on the expression of APP, MAPK-1 and beta-actin genes in rat brain]. / Az immobilizációs stressz és a sertindol hatása az APP, MAPK-1 és beta-aktin gének kifejezodésére patkányagyban.

Stress, depending on its level and quality, may cause adaptive and maladaptive alterations in brain functioning. As one of its multiple effects, elevated blood cortisol levels decrease the synthesis of the neuroprotective BDNF, thus leading to hippocampal atrophy and synapse loss, and rendering it a possible cause for the Alzheimer's disease (AD) related neuropathological and cognitive changes. As a result of the stress response, intraneuronal alterations--also affecting the metabolism of beta-actin--can develop. These have a role in the regulation of memory formation (LTP), but in pathological conditions (AD) they could lead to the accumulation of Hirano bodies (actin-cofilin rods). According to the dementia treatment guidelines, the behavioural and psychological symptoms of AD can be treated with certain antipsychotics. Therefore, the aim of our study was to examine the effects of sertindole (currently not used in the standard management of AD) on the transcription of some AD associated genes (amyloid precursor protein [APP], mitogen activated protein kinase-1 [MAPK-1], beta-actin) in the brain of rats exposed to chronic immobilization stress (CIS). Male Wistar rats were exposed to CIS for three weeks. The four groups were: control (n = 16), CIS (n = 10), 10 mg/kg sertindole (n = 5) and 10 mg/kg sertindole + CIS (n = 4). Following transcardial perfusion, the relative levels of hippocampal and cortical mRNA of the previously mentioned genes were measured with real-time PCR. CIS induced hippocampal beta-actin (p < 0.01), MAPK-1 and APP (p < 0.05) mRNA overexpression. The simultaneous administration of sertindole suppressed this increase in beta-actin, MAPK-1 and APP expression (p < 0.05). Ours is the first report about CIS induced beta-actin gene overexpression. This finding, in accordance with the similar results in APP and MAPK-1 expression, underlines the significance of cytoskeletal alterations in AD pathogenesis. The gene expression reducing effect of sertindole suggests that antipsychotic drugs may have a neuroprotective effect.

[Acute and chronic stress induced changes in gene transcriptions related to Alzheimer's disease]. / Az akut es krónikus stressz hatása az Alzheimer- kór patomechanizmusában szerepet játszó gének transzkripciójára.

Preclinical and clinical studies demonstrate that stress may be implicated in the risk of neurodegenerative diseases such as Alzheimer's disease (AD). Our study aimed to investigate the effects of acute and chronic immobilization stress (IS) on the gene transcriptions of beta-actin, amyloid precursor protein (APP) and mitogen activated protein kinase-1 (MAPK-1), proteins related to synaptic plasticity and neuronal degeneration. Male Wistar rats were exposed to IS for five hours daily for 3 days (acute stress) or through 7-14-21 days (chronic stress). At the end of exposure periods, total RNA was purified from the cortex and hippocampus. The amounts of beta-actin, APP and MAPK-1 mRNA were determined with real time PCR method. Our results indicate that the mRNA expression of beta-actin and APP followed a U-shaped time-response curve. Both acute and chronic IS caused a significant increase in beta-actin and MAPK-1 mRNA expression. Significant APP mRNA elevation was observed only by the 3rd week after RS. Our findings demonstrate that both acute and chronic IS lead to gene transcriptional changes of beta-actin, APP and MAPK-1. These proteins maintain the normal function of the cytoskeleton and the synaptic plasticity. The above changes may lead to cognitive deterioration, and the development of AD.

[Validation of the Hungarian version of Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) in patients with mild cognitive impairment]. / Az Alzheimer's Disease Assessment Scale kognitiv alskala (ADAS-Cog) validalasa enyhe kognitiv zavarban.

INTRODUCTION: Early recognition of mild cognitive impairment (MCI) has increasing clinical relevance in the treatment process of dementia, since it is considered as prodromal period. A great variety of instruments have been developed for measuring cognitive performance of the demented patients. The cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog) is one of the most frequently applied instrument to determine the severity of dementia and the efficiency of pharmacotherapy. The aim of this study is to examine the sensitivity parameters of the Hungarian ADAS-Cog in differentiating healthy elderly from MCI patients, furthermore to compare the sociodemographic data of the two groups. METHODS: Fourty-five patients with MCI and 47 healthy subjects (HS) participated in the study. Their age variated between 52 and 88 years, the mean age was 68.8 (standard deviation=8.6). The mean of the years of education was 11.8 (standard deviation=3.5). Mental state was determined by ADAS-Cog and Mini-Mental State Examination (MMSE) and Beck Depression Inventory (BDI) was used to exclude depression. Data analysis was performed with SPSS 17. RESULTS: There were no significant differences between the two groups considering the sociodemographic data. The total score of ADAS-Cog is the most sensitive index (AUC: 0.875, sensitivity: 95.6%) for determining MCI, although the ratio of false positive cases was very high (specificity: 70.2%). The cut-off scores of the ADAS-Cog in the Hungarian sample were higher than the findings in previous researches. Positive correlation between age and ADAS-Cog total score was only significant in the HS group. On the other hand, negative correlation was found between education and ADAS-Cog total score in the MCI group. CONCLUSION: These results indicate that the currently used Hungarian ADAS-Cog is able to distinguish between MCI patients and HS groups. However, the adaptation of the Hungarian version will be necessary during the further standardization process including the cultural and linguistic aspects.

[Is it pseudo-dementia? The validation of the Adas-Cog questionnaire in Hungary]. / Pszeudo-e a demencia? Az ADAS-Cog validálása Magyarországon.

INTRODUCTION: The cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog) has been established internationally as an instrument for the assessment of treatment efficacy and cognitive performance in clinical trials. There is no data about the validity and characteristics of ADAS-Cog in Hungarian sample. This study is a part of the Hungarian standardization process of ADAS-Cog. It is crucial to examine the cognitive performance of patients with pseudodementia caused by depression (D) because of its' similarities with Alzheimer's disease (AK). The objective of the study was to analyze the characteristics of the cognitive subscale for further validation purposes. The study aimed at analyzing the ADAS-Cog performance of patients with D and AK in a Hungarian sample to make future studies more accurate through more exact differentiation between the two diseases. METHODS: Fourty-seven normal elderly control (KNT) subjects, 66 AK patients and 39 patients with D participated in the study. The mental state and the severity of depressive symptoms of the participants were assessed by the means of ADAS-Cog, Mini Mental State Examination (MMSE) and Beck Depression Inventory. RESULTS: The ADAS-Cog is sensitive to the cognitive decline of the depressed group (sensitivity=69.2%, specificity=89.4%, AUC=0.868, p>0.001). While the performance of the two patient groups differed from the KNT, the groups are overlapping and the characteristic of the ROC curve and the optimal cut-off point (D:11.8; AK:12.1) indicates that the differentiation is mediocre. CONCLUSION: The results suggest that pseudodementia should be considered during the design of studies using ADASCog. Because the cognitive subscale can't accurately differentiate between AK and pseudodementia additional measures like BDI should be administered.

Temporal Speech Parameters Detect Mild Cognitive Impairment in Different Languages: Validation and Comparison of the Speech-GAP Test® in English and Hungarian.

BACKGROUND: The development of automatic speech recognition (ASR) technology allows the analysis of temporal (time-based) speech parameters characteristic of mild cognitive impairment (MCI). However, no information has been available on whether the analysis of spontaneous speech can be used with the same efficiency in different language environments. OBJECTIVE: The main goal of this international pilot study is to address the question of whether the Speech-Gap Test® (S-GAP Test®), previously tested in the Hungarian language, is appropriate for and applicable to the recognition of MCI in other languages such as English. METHODS: After an initial screening of 88 individuals, English-speaking (n = 33) and Hungarianspeaking (n = 33) participants were classified as having MCI or as healthy controls (HC) based on Petersen's criteria. The speech of each participant was recorded via a spontaneous speech task. Fifteen temporal parameters were determined and calculated through ASR. RESULTS: Seven temporal parameters in the English-speaking sample and 5 in the Hungarian-speaking sample showed significant differences between the MCI and the HC groups. Receiver operating characteristics (ROC) analysis clearly distinguished the English-speaking MCI cases from the HC group based on speech tempo and articulation tempo with 100% sensitivity, and on three more temporal parameters with high sensitivity (85.7%). In the Hungarian-speaking sample, the ROC analysis showed similar sensitivity rates (92.3%). CONCLUSION: The results of this study in different native-speaking populations suggest that changes in acoustic parameters detected by the S-GAP Test® might be present across different languages.

[Cytoskeletal alterations in Alzheimer's disease: the "skeleton" of therapeutic hope?]. / Az Alzheimer-kór citoszkeletális változásai: a terápiás remény "váza"?

Damage to and functional alteration of structures responsible for synaptic plasticity correlate with memory loss and cognitive decline in Alzheimer's disease. The results of recent research in the pathomechanism of Alzheimer's disease emphasize the significance of cytoskeletal changes. The changes in actin dynamics and its regulation by actin-binding proteins have been proven in Alzheimer's disease, which may have a key role in the conformation and alteration of synapses and dendritic spines. The most important proteins in the regulation of actin dynamics are ADF/cofilin, kinases and drebrin. In this review, we summarize the physiological functions and complex regulation of these cytoskeletal proteins and their alterations in Alzheimer's disease. Additionally, the effects of some psychopharmacons on the actin cytoskeleton and cytoskeletal changes induced by stress are also summarized.

[9-hydroxy-risperidone (9OHRIS) prevents stress-induced ß-actin overexpression in rat hippocampus]. / A 9-hidroxi-risperidon kivédi a stressz indukálta ß-aktin választ patkány hippokampuszban.

Alzheimer's disease (AD) is the most frequent form of neurodegenerative dementias. The aetiology and the exact pathomechanism of AD is not known, but stress has been considered recently in the aetiology. Beside the abnormal metabolism of the amyloid protein precursor (APP), the hyperactivity of the mitogen-activated protein kinase 1 (MAPK1) involved in the hyperphosphorylation of the tau proteins, which are considered the major component of neurofibrillary tangles, in addition to ß-actin, being involved in synaptogenesis and neuronal plasticity, are all considered important contributors to the development of AD specific neuropathological changes. The chief aim of our present investigation was to examine the effect of stress on the expression of APP, MAPK1 and ß-actin mRNAs in the rat hippocampus and cortex. The effect of 9-hydroxy-risperidone (9OHRIS) on the transcription of these genes was also examined. Adult, male Wistar rats were exposed to chronic immobilization stress for 3 weeks. The 9OHRIS (4 mg/bwkg) was administred by gastric tube. Four groups were formed depending on the treatment: (1) control, (2) stress, (3) 9OHRIS, (4) stress and parallel 9OHRIS treatment (n=5-6). The expression of APP, MAPK1, ß-actin mRNAs from the perfused brain samples was measured with real-time PCR technique. The ß-actin mRNA was significantly overexpressed in the hippocampus after 3 weeks of stress treatment. On the other hand, the stress induced hippocampal ß-actin mRNA overexpression was repressed by the 9OHRIS treatment. There were no changes in the cortical or hippocampal expression of APP and MAPK1 mRNAs after neither the stress nor the 9OHRIS treatments. These results emphasize the importance of the stress induced ß-actin expression in rat hippocampus. The stress induced alterations in the ß-actin RNA expression could be associated with neuronal plasticity and adaptional processes, which could be modified by the 9OHRIS treatment. Our findings indicate that a second generation antipsychotic drug could have a beneficial effect in the pathomechanism of stress and this may have relevance in the treatment of such devastating conditions like AD and psychotic disorders.

[The effects of duloxetine on beta-actin stress response in rat brain]. / A duloxetin hatása a beta-aktin stresszválaszra patkány agyban.

Depression is a frequent prodromal symptom of Alzheimer's disease (AD). Stress factors play an important role in the etiopathology of both diseases, since increased corticosteroid levels caused by chronic stress indirectly induce neuronal damage. The aim of our experiments was to evaluate the changes induced by stress in the transcription of amyloid precursor protein (APP), mitogen activated protein kinase-1 (MAPK-1) and beta-actin, of which the latest plays a leading role in synaptic plasticity. Additionally we intended to examine how duloxetine - a serotonin-norepinephrin reuptake inhibitor type antidepressant - would modify the stress-induced changes. Wistar rats were exposed to immobilization stress for five hours daily through 21 days, while part of the animals received 45 mg/bwkg of duloxetine. At the end of the third week total RNA was purified from the cortex and hippocampus. The amount of beta-actin, APP and MAPK-1 mRNA was determined by real time PCR method. On protein level, semiquantitative measurement was performed by Western blot. The expression of beta-actin mRNA in the animals exposed to stress was four times as intense as in the control group. The increase in the beta-actin mRNA levels was repressed by the duloxetine treatment. In the case of APP and MAPK-1 no changes were detected. According to the Western blot results, the antidepressant treatment slightly, the drug along with the stress treatment strongly decreased the amount of the beta-actin protein. Our findings indicate that antidepressant treatment with duloxetine could play a protective role against the chronic stress-induced changes in the nervous system, such as disorders of synaptic plasticity, and the consequent cognitive dysfunctions in case of both affective disorders and AD.

Dementia in Hungary: General practitioners' routines and perspectives regarding early recognition.

Background: Undetected dementia in primary care is a global problem. Since general practitioners (GPs) act as the first step in the identification process, examining their routines could help us to enhance the currently low recognition rates.Objectives: The study aimed to explore, for the first time in Hungary, the dementia identification practices and views of GPs.Methods: In the context of an extensive, national survey (February-November 2014) 8% of all practicing GPs in Hungary (n = 402) filled in a self-administered questionnaire. The questions (single, multiple-choice, Likert-type) analysed in the present study explored GPs' methods and views regarding dementia identification and their ideas about the optimal circumstances of case-finding.Results: The vast majority of responding GPs (97%) agreed that the early recognition of dementia would enhance both the patients' and their relatives' well-being. When examining the possibility of dementia, most GPs (91%) relied on asking the patients general questions and only a quarter of them (24%) used formal tests, even though they were mostly satisfied with both the Clock Drawing Test (69%) and the Mini-Mental State Examination (65%). Longer consultation time was chosen as the most important facet of improvement needed for better identification of dementia in primary care (81%). Half of the GPs (49%) estimated dementia recognition rate to be lower than 30% in their practice.Conclusions: Hungarian GPs were aware of the benefits of early recognition, but the shortage of consultation time in primary care was found to be a major constraint on efficient case-finding.

[The transcription of the amyloid precursor protein and tryptophan 2,3-dioxygenase genes are increased by aging in the rat brain]. / Az öregedés fokozza az amiloid prekurzor protein és a triptofán 2,3-dioxigenáz gének transzkripcióját patkányagyban.

Aging itself is considered as a major risk factor of dementia. The prevalence of the Alzheimer's disease (AD) is increasing exponentially after the age of 65 and doubles every 5 years. The major aim of our present research was to examine the effect of aging on the transcription of certain genes associated with neurodegenerative disorders in the rat brain. The influence of the vasopressin (VP) hormone was also examined in the same experimental paradigm. Age dependent transcriptional changes of the following four genes were examined in the cerebral cortex: the first was the gene of the amyloid precursor protein (APP) which is abnormally cleaved to toxic beta-amyloid fragments. These aggregated peptides are the major components of the senile plaques in the AD brain. The second one was the mitogen-activated protein kinase (MAPK1) gene. The MAPK is involved in the abnormal hyperphosphorylation of the tau-protein which results in aggregated neurofibrillary tangles. The beta-actin gene was the third one. The protein product of this gene is considered to be involved in synaptogenesis, neuronal plasticity and clinical conditions like depression and AD. The last one was the gene of the tryptophan 2,3-dioxygenase (TDO2) enzyme. The activity of this enzyme is considered as a rate limiting factor in the metabolism of the neuro-immune modulator quinolinic acid (QUIN). The transciptional activity of young (2.5 months) and aged (13 months) Brattleboro rats with or without VP expression were compared by means of real time PCR technique. The cortical transciptional activity of the APP and TDO2 genes were increased in the aged animals as compared with the activity of the young ones, and this effect was independent on the presence of the VP. Our results indicate the importance of certain age dependent transcriptional changes might influence the mechanism of AD and other neurodegenerative disorders.