Search

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.

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.

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. Method: 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.

General practitioners (GPs) play a pivotal role in dementia recognition, yet research suggests that dementia often remains undetected in primary care. Lack of knowledge might be a major con...

Background/aim Anti-cancer therapies may deteriorate cognitive functioning, affective functioning and psychological well-being. Materials and methods In this prospective longitudinal pilot study, premenopausal and postmenopausal patients received adjuvant endocrine therapy (ET) (tamoxifen with or without LHRH analog or aromatase inhibitor) or were observed only (control group). At baseline testing and 6, 12 and 24 months thereafter, cognitive, depression and anxiety tests and quality of life (QOL) measurements were performed. Results Overall, 46 cases were evaluated. None of the studied cognitive parameters differed between the subgroups or changed by time. No differences were found regarding anxiety, depression or QOL measures either. Baseline cognitive test and QOL results were in association with later anxiety and depression. Conclusion No cognitive impairment was found during the two years of ET. Baseline cognitive scores and QOL dimensions proved good predictors of later anxiety and depression.

Alzheimer’s disease (AD) is a neurodegenerative disorder that develops for years before clinical manifestation, while mild cognitive impairment is clinically considered as a prodromal stage of AD. For both types of neurodegenerative disorders, early diagnosis is crucial for the timely treatment and to decelerate progression. Unfortunately, the current diagnostic solutions are time-consuming. Here, we seek to exploit the observation that these illnesses frequently disturb the mental and linguistic functions, which might be detected from the spontaneous speech produced by the patient. First, we present an automatic speech recognition based procedure for the extraction of a special set of acoustic features. Second, we present a linguistic feature set that is extracted from the transcripts of the same speech signals. The usefulness of the two feature sets is evaluated via machine learning experiments, where our goal is not only to differentiate between the patients and the healthy control group, but also to tell apart Alzheimer’s patients from those with mild cognitive impairment. Our results show that based on only the acoustic features, we are able to separate the various groups with accuracy scores between 74–82%. We attained similar accuracy scores when using only the linguistic features. With the combination of the two types of features, the accuracy scores rise to between 80–86%, and the corresponding F1 values also fall between 78–86%. We hope that with the full automation of the processing chain, our method can serve as the basis of an automatic screening test in the future.

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.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.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.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.

Background: Even today the reliable diagnosis of the prodromal stages of Alzheimer's disease (AD) remains a great challenge. Our research focuses on the earliest detectable indicators of cognitive decline in mild cognitive impairment (MCI). Since the presence of language impairment has been reported even in the mild stage of AD, the aim of this study is to develop a sensitive neuropsychological screening method which is based on the analysis of spontaneous speech production during performing a memory task. In the future, this can form the basis of an Internet-based interactive screening software for the recognition of MCI. Methods: Participants were 38 healthy controls and 48 clinically diagnosed MCI patients. The provoked spontaneous speech by asking the patients to recall the content of 2 short black and white films (one direct, one delayed), and by answering one question. Acoustic parameters (hesitation ratio, speech tempo, length and number of silent and filled pauses, length of utterance) were extracted from the recorded speech signals, first manually (using the Praat software), and then automatically, with an automatic speech recognition (ASR) based tool. First, the extracted parameters were statistically analyzed. Then we applied machine learning algorithms to see whether the MCI and the control group can be discriminated automatically based on the acoustic features. Results: The statistical analysis showed significant differences for most of the acoustic parameters (speech tempo, articulation rate, silent pause, hesitation ratio, length of utterance, pause-per-utterance ratio). The most significant differences between the two groups were found in the speech tempo in the delayed recall task, and in the number of pauses for the question-answering task. The fully automated version of the analysis process – that is, using the ASR-based features in combination with machine learning - was able to separate the two classes with an F1-score of 78.8%. Conclusion: The temporal analysis of spontaneous speech can be exploited in implementing a new, automatic detection-based tool for screening MCI for the community.

The ATP-binding cassette, sub-family A, member 1 gene (ABCA1) is a relevant positional and functional candidate gene for Alzheimer’s disease (AD). A case-control association study of genetic variations covering the ABCA1 locus was performed in relation to AD risk in a Hungarian sample. Five single nucleotide polymorphisms (rs2422493: C-477T, rs2740483: G-17C, rs2230805: G474A/L158L, rs2230806: G656A/R219 K and rs2066718: G2311A/V771 M) were genotyped in 431 AD patients and 302 cognitively healthy, elderly controls. In single marker analysis, significant associations were found in the case of rs2230805 and rs2230806 polymorphisms: the minor A allele containing genotypes for both polymorphisms were more frequent in the control compared to the AD group. Haplotype analysis revealed that rs2230805, rs2230806 and rs2066718 polymorphisms created a linkage disequilibrium (LD) block with a strong LD between rs2230805 and rs2230806 polymorphisms. In the haplotype risk association tests, A-A-G haplotype of the rs2230805-rs2230806-rs2066718 polymorphisms was found to be nominally significantly more frequent in the control group. After correcting p values for multiple testing, only the effects of the rs2230805 and rs2230806 polymorphisms remained significant in the recessive model suggesting a modest protective effect of their minor alleles in AD, which should be interpreted with considerable caution, until further studies elucidate their role in AD pathology.

Mild Cognitive Impairment (MCI) is a heterogeneous clinical syndrome, often considered as the prodromal stage of dementia. It is characterized by the subtle deterioration of cognitive functions, including memory, executive functions and language. Mainly due to the tenuous nature of these impairments, a high percentage of MCI cases remain undetected. There is evidence that language changes in MCI are present even before the manifestation of other distinctive cognitive symptoms, which offers a chance for early recognition. A cheap non-invasive way of early screening could be the use of automatic speech analysis. Earlier, our research team developed a set of speech temporal parameters, and demonstrated its applicability for MCI detection. For the automatic extraction of these attributes, a Hungarian-language ASR system was employed to match the native language of the MCI and healthy control (HC) subjects. In practical applications, however, it would be convenient to use exactly the same tool, regardless of the language spoken by the subjects. In this study we show that our temporal parameter set, consisting of articulation rate, speech tempo and various other attributes describing the hesitation of the subject, can indeed be reliably extracted regardless of the language of the ASR system used. For this purpose, we performed experiments both on English-speaking and on Hungarian-speaking MCI patients and healthy control subjects, using English and Hungarian ASR systems in both cases. Our experimental results indicate that the language on which the ASR system was trained only slightly affects the MCI classification performance, because we got quite similar scores (67-92%) as we did in the monolingual cases (67-92% as well). As our last investigation, we compared the proposed attribute values for the same utterances, utilizing both the English and the Hungarian ASR models. We found that the articulation rate and speech tempo values calculated based on the two ASR models were highly correlated, and so were the attributes corresponding to silent pauses; however, noticeable differences were found regarding the filled pauses (still, these attributes remained indicative for both languages). Our further analysis revealed that this is probably due to a difference regarding the annotation of the English and the Hungarian ASR training utterances.

There is strong evidence of the increased risk for mild cognitive impairment (MCI) among type 2 diabetes mellitus (T2DM) patients. Since slight changes in speech can indicate cognitive impairments, the main aim of our study was to examine the characteristics of T2DM patients’ speech. Participants with T2DM (all above the age of 50) were divided into two groups: patients with MCI (n =26) or with normal cognition (n = 23). Spontaneous speech samples (containing the subjects’ description of their previous day) were collected and used for extraction of temporal speech parameters via an automatic speech recognition (ASR) based tool. Results indicated longer and more frequent filled pauses in MCI-patients’ speech: frequency of filled pauses (p

Background:Dementia in the elderly constitutes a growing challenge in healthcare worldwide, including Hungary. There is no previous report on the role of general practitioners in the management of dementia.Aim:The purpose of the present study was to investigate the Hungarian general practitioners’ attitude toward their patients living with dementia as well as dementia care. Our goal was also to assess their willingness and habits in assessing dementia. Additionally we wanted to explore the role of education about dementia, and its impact on their attitude in dementia management.Methods:As part of a large survey, a self-administered questionnaire was filled out voluntarily by 402 of general practitioners. According to our preset criteria, 277 surveys were selected for evaluation. Descriptive statistical analysis and Likert-scale analysis were performed.Findings:Half of the doctors (49.8%) indicated that they conducted a test to assess cognitive functions in case of suspicion. Among the respondents who did not assess, 50.0% of physicians cited lack of time as the main reason for not doing so and 14.4% of them had not proper knowledge of testing methods. The respondents most often mentioned feelings toward their patients with dementia, were regret (Likert-scale mean: 3.33), helplessness (3.28) and sadness (3.07). The majority of physicians thought the treatment of dementia was difficult (4.46). Most of the respondents (81.2%) indicated that in the past 2 years they had not participated in any training about dementia. Those practitioners who had participated in some form of education were less likely to feel helpless facing a patient with dementia, and education also determined their approach to dementia care.

One of the world’s chronic neuro-degenerative diseases, Alzheimer’s Disease (AD), leads its sufferers, among other symptoms, to suffer from speech difficulties. In particular, the inability to recall vocabulary which makes patients’ speech different. Furthermore, Mild Cognitive Impairment (MCI) is usually considered as a prodromal neuro-degenerative state of AD. The key to abate the progress of both disorders is their early diagnosis. However, actual ways of diagnosis are costly and quite time-consuming. In this study, we propose the extraction of features from speech through the use of the i-vector approach, by which we seek to model the speech pattern of the three mental conditions from the subjects. To the best of our knowledge, no previous studies have utilized i-vector features to assess Alzheimer’s before. These i-vectors are extracted from Mel-Frequency Cepstral Coefficients (MFCCs), then they are given to a SVM classifier in order to identify the speech in one of the following manners: AD - Alzheimer Disease, MCI - Mild Cognitive Impairment, HC - Healthy Control. We tested these i-vector features by performing a 5-fold cross-validation and we achieved an F1-score of 79.2%.

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 ATP-binding cassette, sub-family A, member 7 (ABCA7) gene has been identified as a strong genetic risk locus for Alzheimer's disease (AD). Our case-control study (416 AD patients and 302 controls) provides further data on the rs3752246 polymorphism in AD in the Hungarian population that has not been investigated so far regarding the ABCA7 gene variants. A modest, marginally significant association of the G allele containing genotypes with AD was observed (p = 0.054). In line with the previous results in other populations, the G allele carriers had an increased risk for developing AD considering C/C genotype as reference category.

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, In a randomised controlled trial, Brian Lawlor and colleagues investigate whether the blood pressure medication nivaldipine can slow the progression of Alzheimer disease., Author summary Why was this study done? There are few licensed drug treatments for Alzheimer disease and none are effective in slowing the rate of disease progression. Nilvadipine is a licensed blood pressure medication and has been shown to lower brain amyloid and improve memory function in animal models of Alzheimer disease. If nilvadipine were shown to be effective in slowing the rate of progression of Alzheimer disease, because it is already licensed and available to treat high blood pressure, it would be possible to introduce the drug for use in Alzheimer disease relatively quickly. What did the researchers do and find? We carried out an investigator-led clinical trial funded by the European Union across 23 academic university sites and involving 511 patients with mild- and moderate-stage Alzheimer disease, as diagnosed by a clinician. We tested whether a single dose of nilvadipine, compared with placebo, was safe and slowed the progression of Alzheimer disease over a period of 18 months. We found that nilvadipine appeared safe and was well tolerated but did not slow decline in cognition or function in this group of mild- and moderate-stage Alzheimer disease patients. What do these findings mean? Nilvadipine does not appear to be effective as a treatment for people with mild- or moderate-stage Alzheimer disease. We cannot rule out that this medication may help at an earlier stage of the disease process, before the person experiences loss of function.

Clinical diagnosis of Alzheimer's disease (AD) relying on symptomatic features has a low specificity, emphasizing the importance of the pragmatic use of neurochemical biomarkers. The most advanced and reliable markers are amyloid-β (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau) in cerebrospinal fluid (CSF) with relatively high levels of sensitivity, specificity, and diagnostic accuracy. Recent advances within the field of proteomics offer the potential to search for novel biomarkers in CSF by using modern methods, such as microarrays. The purpose of this study was to identify pathognostic proteins in CSF obtained from patients whose clinical AD diagnosis was confirmed by the "core" biomarkers. CSF samples were obtained from 25 AD patients and 25 control individuals. The levels of Aβ42, t-tau, and p-tau were measured by ELISA. In the microarray experiments, ultrasensitive slides representing of 653 antigens were used. Apolipoprotein E genotyping was also determined. A decrease of seven CSF proteins in AD were found, four of them (POLG, MGMT, parkin, and ApoD) have a protective function against neuronal death, while the remaining three proteins (PAR-4, granzyme B, Cdk5) trigger multiple pathways facilitating neuronal cell death. Since these proteins from CSF samples could not be identified by western blot, their decreased levels in AD patients were not verified. Our results provide new information of pathognostic importance of POLG and granzyme B in AD. Although the function of MGMT, parkin, ApoD, PAR-4, and Cdk5 was previously known in AD, the findings presented here provide novel evidence of the significance of CSF analysis in the mapping of the AD pathomechanism.

Background: Adiponectin and leptin are implicated in the initiation and pathomechanism of Alzheimer's disease (AD). The serum concentrations of these adipokines has been extensively studied in AD, however little is known about their receptors in this disease. Objective: We developed a novel approach to examine whether the receptors of adiponectin (AdipoR1 and -R2) and/or leptin (LepR) can contribute to AD pathomechanism. To achieve this, we investigated the effect of both genetic and environmental factors associated with AD on the expression of these receptors. Method: We used C57BL/6J (WT) and APP(swe)/Presen(e9d)1 (AD) mice. Both strains were exposed to restraint stress (RS) daily for 6h over different time periods. Then, we measured the mRNA expression of AdipoR1, AdipoR2 and LepR and the level of AdipoR1 and AdipoR2 proteins in the hippocampal and prefrontal cortical areas of each mouse. Results: We detected brain region specific transcriptomic changes of adiponectin receptors induced by APP and PS1 transgenes. Both acute and chronic RS caused significant elevations in AdipoR1 mRNA expression in the hippocampus of WT mice. In the prefrontal cortex, the mRNA expression of AdipoR1 followed a biphasic course. In AD mice, RS did not promote any changes in the expression of AdipoR1 mRNA and AdipoR1 protein levels. AdipoR2 mRNA in AD animals, however, showed a significant increase in the prefrontal cortex during RS. Regarding AdipoR1 and AdipoR2 mRNA and protein expression, relevant changes could be measured during stress exposure in both brain areas. Furthermore, stress exposed groups exhibited little change in LepR mRNA expression. Conclusion: Our findings indicate that carrying the transgenes associated with AD induces modification in the expression of both adiponectin receptors. In the case of a normal genetic background, these receptors also appear to be sensitive to environmental factors, while in a genetically determined AD model less response to stress stimuli could be observed. The results suggest that modification of adipokine receptors could also be considered in the therapeutic approach to AD.

In many biology- and chemistry-related research fields and experiments the quantification of the peptide and/or protein concentration in samples are essential. Every research environment has unique requirements, e.g. metal ions, incubation times, photostability, pH, protease inhibitors, chelators, detergents, etc. A new protein assay may be adequate in different experiments beyond or instead of the well-known standard protocols (e.g. Qubit, Bradford or bicinchoninic acid) in related conceptions. Based on our previous studies, we developed a novel protein assay applying the 4,4'-Dianilino-1,1'-binaphthyl-5,5'-disulfonic acid dipotassium salt (BisANS) fluorescent dye. This molecule has several advantageous properties related to protein detection: good solubility in water, high photostability at adequate pH, quick interaction kinetics (within seconds) with proteins and no exclusionary sensitivity to the chelator, detergent and inhibitor ingredients. The protocol described in this work is highly sensitive in a large spectrum to detect protein (100-fold diluted samples) concentrations (from 0.28 up to more than 100 μg/mL). The BisANS protein assay is valid and applicable for quantification of the amount of protein in different biological and/or chemical samples.

ATP binding cassette subfamily G member 2 (ABCG2) is involved in amyloid-β transport and was found to be significantly up-regulated in Alzheimer's disease (AD) brain. A functional polymorphism of the ABCG2 gene (C421A; rs2231142) was genotyped in a sample of 299 Hungarian late-onset AD patients and 259 elderly, non-demented controls to investigate for the first time its association with AD, either alone or in combination with apolipoprotein E (APOE) ɛ2/ɛ3/ɛ4 polymorphism. A significantly increased susceptibility to AD (OR=1.741, 95% CI: 1.075-2.819, p=0.024) associated with ABCG2 C/C genotype was found when compared with the variant allele containing genotypes (CA and AA) as the reference category. Logistic regression analysis revealed a significant interaction effect between the ABCG2 C/C genotype and APOE ɛ4 allele on AD risk (p=0.003). It seems that the potential modest risk effect of the ABCG2 C/C genotype on AD risk is more pronounced in combination with the APOE ɛ4 allele. Further independent replications of our findings are required.

The DEFB4 gene copy numbers were investigated in 206 AD patients and in 250 controls. The levels of the human defensin β−2 (hBD2) and α-defensins (HNP 1-3) in the sera and in the cerebrospinal fluid (CSF) of the patients and the controls were determined. Higher copy numbers of the DEFB4 gene was observed in AD patients as compared with the controls. The levels of hBD-2 and HNP 1-3 were significantly elevated in the sera and in the CSF of the AD patients These data suggest that both defensin β−2 and α-defensins have potential role in the development of AD.

Stress is well-known to contribute to the development of both neurological and psychiatric diseases. While the role of the blood-brain barrier is increasingly recognized in the development of neurodegenerative disorders, such as Alzheimer's disease, dysfunction of the blood-brain barrier has been linked to stress-related psychiatric diseases only recently. In the present study the effects of restraint stress with different duration (1, 3, and 21 days) were investigated on the morphology of the blood-brain barrier in male adult Wistar rats. Frontal cortex and hippocampus sections were immunostained for markers of brain endothelial cells (claudin-5, occluding, and glucose transporter-1) and astroglia (GFAP). Staining pattern and intensity were visualized by confocal microscopy and evaluated by several types of image analysis. The ultrastructure of brain capillaries was investigated by electron microscopy. Morphological changes and intensity alterations in brain endothelial tight junction proteins claudin-5 and occludin were induced by stress. Following restraint stress significant increases in the fluorescence intensity of glucose transporter-1 were detected in brain endothelial cells in the frontal cortex and hippocampus. Significant reductions in GFAP fluorescence intensity were observed in the frontal cortex in all stress groups. As observed by electron microscopy, 1-day acute stress induced morphological changes indicating damage in capillary endothelial cells in both brain regions. After 21 days of stress thicker and irregular capillary basal membranes in the hippocampus and edema in astrocytes in both regions were seen. These findings indicate that stress exerts time-dependent changes in the staining pattern of tight junction proteins occludin, claudin-5, and glucose transporter-1 at the level of brain capillaries and in the ultrastructure of brain endothelial cells and astroglial endfeet, which may contribute to neurodegenerative processes, cognitive and behavioral dysfunctions.

Besides being an important component of spices used worldwide, capsaicin has wide-ranging therapeutic potential as a hypolipidemic, antioxidant and anti-inflammatory agent. Accordingly, it is very important to investigate the long-term effect of capsaicin in the pathogenesis of Alzheimer's disease. In this study, the effects of capsaicin on the processing of amyloid precursor protein (APP) were investigated in an in vivo model. The APP mRNA and protein levels were examined in the brain cortices of control and capsaicin-treated rats. The protein kinase C (PKC) translocation state in the soluble and membrane-bound fractions and the levels of β-secretase (BACE) were also evaluated. Capsaicin enhanced the level of membrane-bound APP 1.7-fold. The APP mRNA and PKC and BACE protein levels were unchanged after capsaicin treatment. These in vivo data indicate that capsaicin is able to interfere with the brain APP metabolism by promoting the amyloidogenic route. We suggest that PKC is not involved in the mechanism underlying the effects.

Objective The incidence of dementia is known to vary between nations due to population specific interactions of genetic and epigenetic risk factors. Since this type of data was missing from the Central-Eastern part of Europe, especially from Hungary, an ongoing prospective multicentre study was initiated 3 years ago to determine the impact of some well-known social and biological dementia risk factors and the prevalences and conversion rates of dementia and depression syndromes. Methods As part of this work, the effects of age, gender, education, smoking and alcohol consumption were investigated in residental homes-based cohort of more than 2,100 elderly. Results Forty-eight percent of the entire population showed clinical signs of cognitive decline. Eighteen percent, 22%, 16% and 10% were classified as mild cognitive impairment, mild, moderate and severe stages of cognitive decline, respectively. Considered individually, all the examined dementia risk factors were significantly related to the presence of the cognitive decline. Age, female gender and regular drinking increased the risk, while smoking, higher level of education and occasional or former history of alcohol consumption were protective factors. The male gender associated regular alcohol consumption represented the strongest risk, especially with low education levels. When the different severity subgroups were compared, similar risk tendencies have been observed, but the most robust effects were associated with the most severe stages. Conclusions The well-known dementia risk and protective factors are confirmed in our study. Taking these variables into consideration, the Hungarian cohort is similar to other ethnic groups in Europe. Copyright © 2007 John Wiley & Sons, Ltd.

Many of the risk factors for cerebrovascular disease and atherosclerosis also increase the risk of Alzheimer's disease, characterized by the cerebral deposition of beta-amyloid plaques resulting from the abnormal processing of the transmembrane amyloid precursor protein (APP). The initiating event of cholesterol-induced atherosclerosis is the retention and accumulation of atherogenic apolipoprotein B (apoB) together with low-density lipoproteins in the vascular intima. Biglycan, a member of the small leucine-rich protein family, was suspected of contributing to this process. The individual and combined overexpressions of biglycan and apoB-100 were therefore examined on the cortical APP mRNA levels of transgenic mice by means of semiquantitative PCR. As compared with the control littermates, transgenic biglycan mice had significantly increased cortical APP695 (122%) and APP770 (157%) mRNA levels, while the double transgenic (apoB(+/-)xbiglycan(+/-)) mice did not exhibit any changes. These results provide the first experimental evidence that the atherogenic risk factor biglycan alters APP splicing and may participate in the pathogenesis of both Alzheimer and vascular dementias.

It is known that Alzheimer’s disease (AD) influences the temporal characteristics of spontaneous speech. These phonetical changes are present even in mild AD. Based on this, the question arises whether an examination based on language analysis could help the early diagnosis of AD and if so, which language and speech characteristics can identify AD in its early stage. The purpose of this article is to summarize the relation between prodromal and manifest AD and language functions and language domains. Based on our research, we are inclined to claim that AD can be more sensitively detected with the help of a linguistic analysis than with other cognitive examinations. The temporal characteristics of spontaneous speech, such as speech tempo, number of pauses in speech, and their length are sensitive detectors of the early stage of the disease, which enables an early simple linguistic screening for AD. However, knowledge about the unique features of the language problems associated with different dementia variants still has to be improved and refined.

Mild Cognitive Impairment (MCI), sometimes regarded as a prodromal stage of Alzheimer’s disease, is a mental disorder that is difficult to diagnose. However, recent studies reported that MCI causes slight changes in the speech of the patient. Our starting point here is a study that found acoustic correlates of MCI, but extracted the proposed features manually. Here, we automate the extraction of the features by applying automatic speech recognition (ASR). Unlike earlier authors, we use ASR to extract only a phonetic level segmentation and annotation. While the phonetic output allows the calculation of features like the speech rate, it avoids the problems caused by the agrammatical speech frequently produced by the targeted patient group. Furthermore, as hesitation is the most important indicator of MCI, we take special care when handling filled pauses, which usually correspond to hesitation. Using the ASR-based features, we employ machine learning methods to separate the subjects with MCI from the control group. The classification results obtained with ASR-based feature extraction are just slightly worse that those got with the manual method. The F1 value achieved (85.3) is very promising regarding the creation of an automated MCI screening application.

Association between genetic variants of the reelin (RELN) gene and the risk for developing Alzheimer's disease (AD) was examined in a sample of 432 patients and 308 controls. Single marker and haplotype analyses revealed that the strongly linked rs528528 and rs607755 polymorphisms are associated with AD risk in a gender specific manner. Among men, but not in women the rs528528 T/T and rs607755 A/A genotypes were significantly associated with the susceptibility to AD.

Epidemiological and biochemical data suggest a link between the cholesterol metabolism, the amyloid precursor protein (APP) processing and the increased cerebral beta-amyloid (Abeta) deposition in Alzheimer's disease (AD). The individual and combined effects of a high-cholesterol (HC) diet and the overexpression of the human apoB-100 gene were therefore examined on the cerebral expression and processing of APP in homozygous apoB-100 transgenic mice [Tg (apoB(+/+))], a validated model of atherosclerosis. When fed with 2% cholesterol for 17 weeks, only the wild-type mice exhibited significantly increased APP695 (123%) and APP770 (138%) mRNA levels in the cortex. The HC diet-induced hypercholesterolemia significantly increased the APP isoform levels in the membrane-bound fraction, not only in the wild-type animals (114%), but also in the Tg apoB(+/+) group (171%). The overexpression of human apoB-100 gene by the liver alone reduced the brain APP isoform levels in the membrane-bound fraction (78%), whereas the levels were increased by the combined effect of HC and the overexpression of the human apoB-100 gene (134%). The protein kinase C and beta-secretase protein levels were not altered by the individual or combined effects of these two factors. Our data indicate that the two atherogenic factors, the HC diet and the overexpression of the human apoB-100 gene by the liver, could exert different effects on the processing and expression of APP in the mice brain.

SummaryBackground and objective: Recent studies emphasize a positive correlation between (cardiac) surgical interventions and increased risk for developing Alzheimer's disease in the late postoperative period. Since amyloid precursor protein and its neurotoxic derivatives play key roles in the development of Alzheimer's dementia, the impact of several agents used in the intra- and perioperative period is examined. Method: Amyloid precursor protein concentrations were assessed by semi-quantitative Western-immunoblot in brains of rats following intraperitoneal treatment with diazepam and midazolam. Results: There were no significant changes in the amyloid precursor protein concentrations. Conclusion: Both diazepam and midazolam are considered to be relatively safe with respect to amyloid precursor protein metabolism.

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.Az esendőségszindróma fokozott stresszérzékenységgel, csökkent alkalmazkodási potenciállal járó állapot, leginkább az időskorúakat és krónikus betegeket érinti. Növeli az adverz egészségügyi kimenetel kockázatát (fertőzés, elesés, delírium, institucionalizáció és mortalitás), gyorsítja a társbetegségek progresszióját. A szindróma hátterében immun és neuroendokrin diszreguláció állhat. A fenotípusmodell szerint kritériumai az izomgyengeség, kimerültség, meglassultság, fogyás, aktivitáscsökkenés, míg a kumulatív modell szerint az egészségügyi problémák száma határozza meg. Hangsúlyozandó, hogy az öregedés, esendőség, dementia és depresszió önálló klinikai entitások: fennállhatnak egymástól függetlenül, de potencírozhatják is egymást, így a szűrőtesztek többsége a fizikai, mentális, szociális dimenziókat együtt vizsgálja. Egyénre szabott gondozási tervvel az enyhe-mérsékelt esendőség potenciálisan reverzíbilis, progressziója lassítható. Ennek feltételei a primer ellátásban használható gyors, egyszerű szűrőtesztek, amelyek alapján e kockázati csoport további diagnosztika és kezelés céljából szakambulanciákra irányítható. Jelen írásban a szerzők áttekintik ezen újra felfedezett, napjainkban időszerűvé váló klinikai fogalom irodalmát, különös tekintettel az alapellátás gyakorlati vonatkozásaira. Orv. Hetil., 2014, 155(49), 1935–1951.

Despite the clinical efficacy of the most thoroughly studied conventional neuroleptic agent haloperidol, and the atypical antipsychotic risperidone is well established, little information is available on their molecular effects. Recent advances in high-density DNA microarray techniques allow the possibility to analyze thousands of genes simultaneously for their differential gene expression patterns in various biological processes, and to determine mechanisms of drug action. The aim of this series of experiments was to gain experience in antipsychotic gene-expression profiling and characterize (in the parlance of genomics) the "antipsychotic transcriptome." In this prospective animal study, broad-scale gene expression profiles were characterized for brains of rats treated with antipsychotics and compared with those of sham controls. We used DNA microarrays containing 8000 sequences to measure the expression patterns of multiple genes in rat fronto-temporo-parietal cortex after intraperitoneal treatment with haloperidol or risperidone. A number of transcripts were differentially expressed between control and treated samples, of which only 36 and 89 were found to significantly differ in expression as a result of exposure to haloperidol or risperidone, respectively (P0.05). Acutely, 13 genes were more highly expressed and 15 transcripts were found to be significantly less abundant, whereas chronically nine genes were up-regulated and none of them was repressed in haloperidol-treated cortices. Risperidone acutely induced 43 and repressed 46 genes, and chronically over-expressed 6 and down-regulated 11 transcripts. Selected genes were assayed by real-time PCR, then normalized to beta-actin. These assays confirmed the significance of the array results for all transcripts tested. Despite their differing receptor affinity and selectivity, our findings indicate that haloperidol and risperidone interfere with cell survival, neural plasticity, signal transduction, ionic homeostasis and metabolism in a similar manner.

Multiple genetic and environmental factors regulate the susceptibility to Alzheimer's disease (AD). Recently, several independent studies have reported that a locus on chromosome 14q32.1, where a gene encoding a cholesterol degrading enzyme of the brain, called 24-hydroxylase (CYP46A1) is located, has been linked with AD. The single nucleotide polymorphism (T/C) in intron 2 of CYP46 gene has been found to confer the risk for AD. The water soluble 24(S)-hydroxysterol is the product of the CYP46A1, and elevated plasma and cerebrospinal fluid hydroxysterol concentrations have been found in AD, reflecting increased brain cholesterol turnover or cellular degradation, due to the neurodegenerative process. A case-control study was performed on 125 AD and 102 age- and gender-matched control subjects (CNT) from Hungary, to test the association of CYP46 T/C and apolipoprotein E (ApoE) gene polymorphisms in AD. The frequency of the CYP46 C allele was similar (chi2=0.647, df=1, P=0.421, exact P=0.466, OR=0.845; 95% CI: 0.561-1.274) in both groups (CNT: 27%; 95% CI: 21.3-33.4; AD 30%; 95% CI: 25.0-36.3). The ApoE varepsilon4 allele was significantly over-represented (chi2=11.029, df=2, P=0.004) in the AD population (23.2%; 95% CI: 18.2-29.0) when compared with the CNT (11.3%; 95% CI: 7.4-16.6). The presence or absence of one or two CYP46C alleles together with the ApoE varepsilon4 allele did not increase the risk of AD (OR=3.492; 95% CI: 1.401-8.707; P0.007 and OR=3.714; 95% CI: 1.549-8.908; P0.003, respectively). Our results indicate that the intron 2 T/C polymorphism of CYP46 gene (neither alone, nor together with the varepsilon4 allele) does not increase the susceptibility to late-onset sporadic AD in the Hungarian population.

Comorbid depression of Alzheimer's disease (AD) is a common mood disorder in the elderly and a broad spectrum of antidepressants have been used for its treatment. Abeta peptides and other derivatives of the amyloid precursor protein (APP) have been implicated as central to the pathogenesis of AD. However, the functional relationship of APP and its proteolytic derivatives to antidepressant therapy is not known. In this study, Western blotting was used to test the ability of the tricyclic antidepressant (TCA) imipramine or the selective serotonin reuptake inhibitor (SSRI) citalopram to change the release of APP and the protein kinase C (PKC) content. Both antidepressants increased APP secretion in primary rat neuronal cultures. Imipramine or citalopram enhanced the level of secreted APP by 3.2- or 3.4-fold, respectively. Increases in PKC level were observed only after imipramine treatment. These in vitro data suggest that both TCA and SSRI are able to interfere with the APP metabolism. Imipramine promotes the non-amyloidogenic route of APP processing via stimulatory effects on PKC. We propose that PKC is not involved in the mechanism underlying the effects of citalopram on the APP metabolism. Since the secreted APP is not further available for the pathological cleavage of beta- and gamma-secretases, antidepressant medication might be beneficial in AD therapy.

Since the function and metabolism of peripheral lymphocytes is known to be altered in Alzheimer's disease (AD), a pilot study was carried out to examine differences in gene expression profiles of these cells in 16 AD patients and aged control probands. Using a cDNA microarray representing 3200 distinct human genes, we identified 20 candidate genes whose expression is altered in AD lymphocytes compared with the control probands. Among these were the alpha2C-adrenoreceptor gene, known to regulate blood pressure and learning, the defensin, histocompability complex enhancer-binding protein, carboxypeptidase M, and the Fc fragment of IgE known to be involved in cellular and humoral immune responses. Others, like human cell death protein, TRAIL, and galectin-4 participate in the regulation of apoptosis. Real-time quantitative reverse transcription-polymerase chain reaction analysis was performed in order to confirm the expression changes in AD lymphocytes, and it could detect down-regulation of defensin and alpha2c-adrenoceptor genes, while other genes seemed unaltered in their expression, including heat-shock protein (hsp90), cholesteryl ester transfer protein, and apolipoprotein B100 (apoB). The altered expression profile of these genes might be connected with the previously reported AD-specific lymphocyte abnormalities. It remains to be elucidated, however, how these genes are related to the pathomechanism of dementia and whether the gene expression differences of AD lymphocytes reflect disease traits or stage processes.