Magdolna Pákáski

Epidemiological and biological evidence indicate a close connection between Alzheimer’s disease (AD) and type-2 diabetes mellitus. Glucose transporter 1 (GLUT1), encoded by the SLC2A1 gene, has a major role in glucose metabolism, the dysregulation of which has been implicated in both diseases. We conducted a case-control association study in a sample of 439 non-diabetic patients with late-onset AD and 304 cognitively healthy, non-diabetic elderly controls to determine the potential risk for developing AD associated with SLC2A1 rs841847 polymorphism. The rs841847 C/C genotype occurrence was higher in the AD group (AD: 60.4%, controls: 50.7%), while the minor T allele-containing genotypes were more frequent among controls (AD: 39.6%, controls: 49.3%). A multivariate logistic regression model adjusted for age, sex, and apolipoprotein E (APOE) ε4 status (ε4 allele carriers versus non-carriers) demonstrated that carriers of the T allele had a significantly reduced risk for AD compared to C/C homozygotes (OR = 0.672; 95% CI: 0.493–0.916; p = 0.012). Although the rs841847 polymorphism has been linked to type-2 diabetes mellitus, the present study investigated this gene variant in AD for the first time. Our findings indicate a moderate protective effect for the rs841847 T allele on the susceptibility to AD. We demonstrated the rs841847 polymorphism as a candidate single nucleotide polymorphism for further examination as a predisposing genetic factor for AD.

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.

One of the most important neurodegenerative diseases of our time is Alzheimer's disease, which mainly affects the elderly population. The accumulation of β-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 β-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.

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.

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. 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. 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. 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.

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. 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. 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. 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.

Calcium homeostasis modulator 1 (CALHM1), a promising candidate gene for Alzheimer's disease risk, has been recently identified. We tested the hypothesis that the T-allelic variant of the CALHM1 rs2986017 polymorphism confers susceptibility to Alzheimer's disease in a Hungarian case–control sample that was also genotyped for apolipoprotein E. This study included 238 probable patients with Alzheimer's disease who met the diagnostic criteria for National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association and 202 elderly healthy control participants. We failed to detect an association between the CALHM1 polymorphism and the risk for Alzheimer's disease (P=0.153 for genotypes and P=0.090 for alleles), nor did we find an effect on age at onset. However, a potential weak correlation between the presence of the T allele (CT and TT genotypestogether) and Alzheimer's disease was observed (P=0.056).

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.