Publications by authors named "Małgorzata Bednarska-Makaruk"

31 Publications

Evaluation of the Frequency of RETN c.62G>A and RETN c.-180C>G Polymorphisms in the Resistin Coding Gene in Girls with Anorexia Nervosa.

Endokrynol Pol 2021 Jul 22. Epub 2021 Jul 22.

Department of Adult Psychiatry, University of Medical Sciences in Poznań, Poland.

Introduction: Anorexia nervosa (AN) is a serious psychosomatic syndrome, classified as an eating disorder. AN patients strive to lose weight below normal limits defined for a specific age and height, achieving their goal even at the expense of extreme emaciation. AN has a multifactorial etiology. Genetic factors are believed to be significant in the predisposition to the development of AN. In girls suffering from AN significantly lower levels of resistin (RES) in blood serum are observed as compared to healthy girls. These differences may lead to a thesis that functional genetic polymorphisms in RES coding genes can be responsible for this phenomenon. In our pilot study we demonstrated significant differences in the distribution of genotypes in the loci RETN c.-180C>G of the RES gene in 67 girls with AN and 38 healthy girls. It seems reasonable to compare the frequency of polymorphisms of RETN c.62G>A and RETN c.-180C>G in the RES gene in girls with AN and in healthy subjects in a bigger cohort and to analyse correlations between individual variants of the polymorphisms referred to above and the RES levels in blood plasma.

Material And Methods: The study covered 308 girls with the restrictive form of AN (AN) and 164 healthy girls (C) (aged 11-19). The RES levels in blood serum were determined by means of the ELISA method on Bio-Vendor, LLC (Asheville, North Carolina, USA). The DNA isolation was carried out by means of Genomic Mini AX BLOOD (SPIN). The PCR reaction was carried out in the thermocycler ThermoCycle T100. 80-150 ng of the studied DNA and relevant starters F and R were added to the reaction mixture. The reaction products were subjected to digestion by restriction enzymes and separated on agarose gels (RFLP).

Results: The average RES level in blood serum in the AN group was significantly lower (p< 0.0001) than in the C group. The distribution of genotypes in the loci RETN c.62 of the RES gene was similar in both groups. A significant difference was demonstrated in the distribution of genotypes in the polymorphic site RETN c.-180 of the RES gene between AN and C (p=0.0145) and in the distribution of the C and G alleles in the loci RETN c.-180 (p< 0.0001). The C allele occurred significantly more frequently than the G allele in the C group as compared to the AN group. In all the study subjects jointly (AN and C) a significant positive correlation between the blood RES levels on one hand and the body mass (r= 0.42; p< 0.0001) and BMI (r= 0.61; p< 0.0001) on the other hand was observed. There was no correlation between the concentration of RES in blood serum and the distribution of genotypes in the loci of the resistin gene referred to above.

Conclusions: The CG genotype in the loci RETN c.-180 C>G of the RES gene may constitute one of the factors predisposing to the development of AN in girls. The genotype in the loci RETN c.62 G>A and RETN c.-180 C>G of the resistin gene has no influence on the levels of this hormone in blood in AN patients.
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http://dx.doi.org/10.5603/EP.a2021.0065DOI Listing
July 2021

Evaluation of the Frequency of ADIPOQ c.45 T>G and ADIPOQ c.276 G>T Polymorphisms in the Adiponectin Coding Gene in Girls with Anorexia Nervosa.

Endokrynol Pol 2021 Jul 22. Epub 2021 Jul 22.

Department of Adult Psychiatry, University of Medical Sciences in Poznań, Poland.

Introduction: Anorexia nervosa (AN) is a serious chronic psychosomatic disorder, the essence of which are attempts to obtain a slim silhouette by deliberate weight loss (restrictive diet, strenuous physical exercise, provoking vomiting). The etiology of this disorder is multifactorial. Genetic factors which influence the predisposition to AN have been searched for. A broad meta-analysis points to a strong genetic correlation between AN and insulin resistance. Adiponectin (ADIPO) increases insulin sensitivity. In our pilot study we demonstrated that the TT genotype in loci ADIPOQ c.276 G>T of the ADIPO gene and a higher concentration of ADIPO in blood serum occurs significantly more frequently in 68 girls suffering from AN than in 38 healthy girls. The objective of this study is to evaluate the frequency of the occurrence of ADIPOQ c.45 T>G and ADIPOQ c.276 G>T in the ADIPO gene in a bigger cohort of girls with AN and healthy girls, as well as an analysis of correlations between variants of the aforementioned polymorphisms and the levels of ADIPO in blood serum.

Materials And Methods: The study covered 472 girls (age: 11-19): 308 with the restrictive form of AN (AN), and 164 healthy girls (C). The level of ADIPO in blood serum was determined by means of the ELISA method on Bio-Vendor, LLC (Asheville, North Carolina, USA). The DNA isolation was carried out by means of Genomic Mini AX BLOOD (SPIN). The PCR reaction was carried out in the thermocycler ThermoCycle T100. 80-150 ng of the studied DNA and relevant starters F and R were added to the reaction mixture. The reaction products were subjected to digestion by restriction enzymes and separated on agarose gels (RFLP).

Results: The distribution of genotypes in the polymorphic site ADP c.45 of the ADIPO gene and ADP c.276 was similar in both groups. In both groups the T allele was most frequent in loci ADIPOQ c.45 and the G allele in loci ADIPOQ c.276. In all the study subjects collectively (AN and C) a statistically significant negative correlation between the levels of ADIPO in blood serum on one hand and the body weight (r= -0.46; p< 0.0001) and BMI (r= -0.67; p< 0.0001) on the other was demonstrated. Exclusively in the AN group a significant correlation between the level of ADIPO in blood and the distribution of TG, TT, and GG alleles in loci ADIPOQ c.45 and ADIPOQ c.276 was demonstrated (p= 0.0052 and p< 0.0001; respectively).

Conclusions: The genotype in loci ADIPOQ c.45 and ADIPOQ c.276 of the ADIPO gene seems to have no effect on the predisposition to AN. Girls suffering from AN with the TT genotype in loci ADIPOQ c.45 and ADIPOQ c. 276 may demonstrate higher insulin sensitivity as they have significantly higher levels of ADIPO than girls suffering from AN with other genotypes. This may be suggestive of their better adaptation to the state of malnutrition, as well as it can have a potential effect on treatment effects.
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http://dx.doi.org/10.5603/EP.a2021.0064DOI Listing
July 2021

Elevated Dipeptidyl Peptidase IV (DPP-IV) Activity in Plasma from Patients with Various Lysosomal Diseases.

Diagnostics (Basel) 2021 Feb 16;11(2). Epub 2021 Feb 16.

Department of Genetics, Institute of Psychiatry and Neurology, 02-957 Warsaw, Poland.

Increased activity of dipeptidyl peptidase IV (DPP-IV) was reported earlier in patients with different types of mucopolysaccharidoses. DPP-IV (also known as CD26 lymphocyte T surface antigen) is a transmembrane protein showing protease activity. This enzyme displays various functions in the organism and plays an important role in multiple processes like glucose metabolism, nociception, cell-adhesion, psychoneuroendocrine regulation, immune response and cardiovascular adaptation. In order to evaluate DPP-IV in lysosomal storage diseases (LSD), we examined its activity in plasma samples from 307 patients affected with 24 different LSDs and in 75 control persons. Our results revealed elevated DPP-IV activity especially in individuals affected with mucolipidosis II/III, alpha-mannosidosis, and mucopolysaccharidoses types III, II, and I ( < 0.05). In other LSDs the DPP-IV activity was still significantly increased, but to a lesser extent. In patients with Gaucher disease, ceroid lipofuscinosis type 1 (CLN1), Niemann-Pick disease type C and A, Krabbe and Pompe diseases, gangliosidosis GM2 and metachromatic leukodystrophy discreet or no changes in DPP-IV activity were observed. DPP-IV may serve as a first-tier diagnostic procedure or additional biochemical analysis in recognizing patients with some LSDs. DPP-IV may become an object of basic research for a better understanding of LSDs.
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http://dx.doi.org/10.3390/diagnostics11020320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920438PMC
February 2021

Spinal muscular atrophy with an overlapping syndrome - "double trouble" or a potentially better outcome?

Neurol Neurochir Pol 2020 5;54(5):475-477. Epub 2020 Aug 5.

Department of Neurology, Medical University of Warsaw, Banacha 1a, 02-097 Warsaw, Poland.

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http://dx.doi.org/10.5603/PJNNS.a2020.0060DOI Listing
November 2020

Changes in global gene expression indicate disordered autophagy, apoptosis and inflammatory processes and downregulation of cytoskeletal signalling and neuronal development in patients with Niemann-Pick C disease.

Neurogenetics 2020 04 11;21(2):105-119. Epub 2020 Jan 11.

Department of Genetics, Institute of Psychiatry and Neurology, Al. Sobieskiego 9, 02-957, Warsaw, Poland.

Changes in gene expression profiles were investigated in 23 patients with Niemann-Pick C1 disease (NPC). cDNA expression microarrays with subsequent validation by qRT-PCR were used. Comparison of NPC to control samples revealed upregulation of genes involved in inflammation (MMP3, THBS4), cytokine signalling (MMP3), extracellular matrix degradation (MMP3, CTSK), autophagy and apoptosis (CTSK, GPNMB, PTGIS), immune response (AKR1C3, RCAN2, PTGIS) and processes of neuronal development (RCAN2). Downregulated genes were associated with cytoskeletal signalling (ACTG2, CNN1); inflammation and oxidative stress (CNN1); inhibition of cell proliferation, migration and differentiation; ERK-MAPK pathway (COL4A1, COL4A2, CPA4); cell adhesion (IGFBP7); autophagy and apoptosis (CDH2, IGFBP7, COL4A2); neuronal function and development (CSRP1); and extracellular matrix stability (PLOD2). When comparing NPC and Gaucher patients together versus controls, upregulation of SERPINB2 and IL13RA2 and downregulation of CSRP1 and CNN1 were characteristic. Notably, in NPC patients, the expression of PTGIS is upregulated while the expression of PLOD2 is downregulated when compared to Gaucher patients or controls and potentially could serve to differentiate these patients. Interestingly, in NPC patients with (i) jaundice, splenomegaly and cognitive impairment/psychomotor delay-the expression of ACTG2 was especially downregulated; (ii) ataxia-the expression of ACTG2 and IGFBP5 was especially downregulated; and (iii) VSGP, dysarthria, dysphagia and epilepsy-the expression of AKR1C3 was especially upregulated while the expression of ACTG2 was downregulated. These results indicate disordered apoptosis, autophagy and cytoskeleton remodelling as well as upregulation of immune response and inflammation to play an important role in the pathogenesis of NPC in humans.
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http://dx.doi.org/10.1007/s10048-019-00600-6DOI Listing
April 2020

Interaction between polymorphisms of the oxytocinergic system genes and emotion perception in inpatients with anorexia nervosa.

Eur Eat Disord Rev 2019 09 5;27(5):481-494. Epub 2019 Aug 5.

The Department of Genetics, The Institute of Psychiatry and Neurology, Poland.

Objective: The empirical literature describes the role of the oxytocinergic system in emotion perception (EP). Variants in the oxytocin (OXT) and oxytocin receptor genes have been associated with mental disorders, including anorexia nervosa (AN), that are characterized by difficulties in socioemotional functioning. Our study aimed to examine whether variability within the genes related to OXT pathways may play a role in facial EP in inpatients with AN.

Method: Single nucleotide polymorphisms (SNPs) of the following genes: oxytocin receptor (rs2254298, rs53576), OXT (rs6133010), OXT-arginine-vasopressin (rs2740204), CD38 (rs6449197, rs3796863), and human leucyl/cystinylaminopeptidase (rs4869317) were genotyped in 60 AN female inpatients and 60 healthy control females (HCs). Associations between genetic polymorphisms and EP as well as clinical symptoms were examined.

Results: The AN group showed decreased EP abilities compared with HCs. SNPs of rs2740204, rs6133010, and rs53576 were associated with differences in EP in women with AN and in HCs. The SNP of rs4869317 was associated with the level of eating disorders symptoms in HCs.

Conclusions: The OXT system may be involved in EP difficulties in AN. SNPs within genes related to OXT pathways may influence EP abilities. The leucyl/cystinylaminopeptidase rs4869317 SNP may be involved in the development of eating disorders psychopathology.
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http://dx.doi.org/10.1002/erv.2698DOI Listing
September 2019

Gene expression profile in patients with Gaucher disease indicates activation of inflammatory processes.

Sci Rep 2019 04 15;9(1):6060. Epub 2019 Apr 15.

Laboratory of Microarray Analysis, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland.

Gaucher disease (GD) is a rare inherited metabolic disease caused by pathogenic variants in the GBA1 gene. So far, the pathomechanism of GD was investigated mainly in animal models. In order to delineate the molecular changes in GD cells we analysed gene expression profile in cultured skin fibroblasts from GD patients, control individuals and, additionally, patients with Niemann-Pick type C disease (NPC). We used expression microarrays with subsequent validation by qRT-PCR method. In the comparison GD patients vs. controls, the most pronounced relative fold change (rFC) in expression was observed for genes IL13RA2 and IFI6 (up-regulated) and ATOH8 and CRISPLD2 (down-regulated). Products of up-regulated and down-regulated genes were both enriched in genes associated with immune response. In addition, products of down-regulated genes were associated with cell-to-cell and cell-to-matrix interactions, matrix remodelling, PI3K-Akt signalling pathway and a neuronal survival pathway. Up-regulation of PLAU, IFIT1, TMEM158 and down-regulation of ATOH8 and ISLR distinguished GD patients from both NPC patients and healthy controls. Our results emphasize the inflammatory character of changes occurring in human GD cells indicating that further studies on novel therapeutics for GD should consider anti-inflammatory agents.
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http://dx.doi.org/10.1038/s41598-019-42584-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6465595PMC
April 2019

Leigh syndrome in individuals bearing m.9185T>C MTATP6 variant. Is hyperventilation a factor which starts its development?

Metab Brain Dis 2018 02 7;33(1):191-199. Epub 2017 Nov 7.

Department of Medical Genetics, The Children's Memorial Health Institute, Aleja Dzieci Polskich 20, 04-730, Warsaw, Poland.

Leigh syndrome (LS), subacute necrotizing encephalomyelopathy is caused by various genetic defects, including m.9185T>C MTATP6 variant. Mechanism of LS development remains unknown. We report on the acid-base status of three patients with m.9185T>C related LS. At the onset, it showed respiratory alkalosis, reflecting excessive respiration effort (hyperventilation with low pCO). In patient 1, the deterioration occurred in temporal relation to passive oxygen therapy. To the contrary, on the recovery, she demonstrated a relatively low respiratory drive, suggesting that a "hypoventilation" might be beneficial for m.9185T>C carriers. As long as circumstances of the development of LS have not been fully explained, we recommend to counteract hyperventilation and carefully dose oxygen in patients with m.9185T>C related LS.
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http://dx.doi.org/10.1007/s11011-017-0122-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5769826PMC
February 2018

Interaction Between Val158Met Catechol-O-Methyltransferase Polymorphism and Social Cognitive Functioning in Schizophrenia: Pilot Study.

Ann Hum Genet 2017 Nov 30;81(6):267-275. Epub 2017 Aug 30.

Institute of Psychiatry and Neurology, Warsaw, Poland.

The Val158Met catechol-O-methyltransferase (COMT) functional polymorphism may influence social cognitive functioning in patients with schizophrenia. Aspects of social cognition were evaluated with the Facial Expression Recognition Test, the Voice Emotion Recognition Test, and the Reading the Mind in the Eyes Test. The Short Recognition Memory Test for Faces was used as a control measure. The Schedule for the Assessment of Negative Symptoms, Schedule for the Assessment of Positive Symptoms, and Beck Depression Inventory were used to rate of patient symptoms. There were 100 patients with the following genotypes: Val/Val (21), Met/Met (30), and Val/Met (49). The genotype distribution of polymorphism of Val158Met COMT did not differ between the patient and control groups. Schizophrenia carriers of the Val/Val genotype performed worse in social cognitive measures, in comparison with the other groups. No statistically significant correlations were recorded between age at schizophrenia onset and polymorphism of Val158Met COMT. There was an influence of genotype in the control group: the Met homozygotes performing better. Schizophrenia patients homozygous for the Val allele showed significant disadvantages over patients homozygous or heterozygous for the Met allele in social cognitive processes. The COMT genotype may not, however, contribute to the age of onset of schizophrenia.
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http://dx.doi.org/10.1111/ahg.12209DOI Listing
November 2017

Genetic polymorphisms and serum concentrations of adiponectin and resistin in anorexia nervosa and healthy controls - pilot study.

Neuro Endocrinol Lett 2017 Jul;38(3):215-223

Department of Adult Psychiatry, Poznan University of Medical Sciences, ul.Szpitalna 27/33, 60-572 Poznan, Poland.

Background: A possible role of adipokines in the regulation of body weight in patients with anorexia nervosa (AN) has been proposed. Polymorphisms in genes encoding adiponectin and resistin in AN have not been widely assessed, yet.

Objectives: 1) Assessment the frequency of ADIPOQ c.45T>G, ADIPOQ c.276G>T polymorphisms in adiponectin and RETN c.62G>A, RETN c.-180C>G in resistin genes in AN patients and control group (C) 2) Analysis of correlation between these polymorphisms and serum ADP or RETN.

Methods: We examined 67 AN girls and 38 C aged 11-18. Analyses of polymorphisms in ADIPOQ and RETN genes were performed using RFLP method and adiponectin and resistin serum levels - with commercially available ELISA kits.

Results: In AN subjects, TT genotype in ADIPOQ c.276 polymorphism as well as GG genotype of RETN c.-180 were significantly more frequent than in CG. In ADIPOQ c.45 polymorphic site, TT alleles were the most frequent in both examined groups. In RETN c.62 GA and GG alleles distribution did not differ between the groups and the most frequently observed genotype was GG. The mean serum adiponectin level in AN was significantly higher and resistin - lower than in controls. There were no statistically significant relationships between serum adiponectin and resistin levels and allele frequency in polymorphisms ADIPOQ c.276 as well as RETN c.-180 in the examined groups.

Conclusion: Differences in genotype frequencies of ADIPOQ c.276 and RETN c.-180 suggest a need for studies on a larger cohort of patients with AN.
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July 2017

Prenatal diagnosis of Duchenne and Becker muscular dystrophies: Underestimated problem of the secondary prevention of monogenetic disorders.

J Obstet Gynaecol Res 2017 Jul 31;43(7):1111-1121. Epub 2017 May 31.

Department of Genetics, Institute of Psychiatry and Neurology, Warsaw, Poland.

Aim: The aim of this study was to analyze the influence of effective preconceptional testing for carrier status in women at risk for Duchenne and Becker muscular dystrophies (D/BMD) on the prenatal diagnosis.

Methods: A retrospective analysis of 201 prenatal tests was performed in 169 Polish women at risk, in regard to time of testing for carrier status (prior to conception or during pregnancy) and carrier status of tested women, including confirmed D/BMD carriers (n = 78; 46.2%), D/BMD non-carriers - tested for germline mosaicism risk (n = 23; 13.6%), and women at risk with uncertain carrier status (n = 68; 40.2%).

Results: Only 52.7% of women were tested for D/BMD carrier status prior to conception and in these women prenatal diagnosis was carried out more frequently in the first trimester of pregnancy (64.7% vs 47.8%; P = 0.035). The results of prenatal testing in male fetuses in pregnancies of confirmed D/BMD carriers and D/BMD non-carriers - tested for germline mosaicism risk were conclusive in all cases, whereas in women with uncertain carrier status, only 60.0% of results were conclusive. Eighty-five of 103 female fetuses (82.5%) were tested prenatally and in 31.8% of them fetal carrier status was confirmed.

Conclusion: Carrier status testing in women prior to conception has a positive impact on the frequency of first-trimester prenatal diagnosis and known D/BMD carrier status on the effectiveness of prenatal diagnosis. Due to the low percentage of women tested effectively prior to conception, carrier status testing in the families at risk should be propagated (including possibility of prenatal diagnosis of female fetuses).
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http://dx.doi.org/10.1111/jog.13344DOI Listing
July 2017

Association of adiponectin, leptin and resistin with inflammatory markers and obesity in dementia.

Biogerontology 2017 08 18;18(4):561-580. Epub 2017 Apr 18.

Department of Genetics, Institute of Psychiatry and Neurology, Sobieskiego 9, 02-957, Warsaw, Poland.

The aim of the study was to determine the role of adiponectin, leptin and resistin in various types of dementia and to investigate their association with inflammatory markers, insulin resistance and abdominal obesity. In 205 patients with dementia [89 with Alzheimer's disease (AD), 47 with vascular dementia (VaD), 69 with mixed dementia (MD)], 113 persons with mild cognitive impairment and in 107 controls serum adiponectin, leptin and resistin levels, pro-inflammatory [interleukin-6 (IL-6), C-reactive protein (hsCRP) and chitotriosidase] and anti-inflammatory (25-OH vitamin D, HDL-cholesterol and paraoxonase 1) markers, as well as glucose metabolism parameters (glucose, insulin and HOMA-IR) were determined. In all-cause dementia adiponectin and resistin levels were significantly higher as compared to the controls; leptin levels did not show differences. Higher adiponectin levels concerned AD and MD, whereas higher resistin-VaD and MD. After stratification by abdominal obesity the differences in adiponectin levels remained significant in subjects without obesity. In all-cause dementia negative correlation of adiponectin with obesity, glucose metabolism parameters, IL-6 and hsCRP and positive correlation with HDL-cholesterol were found. Positive correlation of resistin with age, IL-6, hsCRP and chitotriosidase and negative correlation with HDL-cholesterol and paraoxonase 1 were stated. We conclude that dementia of neurodegenerative origin is characterized by elevated adiponectin levels, whereas dementia with vascular changes by increase of resistin. Association with inflammatory indicators may suggest the pro-inflammatory role of resistin in the development of dementia, especially in dementia of vascular mechanism. Identification of this novel biomarker may be important in preventing dementia.
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http://dx.doi.org/10.1007/s10522-017-9701-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5514216PMC
August 2017

Homocysteine metabolism and the associations of global DNA methylation with selected gene polymorphisms and nutritional factors in patients with dementia.

Exp Gerontol 2016 08 7;81:83-91. Epub 2016 May 7.

Department of Genetics, Institute of Psychiatry and Neurology, Warsaw, Poland.

Epigenetics (particularly DNA methylation) together with environmental and genetic factors, are key to understanding the pathogenesis of many diseases including dementia. Disturbances in DNA methylation have already been implicated in dementia. Homocysteine metabolism, with folate and vitamin B12 as essential cofactors, is integral to methylation processes. We evaluated in a case-control study the association of global DNA methylation, homocysteine, folate and vitamin B12 status with dementia. Selected polymorphisms of genes previously associated with dementia development and the influence of various factors on DNA methylation were also investigated. 102 patients with dementia (53 with Alzheimer's disease, 17 with vascular dementia and 32 with mixed dementia) were recruited. The non-demented controls consisted of 45 age-matched subjects without dementia and 47 individuals with mild cognitive impairment. Global DNA methylation was determined by Imprint Methylated DNA Quantification Kit MDQ1 (Sigma-Aldrich, Gillingham, Dorset, UK). Plasma homocysteine, serum folate and vitamin B12 were determined by chemiluminescence. Plasma and erythrocyte 5-methyltetrahydrofolate and plasma methylmalonic acid (markers of folate and vitamin B12 status) were measured by HPLC. APOE, PON1 p.Q192R, MTHFR 677C>T (c.665C>T) and IL1B-511C>T polymorphisms were identified using PCR-RFLP methods. Patients with dementia had significantly higher concentrations of homocysteine (p=0.012) and methylmalonic acid (p=0.016) and lower folate (p=0.002) and plasma 5-methyltetrahydrofolate (p=0.005) than non-demented subjects. There was no difference in DNA methylation between patients and controls. A non-significant tendency to higher DNA methylation in patients with vascular dementia (p=0.061) was observed. Multivariate regression analysis of all recruited individuals demonstrated a significant positive association between DNA methylation and folate (p=0.013), creatinine (p=0.003) concentrations and IL1B-511T (p=0.002) and PON1 192R (p=0.049) alleles and negative association with fasting glucose (p=0.004). The biochemical results showed significantly lower folate and vitamin B12 status in demented patients than controls. Global DNA methylation was associated with markers of folate status, creatinine, glucose and PON1 and IL1B polymorphisms.
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http://dx.doi.org/10.1016/j.exger.2016.05.002DOI Listing
August 2016

Monitoring of dipeptidyl peptidase-IV (DPP-IV) activity in patients with mucopolysaccharidoses types I and II on enzyme replacement therapy - Results of a pilot study.

Clin Biochem 2016 Apr 23;49(6):458-462. Epub 2015 Nov 23.

Institute of Psychiatry and Neurology, Department of Genetics, Warsaw, Poland. Electronic address:

Objectives: Mucopolysaccharidoses (MPSs) are a group of rare, inherited metabolic disorders which result from the lack of one of the lysosomal enzymes responsible for the degradation of glycosaminoglycans. Early recognition of MPS is important as it enables prompt implementation of enzyme replacement therapy (ERT). Dipeptidyl peptidase-IV (DPP-IV) is a ubiquitous ectopeptidase which activity has been associated with the cell surface protein CD26. Our aims were to investigate plasma DPP-IV activity in untreated patients with MPS type II in comparison to control individuals and to evaluate changes of DPP-IV during ERT in MPS I or II patients.

Design And Methods: One MPS I and five MPS II patients were treated with ERT for up to 19 months. DPP-IV activity was measured in plasma with a colorimetric method using Gly-Pro-p-nitroanilide as a substrate. The reference intervals were observed in 17 healthy donors and in 9 MPS II individuals before ERT implementation.

Results: DPP-IV activity ranged from 557 to 1959 nmol/ml/h (median and interquartile range: 1453 [955– 1554], n = 17) in plasma of control samples. In 9 untreated MPS II individuals, DPP-IV activity was higher and ranged from 2565 to 5968 nmol/ml/h (median and interquartile range: 4458 [4031–5161]). In 6 MPS patients receiving ERT, DPP-IV activity ranged from 2984 to 8628 nmol/ml/h. No declining tendency was observed during the treatment.

Conclusions: DPP-IV activity is a good, newa nd valuable biomarker distinguishing between MPS and healthy individuals. However, it is not a useful marker of treatment efficacy and is unsuitable for monitoring.
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http://dx.doi.org/10.1016/j.clinbiochem.2015.11.011DOI Listing
April 2016

Paraoxonase 1 activity and level of antibodies directed against oxidized low density lipoproteins in a group of an elderly population in Poland - PolSenior study.

Arch Gerontol Geriatr 2015 Jan-Feb;60(1):153-61. Epub 2014 Nov 6.

Department of Genetics, Institute of Psychiatry and Neurology, Warsaw, Poland. Electronic address:

Unlabelled: The aim of this study was to assess two factors influencing the amount of oxidized LDL-paraoxonase 1 (PON1) activity and the level of anti-oxidized LDL antibodies (anti-ox LDL) in a large group of elderly individuals in Poland. The effects of cognitive status, hypertension and metabolic syndrome and of selected serum lipids and inflammation indicators on PON1 activity and anti-ox LDL level were also examined. The investigated population consisted of 3154 individuals aged 65 and more - participants of the population-based PolSenior project. PON1 arylesterase activity was determined spectrophotometrically, anti-ox-LDL antibodies using ELISA method. PON1 activity significantly decreased with advancing age, was lower in males than in females and decreased in persons with impaired cognition. Individuals with hypertension and high lipid levels showed higher PON1 activity. Lower PON1 activity was related to higher level of inflammation indicators - hsCRP and IL-6. The significant association of PON1 activity with age, HDL-C, LDL-C, sex and IL-6 was confirmed in multivariate analysis. Anti-ox LDL antibodies level was significantly higher in the two oldest subgroups of males. It was significantly lower in males than in females. It was decreased in persons with higher serum triglycerides. No relationship of anti-ox LDL level with cognition, hypertension, metabolic syndrome, inflammation indicators and serum lipid levels was observed. In some persons very high levels of anti-ox LDL were stated, most frequently in the oldest persons, particularly in men.

Conclusion: Both investigated antioxidant factors - PON1 activity and anti-ox LDL level, could play an important role in aging.
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http://dx.doi.org/10.1016/j.archger.2014.10.010DOI Listing
August 2015

A homozygote for the c.459+1G>A mutation in the ARSA gene presents with cerebellar ataxia as the only first clinical sign of metachromatic leukodystrophy.

J Neurol Sci 2014 Mar 31;338(1-2):214-7. Epub 2013 Dec 31.

Institute of Psychiatry and Neurology, Department of Genetics, Warsaw, Poland.

Metachromatic leukodystrophy (MLD) is a rare lysosomal disorder caused by deficient activity of arylsulfatase A or the lack of saposin B, which results in the accumulation of sulfatide in the oligodendrocytes and in the Schwann cells. Three main clinical types of MLD can be distinguished according to the age of onset and the dynamics of clinical outcome: late infantile, juvenile, and adult. We report on a case of late infantile MLD presenting with cerebellar ataxia as the only first clinical sign preceding even changes in white matter visible in MR imaging. The diagnosis was made on the basis of successive MRI, characteristic of demyelination, which developed in the course of the disease, and on the results of the following biochemical and molecular analyses. Very low residual activity of arylsulfatase A was demonstrated in blood leukocytes and the patient was a homozygote for a common mutation c.459+1G>A in the ARSA gene. Since cerebellar ataxia is a relatively common but unspecific neurological symptom in toddlers, it is recommended that MLD be considered as part of the differential diagnosis even if the initial neuroimaging studies are normal and ataxia is the only clinical symptom of the disease.
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http://dx.doi.org/10.1016/j.jns.2013.12.030DOI Listing
March 2014

Correlations between cerebellar and brain volumes, cognitive impairments, ApoE levels, and APOE genotypes in patients with AD and MCI.

Curr Alzheimer Res 2013 Nov;10(9):964-72

First Department of Neurology, Institute of Psychiatry and Neurology, Sobieskiego 9, 02-957 Warsaw, Poland.

Due to the increasing incidence of Alzheimer's disease (AD), many studies have aimed to improve its diagnosis. Particular attention has been focused on measuring volumes of brain structures. Only few studies have investigated whether the cerebellar volume changes with the stage of dementia. It is controversial whether the serum apolipoprotein E (ApoE) level is an appropriate AD marker. This study was designed to clarify the significance of both cerebellar volume measurements and ApoE level measurements as markers of neurodegenerative changes. This study included 55 subjects with AD, 30 subjects with mild cognitive impairments (MCI), and a control group with 30 subjects. We measured the brain, cerebellum, and brain stem volumes with magnetic resonance imaging (MRI). We determined serum ApoE levels, APOE genotypes, and neuropsychological test scores. In the control group, we found that ApoE levels were significantly higher for subjects with the APOE 2/3 genotype than those with the 4/4 genotype. This finding may indicate that ApoE plays a protective role against AD development in subjects with the APOE 2/3 genotype. ApoE levels were not significantly different in patients with AD and MCI. No correlations were found between serum ApoE levels and Mini-Mental State Examination (MMSE) scores or the volumes of brain structures. This study could not confirm the appropriateness of the cerebellum volume as an early AD marker. Correlations were found between cerebellar volume, brain volume, and the MMSE scores.
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http://dx.doi.org/10.2174/15672050113106660161DOI Listing
November 2013

Paraoxonase 1 (PON1) gene-108C>T and p.Q192R polymorphisms and arylesterase activity of the enzyme in patients with dementia.

Folia Neuropathol 2013 ;51(2):111-9

Department of Genetics, Institute of Psychiatry and Neurology, Warsaw, Poland.

Paraoxonase 1 (PON1) activity was determined using phenylacetate as substrate (arylesterase activity) in 304 individuals with dementia--136 recognised as probable Alzheimer's disease (AD), 64 as dementia of vascular origin (VaD) and 104 as mixed dementia (MD) and in 129 persons without symptoms of dementia and in a good general health. -108C>T polymorphism in the PON1 gene promoter and p.Q192R polymorphism in the coding region were identified. PON1 activity was significantly lower in demented patients as compared with controls particularly in dementia of a neurodegenerative character (AD and MD). The prevalence of PON1-108T allele carriers was significantly higher in the AD group than in controls. The frequencies of the p.Q192R genotypes did not differ significantly between the investigated groups. An association of the rare T-R haplotype with dementia, particularly with dementia of the neurodegenerative type, was found. Multivariate regression analysis showed a significant association of PON1 activity with PON1 -108C>T and p.Q192R polymorphisms. The influence not only of promoter -108C>T, but also of p.Q192R polymorphism on PON1 arylesterase activity was observed. One has to admit that this kind of polymorphism does not preclude interference with the enzyme activity. It could be concluded that the PON1 gene promoter polymorphism plays an additional role in Alzheimer's disease development. It seems however that PON1 activity has a dominating influence on the dementia risk.
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http://dx.doi.org/10.5114/fn.2013.35953DOI Listing
July 2014

Apolipoprotein E genotype and LRP1 polymorphisms in patients with different clinical types of metachromatic leukodystrophy.

Gene 2013 Sep 20;526(2):176-81. Epub 2013 May 20.

Department of Genetics, Institute of Psychiatry and Neurology, Warsaw, Poland.

Metachromatic leukodystrophy (MLD) is a severe, neurodegenerative, metabolic disease which is caused by deficient activity of arylsulfatase A (ARSA). Sulfatides and other substrates of ARSA are stored in central and peripheral nervous systems, and in some other organs. Accumulated sulfatides are especially toxic to oligodendrocytes and Schwann cells leading to progressive demyelination. The kind of apolipoprotein E (apoE) isoform is of essential significance for the modulation of sulfatide quantity in the brain as apoE4 contains more sulfatides than apoE3. Taking into consideration the fact that apoE4 leads to the loss of sulfatides in CSF of Alzheimer's disease patients, we examined if apoE isoforms display any impact on clinical outcome in patients with different forms of MLD in whom sulfatides accumulate. The significant association of age at the onset of MLD symptoms with APOE ε2/ε3/ε4 and LRP1 c.766C>T polymorphisms was shown in multivariate stepwise regression analysis, in which other factors known to affect age at onset of the disease, i.e. clinical type of MLD, family connection of the patient and sex were also analyzed. As expected, the clinical type of MLD explained about 80% of the variance of the dependent variable. The impact of both polymorphisms on age of onset of the disease was considerably lower: 2.0% in the case of APOE polymorphism and 1.0% in the case of LRP1 polymorphism. Thus, the clinical outcome in MLD patients is related principally to the genotype of the ARSA gene, while the polymorphisms in the APOE and LRP1 genes are only slightly modifying factors.
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http://dx.doi.org/10.1016/j.gene.2013.05.009DOI Listing
September 2013

Positive correlation of paraoxonase 1 (PON1) activity with serum insulin level and HOMA-IR in dementia. A possible advantageous role of PON1 in dementia development.

J Neurol Sci 2013 Jan 22;324(1-2):172-5. Epub 2012 Nov 22.

Department of Genetics, Institute of Psychiatry and Neurology, Warsaw, Poland.

Paraoxonase 1 (PON1) activity and metabolic syndrome traits were evaluated in 169 demented patients (81 recognized as AD, 32 as VaD, 56 as MD) and in 64 control individuals. Paraoxonase activity was determined spectrophotometrically using phenyloacetate as substrate. Metabolic syndrome was recognized according to AHA/NHLBI criteria. In the whole group with dementia significant positive correlation between PON1 activity/HDL cholesterol ratio (i.e. HDL corrected PON1 activity) and insulin level as well as HOMA IR index, was observed. The multivariate analysis showed that the PON1/HDL-C ratio was also significantly positively associated with the presence of metabolic syndrome (with insulin resistance as a major underlying trait) both in dementia and in control group. High insulin level and HOMA-IR are considered to be the traits of insulin resistance. It has however to be taken into account that they both could also depend on insulin production and release which, as was recently stated in cell experiments, are enhanced by PON1. The observed positive correlation suggests an advantageous role of the enzyme in metabolic syndrome influence on dementia development.
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http://dx.doi.org/10.1016/j.jns.2012.11.003DOI Listing
January 2013

Vascular and biochemical risk factors of vascular dementia after lacunar strokes (S-VaD) and after multiinfarcts in strategic areas (M-VaD).

J Neurol Sci 2009 Aug 1;283(1-2):116-8. Epub 2009 Apr 1.

First Department of Neurology and Institute of Psychiatry and Neurology, Warsaw, Poland.

Vascular cognitive impairment is an important cause of cognitive decline in the elderly. Ischemic lesions in the brain have an influence on the natural history of dementia. Vascular dementia can be caused by small-vessels disease (S-VaD) or by large-artery atherosclerosis with vascular lesions in strategic areas of the brain (M-VaD). In both cases changes in white matter are observed. In 60 patients with S-VaD and in 34 with M-VaD the presence of vascular and biochemical risk factors was evaluated and compared to age and sex matched 126 controls without dementia. Coronary artery disease, atrial fibrillation, hypertension and strokes were observed more frequently in both investigated groups. Of biochemical risk factors, hyperhomocysteinemia (associated with low levels of folic acid and vitamin B 12) and low HDL cholesterol levels were found in both forms of VaD.
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http://dx.doi.org/10.1016/j.jns.2009.02.344DOI Listing
August 2009

Antibodies against oxidized LDL and apolipoprotein E polymorphism in demented patients.

J Neurol Sci 2009 Aug 20;283(1-2):137-8. Epub 2009 Mar 20.

Department of Genetics, Institute of Psychiatry and Neurology, Warsaw, Poland.

In serum of 114 patients with dementia and of 102 controls the level of IG class immunoglobulins directed against oxidized LDL and lipids were determined. In isolated DNA apolipoprotein E gene (APOE) polymorphism was identified. In some individuals very high levels of the antibodies were observed. exceeding the 90 percentile in the investigated group. The prevalence of very high anti-ox LDL antibodies level was significantly more frequent in the carriers of epsilon2 allele and less frequent in the carriers of epsilon4 allele.
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http://dx.doi.org/10.1016/j.jns.2009.02.345DOI Listing
August 2009

Paraoxonase activity and dementia.

J Neurol Sci 2009 Aug 5;283(1-2):107-8. Epub 2009 Mar 5.

Department of Genetics, Institute of Psychiatry and Neurology, Warsaw, Poland.

Paraoxonase activity, homocysteine level and lipids were determined in 120 patients with dementia (51 with Alzheimer disease, 28 with dementia of vascular origin, 41 with mixed dementia), 45 with mild cognitive impairment and in 61 age and sex matched controls without dementia. Paraoxonase activity was decreased in Alzheimer disease and in mixed dementia as compared with control group. In the same forms of dementia homocysteine levels were increased. In Alzheimer disease paraoxonase activity was negatively correlated with homocysteine levels. Minimental State Examination results showed positive correlation with paraoxonase activity. The results suggest an important role of oxidative stress in the development of the forms of dementia with prevailing neurodegeneration.
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http://dx.doi.org/10.1016/j.jns.2009.02.317DOI Listing
August 2009

Short-term effects of parenteral nutrition of cholestatic infants with lipid emulsions based on medium-chain and long-chain triacylglycerols.

Nutrition 2007 Feb;23(2):121-6

Division of Gastroenterology, Hepatology and Immunology, The Children's Memorial Health Institute, Warsaw, Poland.

Objective: Infants with chronic cholestasis may require parenteral nutrition with lipid emulsions to provide energy and essential fatty acids but the optimal strategy is controversial.

Methods: We studied the effects of parenteral lipid emulsions with long-chain triacylglycerols (LCTs) or a mixture of LCTs and medium-chain triacylglycerols (MCTs/LCTs) on serum bilirubin and lipid metabolism in cholestatic infants who received these 20% emulsions in alternating order for 3 d each, together with a glucose and amino acid infusion.

Results: Of 11 recruited infants, two dropped out because enteral feeding could be established. In nine infants (2-8 mo of age, mean age 4.2 mo) who completed the study, serum bilirubin decreased from baseline to 6 h after the end of LCT infusion (from 8.5 +/- 2.0 to 7.8 +/- 1.8 mg/dL, mean +/- SEM, P < 0.05) and MCT/LCT infusion (7.9 +/- 6.5 to 7.1 +/- 6.5 mg/dL, P < 0.05). Cholesterol, triacylglycerol, and phospholipid concentrations in plasma and in chylomicrons, very low-density lipoprotein, low-density lipoprotein, and high-density lipoprotein were not changed by either emulsion. Total polyunsaturated fatty acid contents in high-density lipoprotein phospholipids increased during LCT infusion (from 29.8 +/- 0.9 to 35.9 +/- 1.4% wt/wt, P < 0.05) and MCT/LCT infusion (from 30.4 +/- 1.0 to 33.0 +/- 0.7%, P < 0.05). The long-chain polyunsaturated fatty acid docosahexaenoic acid increased only with the LCT infusion. Because docosahexaenoic acid availability during infancy is important for early visual and cognitive development, the use of soybean oil-based lipid emulsions may be preferable for infants with severe progressive cholestasis.

Conclusion: The MCT/LCT and LCT emulsions showed a good metabolic tolerance in infants with chronic cholestasis but had a differential effect on high-density lipoprotein phospholipid contents of arachidonic and docosahexaenoic acids.
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http://dx.doi.org/10.1016/j.nut.2006.10.009DOI Listing
February 2007

[Will statins be used in dementia treatment?].

Neurol Neurochir Pol 2005 Jul-Aug;39(4):318-23

Zakład Genetyki, Instytut Psychiatrii i Neurologii, ul. Sobieskiego 9, 02-957 Warszawa.

The paper presents current opinions on the mechanism of beta-amyloid accumulation, the role of cholesterol in the pathogenesis of dementia and observations of the role of statins in its development. Most of the observations were done on Alzheimer's disease, some of them concerned also dementia of a vascular origin and cognition. Statins are inhibitors of the cholesterol synthesis pathway. The mechanism of their action concerns not only their influence on the cholesterol level but also their influence on prenylation of various proteins and in consequence inhibition of inflammatory reactions. They exert also antioxidative activity. As the number of prospective studies is still insufficient the question whether statins could be used as drugs against dementia remains still unsolved.
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May 2006

Polymorphisms of apolipoprotein E and angiotensin-converting enzyme genes and carotid atherosclerosis in heavy drinkers.

Alcohol Alcohol 2005 Jul-Aug;40(4):274-82. Epub 2005 Apr 4.

Department of Genetics, Institute of Psychiatry and Neurology, Sobieskiego 9, 02-957 Warsaw, Poland.

Aims: To investigate the influence of apolipoprotein E (APOE) and angiotensin-converting enzyme (ACE) gene polymorphisms on carotid artery atherosclerosis in alcoholism.

Methods: Polymorphism of both genes was identified by DNA analysis in 130 male alcohol-dependent patients. Intima-media thickness (IMT) was measured ultrasonographically.

Results: Multivariate regression analysis showed that of all the known risk factors the greatest impact on carotid atherosclerosis in alcoholics was exerted by age, hypertension, LDL cholesterol and fasting plasma glucose levels. Subjects carrying the APO E epsilon4 allele were more liable to develop atherosclerotic changes in carotid arteries compared with subjects with the epsilon3/3 genotype, which showed statistical significance in patients under 50 years of age. No association was shown between ACE I/D polymorphism and carotid atherosclerosis.

Conclusions: APO E polymorphism can increase the risk of carotid atherosclerosis development in an alcoholic subject. The association of the APO E epsilon4 allele with carotid atherosclerosis was significant in younger patients. Since the elevated carotid IMT is considered to be a good marker of increased risk of generalized atherosclerosis the consequences could involve both cardiac and cerebrovascular events.
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http://dx.doi.org/10.1093/alcalc/agh157DOI Listing
September 2005

[Changes in lipoprotein (a) [Lp(a)] level after an ischemic stroke].

Neurol Neurochir Pol 2004 May-Jun;38(3):197-200

Zakład Genetyki, Instytut Psychiatrii i Neurologii, ul. Sobieskiego 9, Warszawa 02-957.

The aim of the work was to recognize whether often observed high levels of apolipoprotein (a) [Lp(a)] in patients shortly after an ischemic stroke are a result of the acute phase reaction. In 13 patients Lp(a) was determined within the first 24 hours after the stroke onset, after the next 7 days and after three months i.e. when it could be considered that Lp(a) level was the same as before onset of the disease. In 17 patients only two determinations were performed. Another acute phase indicator: C-reactive protein (CRP), as well as serum lipids were also determined. CRP level was increased in the first determination and increased further after 7 days. After three months it returned to low values. High density lipoprotein (HDL) cholesterol which demonstrates a negative acute phase response changed in the opposite way. No similar fluctuations of Lp(a) level were observed. It can be concluded that during the investigated period Lp(a) had no properties of the acute phase reactant.
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November 2004

Polymorphism of trinucleotide repeats in non-translated regions of SCA8 and SCA12 genes: allele distribution in a Polish control group.

J Appl Genet 2004 ;45(1):101-5

Department of Genetics, Institute of Psychiatry and Neurology, Warszawa, Poland.

Spinocerebellar ataxias are a group of neurodegenerative disorders caused by dynamic mutations of microsatellite repeats. Two novel forms of SCAs have been described recently: SCA8, with expansions of CTA/CTG repeats in 3'UTR of the SCA8 gene, and SCA12, caused by expansion of the CAG tract in 5'UTR of the SCA12/PP2R2B gene. Analysis of CTA/CTG and CAG polymorphism in those two genes was performed in a Polish control group consisting of 100 individuals without any neurological signs. The distribution and ranges of the number of non-pathogenic repeats were similar to those observed in other populations described previously. Expansion of CTA/CTG repeats in the SCA8 locus was found in 2 of 100 controls and in 5 probands among 150 pedigrees affected with unidentified ataxias. As such expanded alleles were also observed in their healthy relatives, the pathogenic role of expansions in the SCA8 gene remains uncertain.
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April 2004

Apolipoprotein E polymorphism and low density lipoprotein (LDL) oxidation in patients with dementia.

Folia Neuropathol 2003 ;41(2):65-8

Department of Genetics, Institute of Psychiatry and Neurology, Warszawa, Poland.

In patients with dementia, 29 diagnosed as probably suffering from Alzheimer's disease and 46 subjects with dementia of vascular origin, and in 41 non demented control subjects LDL oxidation in vitro was compared in carriers of various apolipoprotein E alleles. Restriction isotyping was performed by gene amplification and cleavage with Hhal, LDL oxidation was investigated by determination of conjugated dienes and vitamin E (alpha tocopherol) plasma level was measured by HPLC. In subjects with dementia oxidation of LDL was shown to be higher in carriers of epsilon4 allele as compared with non-carriers of this allele. It was especially observed in the propagation phase, which illustrates oxidation intensity after the exhaustion of the antioxidant reserve in LDL. Vitamin E level did not show differences between carriers of different alleles. It is concluded that the differences in oxidation susceptibility of LDL between demented subjects possessing particular apolipoprotein E forms can result partially from differing antioxidant properties of apolipoprotein E isoforms and, in a substantial degree, from the size and quality of LDL.
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September 2003

Plasma antioxidant activity and vascular dementia.

J Neurol Sci 2002 Nov;203-204:195-7

Institute of Psychiatry and Neurology, National Institute of Cardiology, Warsaw, Poland.

Little is known about the role of antioxidant activity in the pathogenesis of stroke-associated neuronal damage and impairment following a stroke. Increased free radical formation together with reduced antioxidant defense may increase neuronal injury. A low concentration of antioxidants such as alpha-tocopherol may influence the development of post-stroke dementia. The aim of this study was to evaluate the level of alpha-tocopherol and susceptibility of LDL to oxidation in a group of patients with dementia in comparison to controls. In a group of 68 patients with dementia, according to DSM-IV criteria, 42 with vascular dementia (VaD), 26 with Alzheimer type of dementia (AD) and 46 age-matched persons, with no signs of cognitive disorders (control group), we measured lipids, alpha-tocopherol and the kinetics of LDL oxidation. The levels of triglycerides (TG) and low-density lipoprotein (LDL) were significantly lower in patients with VaD in comparison to AD patients, but the atherogenic index was similar in both groups. alpha-Tocopherol was significantly lower in patients with VaD in comparison to patients with AD and controls: 9.9, 12.6 and 12.6 ng/ml, respectively, p<0.0001. Susceptibility of LDL to oxidation, measured by duration of lag phase did not reveal statistically significant differences between the groups. In patients with VaD, low levels of plasma alpha-tocopherol were observed, which indicate a reduced antioxidant defense in these subjects.
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http://dx.doi.org/10.1016/s0022-510x(02)00290-3DOI Listing
November 2002
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