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

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.

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

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.

[Will statins be used in dementia treatment?]. / Czy statyny znajda zastosowanie w leczeniu otepienia?

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.

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

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.

Plasma antioxidant activity and vascular dementia.

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.

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

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.

Uptake of acetaldehyde-modified (ethylated) low-density lipoproteins by mouse peritoneal macrophages.

The uptake of acetaldehyde-modified (ethylated) low-density lipoproteins (LDLs) by murine peritoneal macrophages is described and compared with the uptake of acetylated LDLs. The fluorescent marker DiI was used. No competition between ethylated and acetylated LDLs was observed. Ethylated LDL uptake was not inhibited by polyinosinic acid or fucoidin. Our conclusion is that uptake of ethylated and acetylated LDLs can be done by two different receptors.

[Changes in lipoprotein (a) [Lp(a)] level after an ischemic stroke]. / Zmiany poziomu lipoproteiny (a) [LP(a)] po udarze niedokrwiennym mózgu.

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.

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.

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.

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

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.

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

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.

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

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.

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

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.

Paraoxonase activity and dementia.

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.

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

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.