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.

Molecular spectrum of the SPAST, ATL1 and REEP1 gene mutations associated with the most common hereditary spastic paraplegias in a group of Polish patients.

Hereditary spastic paraplegias (HSPs) consist of a heterogeneous group of genetically determined neurodegenerative disorders. Progressive lower extremity weakness and spasticity are the prominent features of HSPs resulting from retrograde axonal degeneration of the corticospinal tracts. Three genetic types, SPG3 (ATL1), SPG4 (SPAST) and SPG31 (REEP1), appear predominantly and may account for up to 50% of autosomal dominant hereditary spastic paraplegias (AD-HSPs). Here, we present the results of genetic testing of the three mentioned SPG genetic types in a group of 216 unrelated Polish patients affected with spastic paraplegia. Molecular evaluation was performed by multiplex ligation-dependent probe amplification (MLPA) and DNA sequencing. Nineteen novel mutations: 13 in SPAST, 4 in ATL1 and 2 in REEP1, were identified among overall 50 different mutations detected in 57 families. Genetic analysis resulted in the identification of molecular defects in 54% of familial and 8.4% of isolated cases. Our research expanded the causative mutations spectrum of the three most common genetic forms of HSPs found in a large cohort of probands originating from the Central Europe.

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.

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.

Sweet liking in patients with Parkinson's disease.

Pleasant tastes and odors are considered phylogenetically old natural rewards and their hedonic evaluation is regarded as a good indicator of the reward system function. The primary aim of the present study was to compare pleasantness ratings of sucrose solutions (1-30%, w/w) and sweet liking/disliking status in 20 patients with Parkinson's disease (PD) and in 20 age-matched healthy controls. In addition, basic sensory aspects of gustatory (intensity ratings, electrogustometric thresholds) and olfactory function (identification abilities in the Sniffin' Stick test) were assessed in both groups. The number of odors rated as pleasant, unpleasant, and neutral was also compared. As expected, the PD patients showed a significant impairment in olfactory identification abilities. There were no differences between the PD patients and controls in electrogustometric thresholds. Rated intensity of higher sucrose concentrations did not differ between the groups. The PD patients tended to rate water taste as more intense in comparison with the controls. Pleasantness ratings of sucrose solutions, the proportion of subjects rating 30% sucrose as the most pleasant (sweet likers), and the number of odors rated as pleasant did not differ between the study groups. The present results suggest that PD does not lead to any obvious alterations in pleasantness ratings of chemosensory stimuli. The study requires replication in larger samples.

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.

The effect of vitamin B supplementation on homocysteine metabolism and clinical state of patients with chronic epilepsy treated with carbamazepine and valproic acid.

PURPOSE: To investigate the influence of vitamin B supplementation on the plasma total homocysteine (p-tHcy), serum folate (s-FA), serum B12 (s-B12), and clinical state of patients with chronic epilepsy. METHODS: Beck Depression Inventory (BDI) scores and p-tHcy, s-B12, and s-FA levels were assessed at baseline, after 1 year of supplementation (G1), and before and after 1 year of VPA or CBZ therapy (G2). RESULTS: Eighty-one patients participated in the study: 51 patients with chronic epilepsy (G1) treated with carbamazepine (CBZ) or valproic acid (VPA), and 30 patients with newly diagnosed epilepsy (G2). At baseline, mean p-tHcy level was significantly higher in G1 than G2 (p=0.0001) with no significant differences in s-FA or s-B12 levels. p-tHcy level significantly decreased in CBZ-treated G1 patients (p=0.00002) after 1 year of supplementation and increased in G2 after 1 year of anti-epileptic drug (AED) therapy without supplementation. BDI scores in G1 decreased significantly after 1 year of supplementation (p=0.0001) and increased significantly in VPA-treated G2 patients after 1 year of AED therapy (p=0.02). The number of hyperhomocysteinemic patients significantly decreased in G1 after vitamin B supplementation (p=0.01) and increased in G2 (p=0.002). We also observed improved BDI scores and reduced seizure frequency in patients with chronic epilepsy. CONCLUSIONS: These data support the hypothesis that AEDs play a major role in hyperhomocysteinemia development in patients with epilepsy. Adding folate and vitamin B12 to AED therapy is a safe and inexpensive way to reduce the risk of hyperhomocysteinemia.

Hereditary form of prion disease in Poland.

BACKGROUND AND PURPOSE: The aim of the study was to perform molecular analysis in a group of patients affected with prion disease. Diagnosis was based on results of clinical and/or histopathological examination of the brain. This is the largest investigation of this type performed so far in Poland. MATERIAL AND METHODS: Analysed material contained 36 cases of prion disease, including 35 cases of Creutzfeldt-Jakob disease and one case of Gerstmann-Sträussler-Scheinker disease, as well as two familial cases initially suspected of Huntington disease and Alzheimer disease. The control group consisted of 87 subjects. The most frequent known mutations in the PRNP gene were looked for, namely those in codons 102, 117, 178, 200, 217 and OPRI; the polymorphism Met/Val in codon 129 was also analysed. The methods applied were PCR-RFLP and DNA sequencing. RESULTS: The following mutations were found: E200K in 5 families, P102L in one family (previously identified), D178N in one family and 6OPRI in one family. Overall, mutations were detected in 17 persons (including 8 preclinical ones) from 8 pedigrees. Highly significant difference of codon 129 Met/Val heterozygosity frequencies was found between the affected subjects and the controls. Frequency of the familial form of prion disease in the material analysed was 14%. CONCLUSIONS: Screening for mutations in the PRNP gene should be performed in all diagnosed cases of prion disease and in cases of familial occurrence of early onset dementia of unknown aetiology. Families with identified mutations should be offered genetic counselling and informed of risks of blood and organs' donation.

Kufs' disease: diagnostic difficulties in the examination of extracerebral biopsies.

Kufs' disease or NCL4 (neuronal ceroid lipofuscinosis type 4) is a rare and poorly characterized, adult-onset form of NCL. The mutation in gene CLN, underlying Kufs' disease, still remains unknown. The diagnosis of this disease is difficult because it is based only on clinical and ultrastructural examinations. We report the case of a 45-year-old woman referred to the Neurological Department with suspicion of Creutzfeldt-Jakob disease (CJD). CJD as well as infectious, autoimmune and some lysosomal diseases were excluded. Since clinical symptoms, i.e. psychotic, auditory and visual hallucinations as well as behavioural disturbances, still suggested metabolic or neurodegenerative disease, a skin and muscle biopsy was performed. On ultrastructural examination the muscle biopsy revealed the subsarcolemmal accumulation of lipofuscin, lipofuscin-like and granular osmiophilic deposits (GRODs). The most unique fingerprint deposits (FP) and curvilinear profiles (CP) for diagnosis of Kufs' disease were located in vascular smooth muscle cells (VSMCs). In these cells lipofuscin-like deposits and GRODs were also visible. The fact that FP and CP were found exclusively in VSMCs jointly with clinical and laboratory data allows us to diagnose Kufs' disease in our patient.

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.

[Aortic dissection and carotid arteries dissection complicated by ischaemic stroke in a patient with cystic medial necrosis]. / Rozwarstwienie aorty oraz tetnic szyjnych wspólnych i wewnetrznych powiklane udarem niedokrwiennym mózgu u osoby ze zwyrodnieniem torbielowatym blony srodkowej.

We present a case of a 62-year-old man who was admitted in grave condition to the Institute of Psychiatry and Neurology because of ischaemic stroke. Neurological examination re- vealed left-sided pyramidal hemiparesis. Computed tomography (CT) showed the ischaemic focus in the right cerebral hemisphere. Clinical examination and ultrasound examination revealed dissection of the aortic arch and extracranial arteries. Aortic dissection was confirmed in echocardiography and chest CT. The patient remained comatose and died after 7 days. Post-mortem examination identified dissection of the aortic arch, brachiocephalic truncus, common carotid arteries, internal carotid arteries and dissection extending along the whole aorta into both iliac arteries. This examination also showed a massive haemopericardium and a scar in the heart muscle after myocardial infarction. Microscopic examination identified cystic medial necrosis. This type of dissection is very rarely described.

Depressive symptoms and olfactory function in older adults.

AIMS: Neuroimaging studies suggest a significant overlap between brain regions involved in the regulation of olfaction and mood. The aim of the present study was to search for correlations between depressive symptomatology measured by the 15-item Geriatric Depression Scale (GDS) and olfactory function assessed with Sniffin' Sticks in non-demented older adults (aged 53-79 years). METHODS: Taste detection thresholds were also measured by means of electrogustometry on the anterior tongue. RESULTS: No correlation was found between the GDS scores (range: 0-12) and olfactory thresholds or olfactory identification scores. Similarly, there was no relationship between depressive symptoms and electrogustometric thresholds. Subjects (n = 25) scoring > or = 5 on the GDS were classified as 'depressed' and all other individuals (n = 60) were classified as 'non-depressed'. The two groups did not differ in terms of the olfactory measures and electrogustometric threshold. CONCLUSION: Depressive symptoms are not associated with any major olfactory deficit in non-clinical older adults.

Two novel presenilin 1 gene mutations connected with frontotemporal dementia-like clinical phenotype: genetic and bioinformatic assessment.

Mutations in the amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2) genes are associated with early-onset familial Alzheimer's disease (EOAD). There are several reports describing mutations in PSEN1 in cases with frontotemporal dementia (FTD). We identified two novel mutations in the PSEN1 gene: L226F and L424H. The first mutation was detected in a patient with a clinical diagnosis of FTD and a post-mortem diagnosis of AD. The second mutation is connected with a clinical phenotype of variant AD with strong FTD signs. In silico modeling revealed that the mutations, as well as mutations used for comparison (F177L and L424R), change the local structure, stability and/or properties of the transmembrane regions of the presenilin 1 protein (PS1). In contrast, a silent non-synonymous substitution F175S is eclipsed by external residues and has no influence on PS1 interfacial surface. We suggest that in silico analysis of PS1 substitutions can be used to characterize novel PSEN1 mutations, to discriminate between silent polymorphisms and a potential disease-causing mutation. We also propose that PSEN1 mutations should be considered in FTD patients with no MAPT mutations.

[The effect of rivastigmine on cognitive functions and regional cerebral blood flow in Alzheimer's disease and vascular dementia: follow-up for 2 years]. / Wplyw riwastygminy na funkcje poznawcze i regionalny przeplyw mózgowy w chorobie Alzheimera i w otepieniu naczyniopochodnym -- dwuletnia obserwacja chorych.

BACKGROUND AND PURPOSE: The aim of the work was to investigate the effect of treatment with rivastigmine, one of the inhibitors of acetylcholinesterase (AChE-I) on the regional cerebral perfusion (rCBF) and the cognitive functions of the brain in patients with Alzheimer's Disease (AD) and Vascular Dementia (VaD). MATERIAL AND METHODS: The investigations of rCBF were carried out using SPECT (Single Photon Emission Computed Tomography). The results given concern investigations of patients carried out at the onset of the investigation, after 12 months, and 24 months of rivastigmine treatment. RESULTS: In patients with AD it was found that treatment with rivastigmine increases rCBF by 5-7% in the temporal areas during the first 12 months. In the frontal areas the increase was by 3-5%. During the next 12 months rCBF with an accuracy of 2% returned to the initial level, with the exception of the motor cortex, where it remained on the level increased by 5-6%. However, the cognitive functions remained constant during the first 12 months of treatment and decreased significantly during the next 12 months. In patients with VaD rCBF increased in all the regions of the brain except for the temporal posterior regions, and remained at an elevated level for the next 12 months. The cognitive functions deteriorated slowly, but to a much lesser degree than in the case of AD. CONCLUSIONS: From the investigations carried out it follows that treatment with rivastigmine during 24 months prevents a decrease of rCBF in patients with AD. However, the cognitive functions deteriorate after 24 months.

The effect of cholinesterase inhibitors on the regional blood flow in patients with Alzheimer's disease and vascular dementia.

The effects of therapy with cholinesterase inhibitors (ChE-I) on regional cerebral blood flow (rCBF) disturbances were investigated by means of single photon emission computed tomography (SPECT). The changes in rCBF were compared with the results of the medical examination and neuropsychological tests. The sample consisted of 41 patients with the Alzheimer's dementia (AD) and vascular dementia (VaD). The effect of ChE-I (rivastigmine) treatment was studied on 33 patients, while the nontreated control group consisted of 8 patients. In the treated patients, an increase in the rCBF was observed, while the scores of the neuropsychological tests decreased slightly. In the VaD group, the increase in rCBF was more significant in the frontal regions, whereas in the group with AD in the temporal regions, respectively. In the nontreated patients, a decrease of both rCBF and scores of neuropsychological tests were observed. The scores of the neuropsychological tests correlated with the results of rCBF. Increased levels of acetylcholine in the brain after ChE-I treatment may support the cholinergic regulation of rCBF, and in result increase it. Such effects seem to be more pronounced in the more affected brain regions.

[The clinical and laboratory diagnosis of sCJD and vCJD]. / Diagnostyka kliniczna i laboratoryjna choroby Creutzfeldta-Jakoba (sCJD i vCJD).

Clinical diagnosis of sporadic CJD is usually confirmed by a typical EEG pattern and an increased level of protein 14-3-3 in the CSF, with specificity of 74% and 84%, respectively. However, both these tests are often negative in vCJD patients. Recently MR imaging has substantially improved the diagnosis of sCJD and vCJD. In sCJD patients hyperintense signal in T2-weighted sequences was found to be present in the neostriatum (the caudate nucleus and putamen) with specificity of 93%, while in vCJD cases signal hyperintensity was found in pulvinar thalami. The "pulvinar sign" was evidenced to be highly sensitive (79%) and specific (100%) for the diagnosis of the latter form of CJD.

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.