Mild cognitive impairment has frequently been reported for patients in the early stages of multiple sclerosis. The aim of the present study was to measure whether altered cortical activation during a sustained attention task occurs along with limited extent of neuropsychological problems. Expanded brain activation of multiple sclerosis patients with normal motor function compared with healthy controls during a finger tapping paradigm has previously been reported. Compensatory brain activation in patients with multiple sclerosis compared with normal controls may also be observed when the subjects are performing cognitive functions. In 21 patients with clinically definite relapsing-remitting multiple sclerosis, a psychometric assessment was performed using the Wechsler Memory Scale (WMS) and the Multiple Sclerosis Functional Composite Score (MSFC). In addition, functional MRI was performed during a Paced Visual Serial Addition Task (PVSAT), a visual analogue of the Paced Auditory Serial Addition Task (PASAT). All patients were within 3 years of diagnosis and were not suffering from a relapse at the time of investigation. The multiple sclerosis patients were compared with a control group of 21 healthy volunteers matched for handedness, age, years of education and sex. With regard to psychometric results, the WMS general memory score showed statistically significant differences between patients and controls. We did not find differences for either the MSFC or the PASAT scores. A group analysis of the functional imaging data during the PVSAT revealed different activation patterns for patients compared with control subjects. In healthy volunteers, the main activation was found in the frontal part of the right gyrus cinguli (Brodmann area 32). In patients, the main activation was detected at the right hemispheric frontal cortex (Brodmann areas 6, 8 and 9). In addition, the left hemispheric Brodmann area 39 was activated. We interpret the different patterns of activation, accompanied with intact performance in a sustained attention task of our multiple sclerosis sample compared with healthy controls, as the consequence of compensatory mechanisms. This is an expression of neuronal plasticity during early stages of a chronic disease.

The associations of the adiponectin (APM1) gene with parameters of the metabolic syndrome are inconsistent. We performed a systematic investigation based on fine-mapped single nucleotide polymorphisms (SNPs) highlighting the genetic architecture and their role in modulating adiponectin plasma concentrations in a particularly healthy population of 1,727 Caucasians avoiding secondary effects from disease processes. Genotyping 53 SNPs (average spacing of 0.7 kb) in the APM1 gene region in 81 Caucasians revealed a two-block linkage disequilibrium (LD) structure and enabled comprehensive tag SNP selection. We found particularly strong associations with adiponectin concentrations for 11 of the 15 tag SNPs in the 1,727 subjects (five P values <0.0001). Haplotype analysis provided a thorough differentiation of adiponectin concentrations with 9 of 17 haplotypes showing significant associations (three P values <0.0001). No significant association was found for any SNP with the parameters of the metabolic syndrome. We observed a two-block LD structure of APM1 pointing toward at least two independent association signals, one including the promoter SNPs and a second spanning the relevant exons. Our data on a large number of healthy subjects suggest a clear modulation of adiponectin concentrations by variants of APM1, which are not merely a concomitant effect in the course of type 2 diabetes or coronary artery disease. Diabetes 55: [375][376][377][378][379][380][381][382][383][384] 2006

Our findings lend epidemiologic support to the concept that nutrition rich in spermidine is linked to increased survival in humans. This trial was registered at www.clinicaltrials.gov as NCT03378843.

Background and Purpose-The metabolic syndrome (MetS) is associated with an increased risk for subsequent development of type 2 diabetes mellitus, cardiovascular disease, and stroke. Type 2 diabetes increases the risk of stroke and coronary heart disease in women to a greater extent than in men, and thus the question arises whether there are sex differences in the association of early atherosclerosis and MetS. Methods-1588 middle-aged Austrian subjects (1001 males, 587 females) were included in the present study. MetS was defined by the criteria of the National Cholesterol Education Program Adult Treatment Panel III. Early atherosclerosis was assessed by intima-media thickness (IMT) and extent of plaques (B-score) of the carotid arteries. Results-B-score and carotid artery IMT parameters were significantly higher in subjects with the MetS. After adjustment for established risk factors, the difference in B-score remained significant only in women.

BACKGROUND. The identification of patients with high-risk atherosclerotic plaques prior to the manifestation of clinical events remains challenging. Recent findings question histology- and imaging-based definitions of the “vulnerable plaque,” necessitating an improved approach for predicting onset of symptoms.METHODS. We performed a proteomics comparison of the vascular extracellular matrix and associated molecules in human carotid endarterectomy specimens from 6 symptomatic versus 6 asymptomatic patients to identify a protein signature for high-risk atherosclerotic plaques. Proteomics data were integrated with gene expression profiling of 121 carotid endarterectomies and an analysis of protein secretion by lipid-loaded human vascular smooth muscle cells. Finally, epidemiological validation of candidate biomarkers was performed in two community-based studies.RESULTS. Proteomics and at least one of the other two approaches identified a molecular signature of plaques from symptomatic patients that comprised matrix metalloproteinase 9, chitinase 3-like-1, S100 calcium binding protein A8 (S100A8), S100A9, cathepsin B, fibronectin, and galectin-3-binding protein. Biomarker candidates measured in 685 subjects in the Bruneck study were associated with progression to advanced atherosclerosis and incidence of cardiovascular disease over a 10-year follow-up period. A 4-biomarker signature (matrix metalloproteinase 9, S100A8/S100A9, cathepsin D, and galectin-3-binding protein) improved risk prediction and was successfully replicated in an independent cohort, the SAPHIR study.CONCLUSION. The identified 4-biomarker signature may improve risk prediction and diagnostics for the management of cardiovascular disease. Further, our study highlights the strength of tissue-based proteomics for biomarker discovery.FUNDING. UK: British Heart Foundation (BHF); King’s BHF Center; and the National Institute for Health Research Biomedical Research Center based at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London in partnership with King’s College Hospital. Austria: Federal Ministry for Transport, Innovation and Technology (BMVIT); Federal Ministry of Science, Research and Economy (BMWFW); Wirtschaftsagentur Wien; and Standortagentur Tirol.

Peroxisome proliferator-activated receptor-␥ coactivator-1 (PPARGC1) is a transcriptional coactivator that has been implicated in the regulation of genes involved in energy metabolism. We studied associations of two polymorphisms identified in PPARGC1 transcripts with obesity indices in 591 middle-aged men and 467 middle-aged women of a cross-sectional Austrian population. Because neither polymorphic site was likely to be a functional site, we analyzed sex-specific associations of two loci haplotype combinations with obesity indices. Significant associations with BMI (P ‫؍‬ 0.006), waist (P ‫؍‬ 0.01) and hip circumference (P ‫؍‬ 0.03), and total body fat (P ‫؍‬ 0.005) and borderline significant associations with abdominal visceral and subcutaneous fat were observed in women but not men. In women, plasma triglycerides, HDL cholesterol, and glucose significantly differed by haplotype combinations, but these associations were not maintained after statistical consideration of BMI. The haplotype combination of the double-variant allele with the double-wild-type allele was associated with the lowest obesity indices, whereas homozygosity for the double-variant allele was not discriminatory among haplotype combinations. These studies suggest functional differences of PPARGC1 haplotypes in human energy metabolism and support a role of PPARGC1 in obesity. Diabetes 51:1281-1286, 2002 P eroxisome proliferator-activated receptor-␥ coactivator-1 (PPARGC1) is a coactivator of PPAR-␥ and other nuclear hormone receptors and plays an essential role in energy homeostasis. Studies in rodents and cell culture models showed that Pgc1 stimulates mitochondrial biogenesis and activates genes of the oxidative phosphorylation pathway and thermogenesis (1-4). Human PPARGC1 exhibits 94% amino acid identity with the mouse ortholog and was mapped to chromosome 4p15.1 (5). This chromosomal region has been associated with basal insulin levels in Pima Indians (6) and abdominal subcutaneous fat in the Quebec Family Study (7). Because of these associations and PPARGC1's role in energy metabolism in animal models, we tested the hypothesis that markers at the PPARGC1 gene locus are associated with obesity indices.By sequencing eight cDNA alleles transcribed from muscle RNA, we identified four polymorphisms in PPARGC1 transcripts. Two polymorphisms, a G-to-A transition at position ϩ1,564 in exon 8 (that predicted a glycine to serine amino acid substitution at position 482, and therefore referred to as G482S) and an A-to-G substitution at position ϩ2,962 in the 3Ј-untranslated region (Genbank accession no. NM-013261) were selected because of their heterozygosity indices of 0.449 (95% CI 0.436 -0.462) and 0.499 (0.498 -0.501), respectively, to genotype 591 unrelated men and 467 unrelated women of the Salzburg Atherosclerosis Prevention Program in Subjects at High Individual Risk (SAPHIR) (8). The two other polymorphisms, a silent G-to-A transition at ϩ1,302 in exon 8 and an A-to-T transversion at ϩ3,010 in exon 13 were not considered because heterozygo...

Introduction we examined the consequences of applying the new EWGSOP2 algorithm for sarcopenia screening instead of the former EWGSOP algorithm (EWGSOP1) in geriatric inpatients. Methods the dataset of our formerly published Sarcopenia in Geriatric Elderly (SAGE) study includes 144 geriatric inpatients (86 women, 58 men, mean age 80.7±5.6 years) with measurements of gait speed, handgrip strength and appendicular muscle mass by dual x-ray absorptiometry (DXA). We analysed the agreement between EWGSOP and EWGSOP2 algorithms in identifying patients as sarcopenic/non-sarcopenic. Differences in the distribution sarcopenic vs. non-sarcopenic were assessed by Chi²-test. Results sarcopenia prevalence according to EWGSOP1 (41 (27.7%)) was significantly higher than with EWGSOP2 (26(18.1%), p<0.05). The sex-specific sarcopenia prevalence was 22.1% (EWGSOP1) and 17.4% (EWGSOP2), respectively, for women (difference not significant) and 37.9% vs. 19.4% for men (p<0.05%). The overall agreement in classifying subjects as sarcopenic/non-sarcopenic was 81.25% (81.4% for women, 81.0% for men). However, among the 41 sarcopenia cases identified by EWGSOP1, only 20 (48.8%) were diagnosed with sarcopenia by EWGSOP2 (9/19 w (47.4%), 11/22 m (50.0%)). Ten of 19 women (52.6%) and 11 of 22 men (50.0%) diagnosed with sarcopenia by EWGSOP1 were missed by EWGSOP2, while 6 of 15 women (40.0%) and 0 of 11 men (0.0%) were newly diagnosed. Discussion there is a substantial mismatch in sarcopenia case finding according to EWGSOP1 and EWGSOP2. The overall prevalence and the number of men diagnosed with sarcopenia are significantly lower in EWGSOP2. While the absolute number of women identified as sarcopenic remains relatively constant, the overlap of individual cases between the two definitions is low.

Background: There is strong and consistent evidence that oxidative stress is crucially involved in the development of atherosclerotic vascular disease. Overproduction of reactive oxygen species (ROS) in mitochondria is an unifying mechanism that underlies micro-and macrovascular atherosclerotic disease. Given the central role of mitochondria in energy and ROS production, mitochondrial DNA (mtDNA) is an obvious candidate for genetic susceptibility studies on atherosclerotic processes. We therefore examined the association between mtDNA haplogroups and coronary artery disease (CAD) as well as diabetic retinopathy.