The Journal of Nutrition Nutrition and Disease Tart Cherry Juice Decreases Oxidative Stress in Healthy Older Men and Women 1-3

Abstract Compared with young adults, older adults have significantly impaired capacities to resist oxidative damage when faced with acute stress such as ischemia/reperfusion. This impairment likely contributes to increased morbidity and mortality in older adults in response to acute trauma, infections, and the susceptibility to diseases such as atherosclerosis, cancer, diabetes, and Alzheimer's disease. Consumption of foods high in polyphenols, particularly anthocyanins, have been associated with improved health, but the mechanisms contributing to these salutary effects remain to be fully established. This study tested the hypothesis that consumption of tart cherry juice containing high levels of anthocyanins improves the capacity of older adults to resist oxidative damage during acute oxidative stress. In a double-blind, placebo-controlled, crossover design, 12 volunteers [6 men and 6 women; age 69 6 4 y (61-75 y)] consumed in random order either tart cherry juice or placebo (240 mL twice daily for 14 d) separated by a 4-wk washout period. The capacity to resist oxidative damage was measured as the changes in plasma F 2 -isoprostane levels in response to forearm ischemia-reperfusion (I/R) before and after each treatment. The tart cherry juice intervention reduced the I/R-induced F 2 -isoprostane response (P , 0.05), whereas placebo had no significant effect. The tart cherry juice intervention also reduced basal urinary excretion of oxidized nucleic acids (8-hydroxy-29-deoxyguanosine, 8-hydroxyguanosine) (P , 0.05) but not urinary excretion of isoprostanes. These data suggest that consumption of tart cherry juice improves antioxidant defenses in vivo in older adults as shown by an increased capacity to constrain an oxidative challenge and reduced oxidative damage to nucleic acids

Sorl1 as an Alzheimer's disease predisposition gene?

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressively disabling impairments in memory, cognition, and non-cognitive behavioural symptoms. Sporadic AD is multifactorial and genetically complex. While several monogenic mutations cause early-onset AD and gene alleles have been suggested as AD susceptibility factors, the only extensively validated susceptibility gene for late-onset AD is the apolipoprotein E (APOE) epsilon4 allele. Alleles of the APOE gene do not account for all of the genetic load calculated to be responsible for AD predisposition. Recently, polymorphisms across the neuronal sortilin-related receptor (SORL1) gene were shown to be significantly associated with AD in several cohorts. Here we present the results of our large case-control whole-genome scan at over 500,000 polymorphisms which presents weak evidence for association and potentially narrows the association interval

Oral Abstracts 7: RA ClinicalO37. Long-Term Outcomes of Early RA Patients Initiated with Adalimumab Plus Methotrexate Compared with Methotrexate Alone Following a Targeted Treatment Approach

Background: This analysis assessed, on a group level, whether there is a long-term advantage for early RA patients treated with adalimumab (ADA) + MTX vs those initially treated with placebo (PBO) + MTX who either responded to therapy or added ADA following inadequate response (IR). Methods: OPTIMA was a 78- week, randomized, controlled trial of ADA + MTX vs PBO + MTX in MTX-naïve early (<1 year) RA patients. Therapy was adjusted at week 26: ADA + MTX-responders (R) who achieved DAS28 (CRP) <3.2 at weeks 22 and 26 (Period 1, P1) were re-randomized to withdraw or continue ADA and PBO + MTX-R continued randomized therapy for 52 weeks (P2); IR-patients received open-label (OL) ADA + MTX during P2. This post hoc analysis evaluated the proportion of patients at week 78 with DAS28 (CRP) <3.2, HAQ-DI <0.5, and/or ΔmTSS ≤0.5 by initial treatment. To account for patients who withdrew ADA during P2, an equivalent proportion of R was imputed from ADA + MTX-R patients. Results: At week 26, significantly more patients had low disease activity, normal function, and/or no radiographic progression with ADA + MTX vs PBO + MTX (Table 1). Differences in clinical and functional outcomes disappeared following additional treatment, when PBO + MTX-IR (n = 348/460) switched to OL ADA + MTX. Addition of OL ADA slowed radiographic progression, but more patients who received ADA + MTX from baseline had no radiographic progression at week 78 than patients who received initial PBO + MTX. Conclusions: Early RA patients treated with PBO + MTX achieved comparable long-term clinical and functional outcomes on a group level as those who began ADA + MTX, but only when therapy was optimized by the addition of ADA in PBO + MTX-IR. Still, ADA + MTX therapy conferred a radiographic benefit although the difference did not appear to translate to an additional functional benefit. Disclosures: P.E., AbbVie, Merck, Pfizer, UCB, Roche, BMS—Provided Expert Advice, Undertaken Trials, AbbVie—AbbVie sponsored the study, contributed to its design, and participated in the collection, analysis, and interpretation of the data, and in the writing, reviewing, and approval of the final version. R.F., AbbVie, Pfizer, Merck, Roche, UCB, Celgene, Amgen, AstraZeneca, BMS, Janssen, Lilly, Novartis—Research Grants, Consultation Fees. S.F., AbbVie—Employee, Stocks. A.K., AbbVie, Amgen, AstraZeneca, BMS, Celgene, Centocor-Janssen, Pfizer, Roche, UCB—Research Grants, Consultation Fees. H.K., AbbVie—Employee, Stocks. S.R., AbbVie—Employee, Stocks. J.S., AbbVie, Amgen, AstraZeneca, BMS, Celgene, Centocor-Janssen, GlaxoSmithKline, Lilly, Pfizer (Wyeth), MSD (Schering-Plough), Novo-Nordisk, Roche, Sandoz, UCB—Research Grants, Consultation Fees. R.V., AbbVie, BMS, GlaxoSmithKline, Human Genome Sciences, Merck, Pfizer, Roche, UCB Pharma—Consultation Fees, Research Support. Table 1.Week 78 clinical, functional, and radiographic outcomes in patients who received continued ADA + MTX vs those who continued PBO + MTX or added open-label ADA following an inadequate response ADA + MTX, n/N (%)a PBO + MTX, n/N (%)b Outcome Week 26 Week 52 Week 78 Week 26 Week 52 Week 78 DAS28 (CRP) <3.2 246/466 (53) 304/465 (65) 303/465 (65) 139/460 (30)*** 284/460 (62) 300/460 (65) HAQ-DI <0.5 211/466 (45) 220/466 (47) 224/466 (48) 150/460 (33)*** 203/460 (44) 208/460 (45) ΔmTSS ≤0.5 402/462 (87) 379/445 (86) 382/443 (86) 330/459 (72)*** 318/440 (72)*** 318/440 (72)*** DAS28 (CRP) <3.2 + ΔmTSS ≤0.5 216/462 (47) 260/443 (59) 266/443 (60) 112/459 (24)*** 196/440 (45) 211/440 (48)*** DAS28 (CRP) <3.2 + HAQ-DI <0.5 + ΔmTSS ≤0.5 146/462 (32) 168/443 (38) 174/443 (39) 82/459 (18)*** 120/440 (27)*** 135/440 (31)** aIncludes patients from the ADA Continuation (n = 105) and OL ADA Carry On (n = 259) arms, as well as the proportional equivalent number of responders from the ADA Withdrawal arm (n = 102). bIncludes patients from the MTX Continuation (n = 112) and Rescue ADA (n = 348) arms. Last observation carried forward: DAS28 (CRP) and HAQ-DI; Multiple imputations: ΔmTSS. ***P < 0.001 and **iP < 0.01, respectively, for differences between initial treatments from chi-squar

Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A

The major histocompatibility complex (MHC) on chromosome 6 is associated with susceptibility to more common diseases than any other region of the human genome, including almost all disorders classified as autoimmune. In type 1 diabetes the major genetic susceptibility determinants have been mapped to the MHC class II genes HLA-DQB1 and HLA-DRB1 (refs 1-3), but these genes cannot completely explain the association between type 1 diabetes and the MHC region. Owing to the region's extreme gene density, the multiplicity of disease-associated alleles, strong associations between alleles, limited genotyping capability, and inadequate statistical approaches and sample sizes, which, and how many, loci within the MHC determine susceptibility remains unclear. Here, in several large type 1 diabetes data sets, we analyse a combined total of 1,729 polymorphisms, and apply statistical methods - recursive partitioning and regression - to pinpoint disease susceptibility to the MHC class I genes HLA-B and HLA-A (risk ratios >1.5; Pcombined = 2.01 × 10-19 and 2.35 × 10-13, respectively) in addition to the established associations of the MHC class II genes. Other loci with smaller and/or rarer effects might also be involved, but to find these, future searches must take into account both the HLA class II and class I genes and use even larger samples. Taken together with previous studies, we conclude that MHC-class-I-mediated events, principally involving HLA-B*39, contribute to the aetiology of type 1 diabetes. ©2007 Nature Publishing Group

CR1 Is Associated with Amyloid Plaque Burden and Age-Related Cognitive Decline

OBJECTIVE: Recently, genome-wide association studies have identified three new susceptibility loci for Alzheimer’s disease (AD), CLU, CR1, and PICALM. We leveraged available neuropsychological and autopsy data from two cohort studies to investigate whether these loci are associated with cognitive decline and AD neuropathology. METHODS: The Religious Orders Study (ROS) and Rush Memory and Aging Project (MAP) are longitudinal studies that enroll non-demented subjects and include annual clinical evaluations and brain donation at death. We evaluated CR1 (rs6656401), CLU (rs11136000) and PICALM (rs7110631) in 1666 subjects. We evaluated associations between genotypes and rate of change in cognitive function as well as AD-related pathology. Lastly, we used pathway analysis to determine if relationships between SNPs and cognitive decline were mediated through AD pathology. RESULTS: Among our study cohort, the mean years of follow-up was 7.8 for ROS and 4.3 for MAP. Only the CR1 locus was associated with both global cognitive decline (p=0.011) and global AD pathology (p=0.025). More specifically, the locus affects the deposition of neuritic amyloid plaque (p=0.009). In a mediation analysis, controlling for amyloid pathology strongly attenuated the effect of the CR1 locus on cognitive decline. INTERPRETATION: We found that common variation at the CR1 locus has a broad impact on cognition and that this effect is largely mediated by an individual’s amyloid plaque burden. We therefore highlight one functional consequence of the CR1 susceptibility allele and generalize the role of this locus to cognitive aging in the general population

A survey of genetic human cortical gene expression

It is widely assumed that genetic differences in gene expression underpin much of the difference among individuals and many of the quantitative traits of interest to geneticists. Despite this, there has been little work on genetic variability in human gene expression and almost none in the human brain, because tools for assessing this genetic variability have not been available. Now, with whole-genome SNP genotyping arrays and whole-transcriptome expression arrays, such experiments have become feasible. We have carried out whole-genome genotyping and expression analysis on a series of 193 neuropathologically normal human brain samples using the Affymetrix GeneChip Human Mapping 500K Array Set and Illumina HumanRefseq-8 Expression BeadChip platforms. Here we present data showing that 58% of the transcriptome is cortically expressed in at least 5% of our samples and that of these cortically expressed transcripts, 21% have expression profiles that correlate with their genotype. These genetic-expression effects should be useful in determining the underlying biology of associations with common diseases of the human brain and in guiding the analysis of the genomic regions involved in the control of normal gene expression

Association of CR1, CLU and PICALM with Alzheimer's disease in a cohort of clinically characterized and neuropathologically verified individuals

In this study, we assess 34 of the most replicated genetic associations for Alzheimer's disease (AD) using data generated on Affymetrix SNP 6.0 arrays and imputed at over 5.7 million markers from a unique cohort of over 1600 neuropathologically defined AD cases and controls (1019 cases and 591 controls). Testing the top genes from the AlzGene meta-analysis, we confirm the well-known association with APOE single nucleotide polymorphisms (SNPs), the CLU, PICALM and CR1 SNPs recently implicated in unusually large data sets, and previously implicated CST3 and ACE SNPs. In the cases of CLU, PICALM and CR1, as well as in APOE, the odds ratios we find are slightly larger than those previously reported in clinical samples, consistent with what we believe to be more accurate classification of disease in the clinically characterized and neuropathologically confirmed AD cases and controls

Tart Cherry Juice Decreases Oxidative Stress in Healthy Older Men and Women1–3

Compared with young adults, older adults have significantly impaired capacities to resist oxidative damage when faced with acute stress such as ischemia/reperfusion. This impairment likely contributes to increased morbidity and mortality in older adults in response to acute trauma, infections, and the susceptibility to diseases such as atherosclerosis, cancer, diabetes, and Alzheimer's disease. Consumption of foods high in polyphenols, particularly anthocyanins, have been associated with improved health, but the mechanisms contributing to these salutary effects remain to be fully established. This study tested the hypothesis that consumption of tart cherry juice containing high levels of anthocyanins improves the capacity of older adults to resist oxidative damage during acute oxidative stress. In a double-blind, placebo-controlled, crossover design, 12 volunteers [6 men and 6 women; age 69 ± 4 y (61–75 y)] consumed in random order either tart cherry juice or placebo (240 mL twice daily for 14 d) separated by a 4-wk washout period. The capacity to resist oxidative damage was measured as the changes in plasma F2-isoprostane levels in response to forearm ischemia-reperfusion (I/R) before and after each treatment. The tart cherry juice intervention reduced the I/R-induced F2-isoprostane response (P < 0.05), whereas placebo had no significant effect. The tart cherry juice intervention also reduced basal urinary excretion of oxidized nucleic acids (8-hydroxy-2′-deoxyguanosine, 8-hydroxyguanosine) (P < 0.05) but not urinary excretion of isoprostanes. These data suggest that consumption of tart cherry juice improves antioxidant defenses in vivo in older adults as shown by an increased capacity to constrain an oxidative challenge and reduced oxidative damage to nucleic acids