Brittany Simpson

Blood metabolite markers of preclinical Alzheimer's disease in two longitudinally followed cohorts of older individuals.

Recently, quantitative metabolomics identified a panel of 10 plasma lipids that were highly predictive of conversion to Alzheimers disease (AD) in cognitively normal older individuals (n = 28, area under the curve [AUC] = 0.92, sensitivity/specificity of 90%/90%).

Associations between inflammation and cognitive function in African Americans and European Americans

To examine associations between specific inflammatory biomarkers and cognitive function in African Americans (AAs) and European Americans (EAs) with prevalent vascular risk factors.

Blood metabolite markers of cognitive performance and brain function in aging

We recently showed that Alzheimers disease patients have lower plasma concentrations of the phosphatidylcholines (PC16:0/20:5; PC16:0/22:6; and PC18:0/22:6) relative to healthy controls. We now extend these findings by examining associations between plasma concentrations of these PCs with cognition and brain function (measured by regional resting state cerebral blood flow; rCBF) in non-demented older individuals. Within the Baltimore Longitudinal Study of Aging neuroimaging substudy, participants underwent cognitive assessments and brain 15O-water positron emission tomography. Plasma phosphatidylcholines concentrations (PC16:0/20:5, PC16:0/22:6, and PC18:0/22:6), cognition (California Verbal Learning Test (CVLT), Trail Making Test A&B, the Mini-Mental State Examination, Benton Visual Retention, Card Rotation, and Fluencies—Category and Letter), and rCBF were assessed. Lower plasma phosphatidylcholine concentrations were associated with lower baseline memory performance (CVLT long delay recall task—PC16:0/20:5: −2.17–1.39−0.60 p = 0.001 (β with 95% confidence interval subscripts)) and lower rCBF in several brain regions including those associated with memory performance and higher order cognitive processes. Our findings suggest that lower plasma concentrations of PC16:0/20:5, PC16:0/22:6, and PC18:0/22:6 are associated with poorer memory performance as well as widespread decreases in brain function during aging. Dysregulation of peripheral phosphatidylcholine metabolism may therefore be a common feature of both Alzheimers disease and age-associated differences in cognition.

Impaired Cognition and Brain Atrophy Decades After Hypertensive Pregnancy Disorders

Background—Hypertensive pregnancy disorders have been associated with subjective cognitive complaints or brain white-matter lesions 5 to 10 years after the hypertensive pregnancy. The long-term effects of hypertensive pregnancies on brain structure and cognitive function remain unknown. Methods and Results—This study included 1279 women who participated in the Family Blood Pressure Project Genetic Epidemiology Network of Arteriopathy (GENOA) study. As part of the ancillary Genetics of Microangiopathic Brain Injury (GMBI) study, a neurocognitive battery was administered; 1075 also had a brain magnetic resonance imaging. A history of a hypertensive pregnancy disorder was obtained by a self-report using a validated questionnaire. Linear models fit with generalized estimating equations were used to assess the association between hypertensive pregnancy disorders and cognition, adjusting for age, race, education, body mass index, smoking, current hypertension, hypertension duration, and family history of hypertension. Regression models for the brain magnetic resonance imaging outcomes also were adjusted for total intracranial volume. Women with histories of hypertensive pregnancy disorders performed worse on all measures of processing speed (Digital Symbol Substitution Test [mean score, 41.2 versus 43.4; P=0.005], Trail Making Test Part A [mean seconds, 45.1 versus 42.2; P=0.035], and Stroop [mean score, 173.9 versus 181.0; P=0.002]) and had smaller brain volumes compared with women with histories of normotensive pregnancies (286 versus 297; P=0.023). Conclusions—Hypertensive pregnancy disorders are associated with worse performance on tests of processing speed and smaller brain volumes decades later. Population-based studies are needed to provide critical insight as to the contribution of hypertensive pregnancies to risk of cognitive decline and dementia.

PLASMA PHOSPHATIDYLCHOLINES ARE ASSOCIATED WITH ALZHEIMER'S DISEASE AS WELL AS BRAIN FUNCTION AND COGNITIVE PERFORMANCE DURING AGING

and metabolites from several metabolic pathways including glycerophospholipid and sphingolipid pathways are perturbed in Alzheimer’s disease (AD) brains, CSF, and/or plasma [1-3] and may be related to disease severity. In addition to environment, genetic variation plays an important role in levels of metabolites [4-5]. Therefore, we investigated the role of genetic variation on serum metabolites associated with key AD relevant phenotypes in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort.Methods: Quality-controlled baseline serum metabolites and GWAS (Illumina Human610-Quad) were used in the study. Standard QC and imputation to 1000 Genome reference panel were performed for GWAS data.Metabolites were pre-adjusted for sex, age, and several medications if they were associated with levels of metabolites and selected when they were significantly associated with AD relevant phenotypes. Analysis was restricted to 673 non-Hispanic Caucasian ADNI participants (control1⁄4181, MCI1⁄4331, AD1⁄4161) after removing 69 participants with non-fasting serum samples. Analysis with 49 targeted metabolites was conducted using an additive genetic model including the first principal component to correct for potential population substructure. Results: Five analytes were significantly associated with SNPs on chromosome 1 or 11 after Bonferroni correction (p<1.02x10) and four analytes showed nominal genome-wide significant associations (p<5x10) (Figure 1). Genes associated with medium-chain acylcarnitines and phosphatidylcholine species play important roles in fatty acid beta oxidation and unsaturation of fatty acids. Two out of nine metabolites showed novel genetic associations. Conclusions: This study demonstrates the power of joint analysis combining genetics and metabolomics to investigate genetic risk factors for AD. Further analyses of metabolomics and genetics with contemporaneous neuroimaging endophenotypes is underway to investigate mechanisms underlying perturbed metabolites and the joint impact of genes and metabolites on brain structures and function. [1] Han et al. PLoS One (2011). [2] Kaddurah-Daouk et al. Translational psychiatry (2013). [3] Mapstone et al. Nature Med. (2014). [4] Kettunen et al. Nature Genetics (2012) [5] Shin et al. Nature Genet. (2014).

Response to Mehmet I. Naharci

markers and incident frailty in postmenopausal women. Am J Med 2009;122:947–954. 9. Derosa G, Maffioli P, Ferrari I et al. Different actions of losartan and ramipril on adipose tissue activity and vascular remodeling biomarkers in hypertensive patients. Hypertens Res 2011;34:145–151. 10. Stewart MW, Cirkel DT, Furuseth K et al. Effect of metformin plus roziglitazone compared with metformin alone on glycaemic control in well-controlled type 2 diabetes. Diabet Med 2006;23:1069–1078.

Plasma metabolomic markers associated with cognitive performance and resting state cerebral blood flow during aging: The baltimore longitudinal study of aging

P3-093 PLASMA METABOLOMIC MARKERS ASSOCIATEDWITH COGNITIVE PERFORMANCE AND RESTING STATE CEREBRAL BLOOD FLOW DURING AGING: THE BALTIMORE LONGITUDINAL STUDY OFAGING Brittany Simpson, Kim Min, Yi-Fang Chuang, Lori L. Beason-Held, Melissa Kitner-Triolo, Michael Kraut, Seth Lirette, B Gwen Windham, Michael Griswold, Cristina Legido Quigley, Madhav Thambisetty, National Institute on Aging, Baltimore, MD, USA; University of Mississippi Medical Center, Jackson, MS, USA; King’s College London, London, United Kingdom; Johns Hopkins Hospital, Baltimore, MD, USA. Contact e-mail: brittany.simpson@nih.gov