Molecular phenotyping of a UK population: defining the human serum metabolome.

Phenotyping of 1,200 'healthy' adults from the UK has been performed through the investigation of diverse classes of hydrophilic and lipophilic metabolites present in serum by applying a series of chromatography-mass spectrometry platforms. These data were made robust to instrumental drift by numerical correction; this was prerequisite to allow detection of subtle metabolic differences. The variation in observed metabolite relative concentrations between the 1,200 subjects ranged from less than 5 % to more than 200 %. Variations in metabolites could be related to differences in gender, age, BMI, blood pressure, and smoking. Investigations suggest that a sample size of 600 subjects is both necessary and sufficient for robust analysis of these data. Overall, this is a large scale and non-targeted chromatographic MS-based metabolomics study, using samples from over 1,000 individuals, to provide a comprehensive measurement of their serum metabolomes. This work provides an important baseline or reference dataset for understanding the 'normal' relative concentrations and variation in the human serum metabolome. These may be related to our increasing knowledge of the human metabolic network map. Information on the Husermet study is available at http://www.husermet.org/. Importantly, all of the data are made freely available at MetaboLights (http://www.ebi.ac.uk/metabolights/).

Peripheral inflammatory markers in amnestic mild cognitive impairment.

OBJECTIVE: To prospectively monitor plasma inflammatory marker concentrations in peripheral blood, over 12 months, in subjects with amnestic mild cognitive impairment (MCI), and to determine the relationship between peripheral inflammatory markers and cognitive decline. METHODS: Seventy patients with amnestic MCI were recruited from two sites providing specialist memory assessment services in Manchester. The baseline assessment included physical examination, neuro-psychological testing and venous blood samples for C-reactive protein (CRP) and interleukin 6 (IL-6) concentrations. Sixty two participants were followed up after 12 months and the assessments were repeated. RESULTS: Data analysis revealed a significant rise in CRP, but not IL-6 concentrations over 12 months, which was not confounded by demographic variables. The neuro-psychological test scores had no association with CRP or IL-6 concentrations at baseline or 12 months follow-up. CONCLUSION: This study adopted the unique approach of prospectively investigating peripheral inflammatory markers in a cohort with amnestic MCI. A significant rise in CRP concentrations over 12 months, but lack of significant association with cognition, provide no evidence for a relationship between systemic inflammation and cognitive decline in amnestic MCI.

Under-provision of medical care for vascular diseases for people with dementia in primary care: a cross-sectional review.

BACKGROUND: Vascular diseases contribute to the causation and progression of clinical dementia. AIM: To evaluate the quality of medical care for vascular diseases provided to people with dementia, the patient and practice characteristics that influence quality, and to compare care with that provided to those without dementia. DESIGN AND SETTING: Observational, cross-sectional review of primary care records of people with dementia from 52 general practices from five primary care trusts in the UK, and comparison with publicly available summary data on patients without dementia. METHOD: A total of 700 patients with ≥1 diagnosed vascular disease or risk factor were identified from dementia registers. Quality of care was measured on 30 indicators from the UK Quality and Outcomes Framework (QOF) for hypertension, coronary heart disease, stroke, diabetes mellitus, atrial fibrillation, heart failure, and smoking. Overall quality of vascular care was calculated for each patient with dementia. RESULT: Level of care received by people with dementia was significantly lower compared with those without dementia for 22 of 30 (73%) indicators; most notably for measurement processes such as peripheral pulses check and neuropathy testing for diabetes, and cholesterol measures for stroke. Among people with dementia, women, those in care homes, and those with fewer comorbid physical conditions and medications were associated with lower scores for overall quality of vascular care. CONCLUSION: The quality of medical care provided to people with dementia with regard to vascular diseases is not concordant with quality, as defined by the QOF. Research is needed to improve access to high-quality care.

Endogenous hormones, androgen receptor CAG repeat length and fluid cognition in middle-aged and older men: results from the European Male Ageing Study.

OBJECTIVE: Data remain divergent regarding the activational effects of endogenous hormones on adult cognitive function. We examined the association between cognition, hormones and androgen receptor (AR) CAG repeat length in a large cohort of men. DESIGN: Community-based, cross-sectional study of 3369 men aged 40-79 years. METHODS: Cognition tests were the Rey-Osterrieth Complex Figure, Camden Topographical Recognition Memory and Digit-Symbol Substitution. A fluid cognition (FC) z-score was computed from the individual tests. Testosterone, oestradiol (OE(2)) and 5alpha-dihydrotestosterone were measured by gas chromatography-mass spectrometry; DHEAS, LH, FSH and sex hormone-binding globulin (SHBG) by electrochemiluminescence. Free testosterone and OE(2) were calculated from total hormone, SHBG and albumin. CAG repeat lengths were assayed by PCR genotyping. RESULTS: Total testosterone and free testosterone were associated with higher FC z-scores, LH and FSH with lower FC z-scores in age-adjusted linear regressions. After adjusting for health, lifestyle and centre, a modest association was only observed between DHEAS and a lower FC z-score (beta=-0.011, P=0.02), although this was driven by subjects with DHEAS levels >10 micromol/l. Locally weighted plots revealed no threshold effects between hormones and FC. There was no association between CAG repeat length and FC z-score after adjustment for age and centre (beta=-0.007, P=0.06), nor any interaction effect between CAG repeat length and hormones. CONCLUSION: Our results suggest that endogenous hormones are not associated with a vision-based measure of FC among healthy, community-dwelling men. Further studies are warranted to determine whether 'high' DHEAS levels are associated with poorer performance on a broader range of neuropsychological tests.

Preventing dementia: role of vascular risk factors and cerebral emboli.

INTRODUCTION OR BACKGROUND: Dementia, Alzheimer's disease and vascular dementia being two main causes, is major and growing health problem. Vascular risk factors are thought to be involved in the causation of both dementias. SOURCES OF DATA: A review of the literature was conducted using MedLine to identify current evidence for role of vascular risk factors as potential targets in preventing dementia. Cross-references were hand searched. AREAS OF AGREEMENT: The evidence from prospective epidemiological studies suggests that optimizing the control of vascular risk factors such as hypertension, high cholesterol, diabetes, smoking and heart disease may prevent dementia. However, this has been proven in randomized placebo-controlled trials (RCT) for only hypertension. AREAS OF CONTROVERSY: Dementia is a secondary outcome in most RCTs and it is not known if there is a therapeutic time window between mid- and late-life when interventions are most effective. Also, we do not know precise mechanisms by which interventions for vascular risk factors offer brain protection. GROWING POINTS: Our research suggests that asymptomatic cerebral emboli, which are preventable, may be involved in the causation of dementia. AREAS TIMELY FOR DEVELOPING RESEARCH: There is a need for RCT targeting multiple vascular risk factors in patients at high risk of dementia such as those with mild cognitive impairment.