John Woodside

Adolescent Type 1 Diabetes cardio-renal Intervention Trial (AdDIT): Urinary screening and baseline biochemical and cardiovascular assessments

OBJECTIVE We assessed the association between early increases in albumin excretion and cardiovascular (CV) and renal markers in a large cohort of young people with type 1 diabetes. RESEARCH DESIGN AND METHODS As part of preliminary screening for a multicenter, randomized controlled trial of statins/ACE inhibitors, we measured albumin–creatinine ratio (ACR) in six early morning urine samples from 3,353 adolescents (10–16 years of age) and calculated tertiles based on an established algorithm. From those subjects deemed to be at higher risk (upper ACR tertile), we recruited 400 into the intervention study (trial cohort). From those subjects deemed to be at lower risk (middle–lower ACR tertiles), we recruited 329 to the observation cohort. At baseline, vascular measurements (carotid intima-media thickness, pulse wave velocity [PWV], flow-mediated dilatation, digital pulse amplitude tonometry), renal markers (symmetric dimethylarginine, cystatin C, creatinine), and CV disease markers (lipids and apolipoproteins [Apo] A-1 and B, C-reactive protein, asymmetric dimethylarginine) were assessed. RESULTS Age- and sex-adjusted PWV was higher in the trial than in the observational cohort (5.00 ± 0.84 vs. 4.86 ± 0.70 m/s; P = 0.021). Similarly, non-HDL cholesterol (2.95 ± 0.83 vs. 2.81 ± 0.78 mmol/L; P = 0.02) and ApoB–ApoA-1 ratio (0.50 ± 0.14 vs. 0.47 ± 0.11; P = 0.04) were higher in the trial cohort. Cystatin C and creatinine were decreased (0.88 ± 0.13 vs. 0.90 ± 0.13 mg/L, P = 0.04; 51.81 ± 10.45 vs. 55.35 ± 11.05 μmol/L, P < 0.001; respectively) and estimated glomerular filtration rate (137.05 ± 23.89 vs. 129.31 ± 22.41 mL/min/1.73 m2; P < 0.001) increased in the trial compared with the observational cohort. CONCLUSIONS Our data demonstrate that in adolescents with type 1 diabetes, the group with the highest tertile of albumin excretion showed more evidence of early renal and CV disease than those in the lower tertiles.

Lifelong patterns of BMI and cardiovascular phenotype in individuals aged 60–64 years in the 1946 British birth cohort study: an epidemiological study

BACKGROUND Excess body fat is associated with an increase in risk of type 2 diabetes and hypertension in adulthood and these risks can adversely affect progression of arterial disease. We aimed to assess the impact of lifelong patterns of adiposity on cardiovascular risk factors and carotid intima media thickness (cIMT) in later life in participants in the 1946 British birth cohort study. METHODS The National Survey of Health and Development Study was a nationally representative sample of 5362 singleton births to married parents in England, Scotland, and Wales, stratified by social class, during 1 week in March 1946. Our present study is based on the 60% of participants still alive and with a known present address in England, Scotland, or Wales who attended a clinic assessment after invitation aged 60-64 years. We included participants with lifetime adiposity measures, cardiovascular risk factors, and cIMT measured at 60-64 years. Participants were classified as normal weight or overweight or obese at each age (36, 43, 53, and 60-64 years) in adulthood, and childhood overweight was defined. Patterns of BMI change were identified and we used BMI to define adiposity status. We used multivariable linear regression to establish the cross-sectional association of BMI category at age 60-64 years with cIMT, adjusted for various confounders. FINDINGS We included 1273 (45%) of 2856 participants eligible in 2006-10 (at age 60-64 years) in this study. Compared with normal weight, overweight and obesity were associated with higher cIMT (0·029 mm, 95% CI 0·014-0·043) and systolic blood pressure (7·95 mm Hg, 5·86-10·0). Increased cIMT, systolic blood pressure, leptin, prevalence of diabetes, and reduced adiponectin were all associated with duration of exposure to adult adiposity (p<0·0001 for all). We noted little additional effect of childhood overweight. Individuals who dropped a BMI category in adulthood had lower cIMT (-0·034 mm, -0·056 to -0·013) and leptin concentrations (-0·4 ng/mL, -0·47 to -0·32), even when this change was not maintained, than did those who never lost weight. INTERPRETATION Longer exposure to high adiposity in adulthood had a cumulative adverse effect on cardiovascular phenotype in later life. Reductions in BMI category, even if not sustained, were associated with decreases in cIMT and improvements in cardiovascular risk-factor profile, suggesting that weight loss, at any age in adulthood, is worthwhile because it might result in long-term cardiovascular benefit. FUNDING Medical Research Council and the British Heart Foundation.

Body Mass Index and Height From Infancy to Adulthood and Carotid Intima-Media Thickness at 60 to 64 Years in the 1946 British Birth Cohort Study

Objective— Atherosclerosis begins early in life and obesity is a key determinant. We investigated the role of body mass index (BMI) and height from infancy to adulthood in presenting with high adulthood carotid intima-media thickness. Approach and Results— Odds ratios of BMI, and height Z scores at 2, 4, 6, 7, 11, 15, and 20 years, and changes between 2 and 4, 4 and 7, 7 and 15, and 15 and 20 years, for carotid intima-media thickness at 60 to 64 years in the upper quartile were estimated for 604 men and 669 women. Confounding by early-life environments, mediating by body size and cardiometabolic measures at 60 to 64 years, and effect modification were investigated. In men, there was positive association of BMI at 4 years (odds ratio, 1.256; 95% confidence interval, 1.026–1.538) and 20 years (1.282; 1.022–1.609), negative association of height at 4 years (0.780; 0.631–0.964), and negative association of height growth between 2 and 4 years (0.698; 0.534–0.913) with high carotid intima-media thickness. The childhood estimates were robust, but the estimate for BMI at 20 years was attenuated by adjustment for BMI at 60 to 64 years. The protective influence of greater early childhood height was strongest in those with the lowest systolic blood pressure at 60 to 64 years. In women, there was no pattern of association and all confidence intervals crossed 1. Conclusions— Early childhood in men might be a sensitive developmental period for atherosclerosis, in which changes in BMI and height represent 2 distinct biological mechanisms. The maintenance of healthy weight in men from adolescence onward may be a useful strategy to avoid the atherosclerotic complications of adiposity tracking.

Systemic oxidative–nitrosative–inflammatory stress during acute exercise in hypoxia; implications for microvascular oxygenation and aerobic capacity

What is the central question of this study? Exercise performance is limited during hypoxia by a critical reduction in cerebral and skeletal tissue oxygenation. To what extent an elevation in systemic free radical accumulation contributes to microvascular deoxygenation and the corresponding reduction in maximal aerobic capacity remains unknown. What is the main finding and its importance? We show that altered free radical metabolism is not a limiting factor for exercise performance in hypoxia, providing important insight into the fundamental mechanisms involved in the control of vascular oxygen transport.

Variation at the TRIM11 Locus Modifies Progressive Supranuclear Palsy Phenotype

The basis for clinical variation related to underlying progressive supranuclear palsy (PSP) pathology is unknown. We performed a genome‐wide association study (GWAS) to identify genetic determinants of PSP phenotype.

PO082 Can csf nfl predict progression in progressive supranuclear palsy

There is a need for reliable disease progression biomarkers to complement clinical rating scales such as the PSP rating scale (PSPRS). Predicting progression with such biomarkers may enable better powered clinical trials, and give insights into the mediators of progression. A prospective cohort of 32 clinically diagnosed PSP patients were recruited from a single specialist Neurology centre between June 2011-December 2013, and followed up longitudinally. Baseline CSF samples were obtained from 29 patients. CSF total tau (t-tau), phosphorylated tau (p-tau) and NFL concentrations were measured using standard ELISA. By dividing patients into high and low CSF NFL groups based on a median CSF NFL concentration of 2217 ng/ml, we found that the high CSF NFL group were over 5 times more likely to die during the monitored time period (hazard ratio 5.75, p=0.02, 95% CI 1.35–24.43), when corrected for gender, age at testing and disease severity at testing according to the baseline PSPRS score. In contrast, the levels of CSF t-tau and p-tau did not predict progression (hazard ratio p-values>0.05). Our results suggest that baseline CSF NFL levels can predict progression in PSP. We aim to replicate these findings in both CSF and plasma in a larger cohort.

PO086 European registry of corticobasal degeneration a prospect sister study: recruitment of patients with corticobasal syndrome via the bnsu

Corticobasal degeneration (CBD) is a rare progressive neurodegenerative disease. Our primary aim is to investigate how clinical and biological features can help explain the varying pathology that underlies corticobasal syndrome (CBS) and to define the markers of pathological CBD. The secondary aim is to establish a cohort of patients with clinically well-defined CBS that will be available for future therapeutic and clinical studies. The ABN BNSU is a source of recruitment of patients with CBS to the PROSPECT study. Eligible patients are notified to the study team monthly by ABN members. Patients are provided with a permission to contact form. Following informed consent, patients provide blood samples for genetic analysis and cell lines and complete study questionnaires. Patients can participate remotely or at their local study site. We have received 22 BNSU referrals from 22 consultants over 5 months (mean 4.5/month). So far we have received 1 permission to contact form from a patient who is being recruited to study. The BNSU is an invaluable source of referrals for patients with rare diseases from across the UK. There is a 4 month delay from initial contact to return of reply forms and we will investigate ways to streamline the recruitment process.

THE PROSPECT STUDY: DEVELOPMENT OF A UK-BASED LONGITUDINAL OBSERVATIONAL STUDY OF PSP, CBD, MSA AND ATYPICAL PARKINSONISM SYNDROMES

normal, mild cognitive impairment or dementia). SNAP is also a complement to the new National Institute on Aging–Alzheimer Association (NIA-AA) research criteria of preclinical AD. We aimed to explore the biomarkers in different clinical status with SNAP. Methods:We used the baseline data from Alzheimer’s Disease Neuroimaging Initiative 1 (ADNI1) and collected the individuals with SNAP (clinically normal, mild cognitive impairment or dementia). The criteria were decreased CSF Ab1-42 (<192pg/ml) and elevated CSF Tau (total Tau>93pg/ml, or phosphorylated Tau>23pg/ml). The data of biomarkers from CSF (e.g. Ab, Tau, a-synuclein, sAPPb, neurogranin, b-secretase, neurofilament, isoprostane, multiplex proteomics) and plasma (e.g. Ab, Tau, neurofilament) were extracted. Mann-Whitney U tests were carried out between the groups of different clinical status, and P<0.05 was regarded as statistical significance. Results: A total of 31 SNAP individuals were selected from ADNI1 cohort, with 18 clinically normal, 9 MCI and 4 dementia. APOE4 alleles were only 8%. In comparison with clinically normal, CSF CD40 (Mann-Whitney U test, Z1⁄42.024, P 1⁄40.046) and fibrinogen (Mann-Whitney U test, Z1⁄42.239, P 1⁄40.025) significantly changed in MCI, as well as CSF isoprostane (ISO8PGF2A) was elevated in dementia. In comparison with clinically normal, CSF isoprostane (ISO8PGF2A) (Mann-Whitney U test, Z1⁄4-2.315, P1⁄40.020) was elevated in dementia. Conclusions: APOE4 is less common in SNAP. Only elevated ISO8PGF2A is observed in dementia in comparison with clinically normal and MCI, which is not found between clinically normal and MCI. Large-sample is required to confirm our findings and seek better biomarkers to differentiate the clinical status of SNAP. As the previous opinion “SNAP individuals are stable over time”, biomarkers signature suggests SNAP may be normal aging rather than pathological changes, in which brain atrophy and cognitive decline progress slowly.

PLASMA AND CSF LEVELS OF NEUROFILAMENT LIGHT CHAIN CORRELATE IN ATYPICAL PARKINSONIAN SYNDROMES AND DISTINGUISH THEM FROM PARKINSON’S AND ALZHEIMER’S DISEASE

O4-02-01 PLASMA AND CSF LEVELS OF NEUROFILAMENT LIGHT CHAIN CORRELATE IN ATYPICAL PARKINSONIAN SYNDROMES AND DISTINGUISH THEM FROM PARKINSON’S AND ALZHEIMER’S DISEASE Edwin Jabbari, John Woodside, Nadia Magdalinou, Kaj Blennow, Henrik Zetterberg, Andrew Lees, Huw Morris, Institute of Neurology, University College London, London, United Kingdom; Dementia Research Centre UCL Institute of Neurology, London, United Kingdom; Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, M€olndal, Sweden; Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden. Contact e-mail: e.jabbari@ucl.ac.uk