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      Kynurenine Pathway Metabolites in Alzheimer’s Disease

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          A comparison of 12 algorithms for matching on the propensity score

          Propensity-score matching is increasingly being used to reduce the confounding that can occur in observational studies examining the effects of treatments or interventions on outcomes. We used Monte Carlo simulations to examine the following algorithms for forming matched pairs of treated and untreated subjects: optimal matching, greedy nearest neighbor matching without replacement, and greedy nearest neighbor matching without replacement within specified caliper widths. For each of the latter two algorithms, we examined four different sub-algorithms defined by the order in which treated subjects were selected for matching to an untreated subject: lowest to highest propensity score, highest to lowest propensity score, best match first, and random order. We also examined matching with replacement. We found that (i) nearest neighbor matching induced the same balance in baseline covariates as did optimal matching; (ii) when at least some of the covariates were continuous, caliper matching tended to induce balance on baseline covariates that was at least as good as the other algorithms; (iii) caliper matching tended to result in estimates of treatment effect with less bias compared with optimal and nearest neighbor matching; (iv) optimal and nearest neighbor matching resulted in estimates of treatment effect with negligibly less variability than did caliper matching; (v) caliper matching had amongst the best performance when assessed using mean squared error; (vi) the order in which treated subjects were selected for matching had at most a modest effect on estimation; and (vii) matching with replacement did not have superior performance compared with caliper matching without replacement. © 2013 The Authors. Statistics in Medicine published by John Wiley & Sons, Ltd.
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            Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease.

            Recent studies suggest that vascular disease may contribute to the cause of Alzheimer disease (AD). Since elevated plasma total homocysteine (tHcy) level is a risk factor for vascular disease, it may also be relevant to AD. To examine the association of AD with blood levels of tHcy, and its biological determinants folate and vitamin B12. Case-control study of 164 patients, aged 55 years or older, with a clinical diagnosis of dementia of Alzheimer type (DAT), including 76 patients with histologically confirmed AD and 108 control subjects. Referral population to a hospital clinic between July 1988 and April 1996. Serum tHcy, folate, and vitamin B12 levels in patients and controls at entry; the odds ratio of DAT or confirmed AD with elevated tHcy or low vitamin levels; and the rate of disease progression in relation to tHcy levels at entry. Serum tHcy levels were significantly higher and serum folate and vitamin B12 levels were lower in patients with DAT and patients with histologically confirmed AD than in controls. The odds ratio of confirmed AD associated with a tHcy level in the top third (> or = 14 micromol/L) compared with the bottom third (< or = 11 micromol/L) of the control distribution was 4.5 (95% confidence interval, 2.2-9.2), after adjustment for age, sex, social class, cigarette smoking, and apolipoprotein E epsilon4. The corresponding odds ratio for the lower third compared with the upper third of serum folate distribution was 3.3 (95% confidence interval, 1.8-6.3) and of vitamin B12 distribution was 4.3 (95% confidence interval, 2.1-8.8). The mean tHcy levels were unaltered by duration of symptoms before enrollment and were stable for several years afterward. In a 3-year follow-up of patients with DAT, radiological evidence of disease progression was greater among those with higher tHcy levels at entry. Low blood levels of folate and vitamin B12, and elevated tHcy levels were associated with AD. The stability of tHcy levels over time and lack of relationship with duration of symptoms argue against these findings being a consequence of disease and warrant further studies to assess the clinical relevance of these associations for AD.
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              Blood-brain barrier transport of kynurenines: implications for brain synthesis and metabolism.

              To evaluate the potential contribution of circulating kynurenines to brain kynurenine pools, the rates of cerebral uptake and mechanisms of blood-brain barrier transport were determined for several kynurenine metabolites of tryptophan, including L-kynurenine (L-KYN), 3-hydroxykynurenine (3-HKYN), 3-hydroxyanthranilic acid (3-HANA), anthranilic acid (ANA), kynurenic acid (KYNA), and quinolinic acid (QUIN), in pentobarbital-anesthetized rats using an in situ brain perfusion technique. L-KYN was found to be taken up into brain at a significant rate [permeability-surface area product (PA) = 2-3 x 10(-3) ml/s/g] by the large neutral amino acid carrier (L-system) of the blood-brain barrier. Best-fit estimates of the Vmax and Km of saturable L-KYN transfer equalled 4.5 x 10(-4) mumol/s/g and 0.16 mumol/ml, respectively. The same carrier may also mediate the brain uptake of 3-HKYN as D,L-3-HKYN competitively inhibited the brain transfer of the large neutral amino acid L-leucine. For the other metabolites, uptake appeared mediated by passive diffusion. This occurred at a significant rate for ANA (PA, 0.7-1.6 x 10(-3) ml/s/g), and at far lower rates (PA, 2-7 x 10(-5) ml/s/g) for 3-HANA, KYNA, and QUIN. Transfer for KYNA, 3-HANA, and ANA also appeared to be limited by plasma protein binding. The results demonstrate the saturable transfer of L-KYN across the blood-brain barrier and suggest that circulating L-KYN, 3-HKYN, and ANA may each contribute significantly to respective cerebral pools. In contrast, QUIN, KYNA, and 3-HANA cross the blood-brain barrier poorly, and therefore are not expected to contribute significantly to brain pools under normal conditions.
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                Author and article information

                Journal
                Journal of Alzheimer's Disease
                JAD
                IOS Press
                13872877
                18758908
                September 18 2017
                September 18 2017
                : 60
                : 2
                : 495-504
                Affiliations
                [1 ]Department of Internal Medicine, Haraldsplass Deaconess Hospital, Bergen, Norway
                [2 ]Department of Clinical Science, University of Bergen, Norway
                [3 ]Bevital AS, Norway
                [4 ]Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Norway
                [5 ]OPTIMA, Department of Pharmacology, University of Oxford, UK
                [6 ]Department of Clinical Medicine, University of Bergen, Norway
                [7 ]Laboratory of Clinical Biochemistry, Haukeland University Hospital, Bergen, Norway
                Article
                10.3233/JAD-170485
                28869479
                2b1e7266-31cd-4f75-bec4-6b1f44ef1fc4
                © 2017
                History

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