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Faux N.G.,University of Melbourne | Faux N.G.,Cooperative Research Center for Mental Health | Rembach A.,University of Melbourne | Wiley J.,University of Melbourne | And 11 more authors.
Molecular Psychiatry | Year: 2014

Lower hemoglobin is associated with cognitive impairment and Alzheimer's disease (AD). Since brain iron homeostasis is perturbed in AD, we investigated whether this is peripherally reflected in the hematological and related blood chemistry values from the Australian Imaging Biomarker and Lifestyle (AIBL) study (a community-based, cross-sectional cohort comprising 768 healthy controls (HC), 133 participants with mild cognitive impairment (MCI) and 211 participants with AD). We found that individuals with AD had significantly lower hemoglobin, mean cell hemoglobin concentrations, packed cell volume and higher erythrocyte sedimentation rates (adjusted for age, gender, APOE-ε4 and site). In AD, plasma iron, transferrin, transferrin saturation and red cell folate levels exhibited a significant distortion of their customary relationship to hemoglobin levels. There was a strong association between anemia and AD (adjusted odds ratio (OR)=2.43, confidence interval (CI) (1.31, 4.54)). Moreover, AD emerged as a strong risk factor for anemia on step-down regression, even when controlling for all other available explanations for anemia (adjusted OR=3.41, 95% CI (1.68, 6.92)). These data indicated that AD is complicated by anemia, which may itself contribute to cognitive decline. © 2014 Macmillan Publishers Limited All rights reserved.

Johnson P.,CSIRO | Vandewater L.,CSIRO | Wilson W.,CSIRO | Wilson W.,Cooperative Research Center for Mental Health | And 18 more authors.
BMC Bioinformatics | Year: 2014

Background: Assessment of risk and early diagnosis of Alzheimer's disease (AD) is a key to its prevention or slowing the progression of the disease. Previous research on risk factors for AD typically utilizes statistical comparison tests or stepwise selection with regression models. Outcomes of these methods tend to emphasize single risk factors rather than a combination of risk factors. However, a combination of factors, rather than any one alone, is likely to affect disease development. Genetic algorithms (GA) can be useful and efficient for searching a combination of variables for the best achievement (eg. accuracy of diagnosis), especially when the search space is large, complex or poorly understood, as in the case in prediction of AD development. Results: Multiple sets of neuropsychological tests were identified by GA to best predict conversions between clinical categories, with a cross validated AUC (area under the ROC curve) of 0.90 for prediction of HC conversion to MCI/AD and 0.86 for MCI conversion to AD within 36 months. Conclusions: This study showed the potential of GA application in the neural science area. It demonstrated that the combination of a small set of variables is superior in performance than the use of all the single significant variables in the model for prediction of progression of disease. Variables more frequently selected by GA might be more important as part of the algorithm for prediction of disease development. © 2014 Johnson et al.

Rembach A.,University of Melbourne | Stingo F.C.,University of Texas M. D. Anderson Cancer Center | Peterson C.,Stanford University | Vannucci M.,Rice University | And 10 more authors.
Journal of Alzheimer's Disease | Year: 2015

With different approaches to finding prognostic or diagnostic biomarkers for Alzheimer's disease (AD), many studies pursue only brief lists of biomarkers or disease specific pathways, potentially dismissing information from groups of correlated biomarkers. Using a novel Bayesian graphical network method, with data from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging, the aim of this study was to assess the biological connectivity between AD associated blood-based proteins. Briefly, three groups of protein markers (18, 37, and 48 proteins, respectively) were assessed for the posterior probability of biological connection both within and between clinical classifications. Clinical classification was defined in four groups: high performance healthy controls (hpHC), healthy controls (HC), participants with mild cognitive impairment (MCI), and participants with AD. Using the smaller group of proteins, posterior probabilities of network similarity between clinical classifications were very high, indicating no difference in biological connections between groups. Increasing the number of proteins increased the capacity to separate both hpHC and HC apart from the AD group (0 for complete separation, 1 for complete similarity), with posterior probabilities shifting from 0.89 for the 18 protein group, through to 0.54 for the 37 protein group, and finally 0.28 for the 48 protein group. Using this approach, we identified beta-2 microglobulin (β2M) as a potential master regulator of multiple proteins across all classifications, demonstrating that this approach can be used across many data sets to identify novel insights into diseases like AD. © 2015 -IOS Press and the authors. All rights reserved.

Hare D.J.,University of Technology, Sydney | Hare D.J.,University of Melbourne | Hare D.J.,Mount Sinai School of Medicine | Doecke J.D.,Australian ealth Research Center | And 13 more authors.
ACS Chemical Neuroscience | Year: 2015

Plasma iron levels are decreased in Alzheimer's disease (AD) and associated with an idiopathic anemia. We examined iron-binding plasma proteins from AD patients and healthy controls from the Australian Imaging, Biomarkers and Lifestyle (AIBL) Flagship Study of Ageing using size exclusion chromatography-inductively coupled plasma-mass spectrometry. Peak area corresponding to transferrin (Tf) saturation was directly compared to routine pathological testing. We found a significant decrease in transferrin-associated iron in AD that was missed by routine pathological tests of transferrin saturation, and that was able to discriminate between AD and controls. The AD cases showed no significant difference in transferrin concentration, only a decrease in total transferrin-bound iron. These findings support that a previously identified decrease in plasma iron levels in AD patients within the AIBL study is attributable to decreased loading of iron into transferrin, and that this subtle but discriminatory change is not observed through routine pathological testing. © 2015 American Chemical Society.

Dean B.,Florey Institute for Neuroscience and Mental Health | Dean B.,Cooperative Research Center for Mental Health | Dean B.,University of Melbourne | Hopper S.,Florey Institute for Neuroscience and Mental Health | And 6 more authors.
Neuropsychopharmacology | Year: 2016

Stimulation of the cortical muscarinic M1 receptor (CHRM1) is proposed as a treatment for schizophrenia, a hypothesis testable using CHRM1 allosteric modulators. Allosteric modulators have been shown to change the activity of CHRMs using cloned human CHRMs and CHRM knockout mice but not human CNS, a prerequisite for them working in humans. Here we show in vitro that BQCA, a positive allosteric CHRM1 modulator, brings about the expected change in affinity of the CHRM1 orthosteric site for acetylcholine in human cortex. Moreover, this effect of BQCA is reduced in the cortex of a subset of subjects with schizophrenia, separated into a discrete population because of a profound loss of cortical [3H] pirenzepine binding. Surprisingly, there was no change in [3H] NMS binding to the cortex from this subset or those with schizophrenia but without a marked loss of cortical CHRM1. Hence, we explored the nature of [3H] pirenzepine and [3H] NMS binding to human cortex and showed total [3H] pirenzepine and [3H] NMS binding was reduced by Zn2+, acetylcholine displacement of [3H] NMS binding was enhanced by Mg2+ and Zn2+, acetylcholine displacement of [3H] pirenzepine was reduced by Mg2+ and enhanced by Zn2+, whereas BQCA effects on [3H] NMS, but not [3H] pirenzepine, binding was enhanced by Mg2+ and Zn2+. These data suggest the orthosteric and allosteric sites on CHRMs respond differently to divalent cations and the effects of allosteric modulation of the cortical CHRM1 is reduced in a subset of people with schizophrenia, a finding that may have ramifications for the use of CHRM1 allosteric modulators in the treatment of schizophrenia. © 2016 American College of Neuropsychopharmacology. All rights reserved.

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