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Metals in alzheimer’s disease
Pathology (2012) 44(S1), pp. S17–S20
Chemical Pathology
DIAGNOSTIC AND THERAPEUTIC APPROACHES TO ALZHEIMER’S DISEASE Simon M. Laws1,2, Giuseppe Verdile1,2, James Doecke3,4,5, Ralph N. Martins,1,2 and the AIBL research group6 1 Centre of Excellence for Alzheimer’s Disease Research and Care, School of Medical Sciences, Edith Cowan University, Joondalup, WA, 2Sir James McCusker Alzheimer’s Disease Research Unit (Hollywood Private Hospital), Perth, WA, 3The Australian E-Health Research Centre, Royal Brisbane and Women’s Hospital, Herston, Qld, 4CSIRO Preventative Health Flagship, Parkville, Vic, 5CSIRO Mathematics and Information Sciences, Macquarie University, Sydney, NSW, Australia, 6http://www.aibl.csiro.au/ Background: The definitive diagnosis of Alzheimer’s disease (AD) is currently only possible following post-mortem examination of the brain for the disease’s characteristic neuropathology. The successful implementation of disease interventions makes the discovery of biomarkers for early diagnosis and response to treatment paramount. Here we present results from two studies that have implications for AD diagnosis and treatment. Methods: The Australian Imaging Biomarker and Lifestyle (AIBL) study of ageing provided the cohorts and data studied. The first study aimed to identify plasma biomarkers for the diagnosis of disease through the screening of 224 plasma analytes. The second study investigated the impact of testosterone and gonadotropins on AD biomarkers. Results: A panel of eight biomarkers was identified that obtained sensitivity and specificity of 83% and an AUC of 87%. Testosterone and luteinizing hormone were both found to be associated with plasma and cerebral amyloid-beta levels. Conclusions: The identification and validation of a short panel of biomarkers has significant implications for the future diagnosis, prediction and monitoring of AD. The close association of hormones with AD pathology likewise has significant implications on future treatments of the disease, with a clinical trial being the next stage in assessing the efficacy of this approach. METALS IN ALZHEIMER’S DISEASE Ashley Bush Department of Pathology, and Mental Health Research Institute, The University of Melbourne, Vic, Australia The brain houses high concentrations of transition metals zinc, copper and iron, which it uses for specialised neurochemistry and the synthesis of heme. It is in this high flux environment that several of the culprit proteins of Alzheimer’s disease (AD) aggregate, losing function and possibly becoming toxic. These include amyloid (Ab) that aggregates outside of the cell forming plaques, and tau, which aggregates inside the neurons forming tangles. Both pathologies recruit high concentrations of metal ions. Presenilins, whose mutations cause aggressive familial AD, play a major role in metal uptake. The levels of iron in the brain rise with aging and rise even more with AD. This is caused by dissociating zinc within Print ISSN 0031-3025/Online ISSN 1465-3931
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amyloid deposits inhibiting the iron-export activity of the Ab precursor protein (APP), which is a major component of neuronal iron efflux. We have recently found that tau plays a major role in neuronal iron homeostasis by mediating APP trafficking. The metal-centred neuropathology of AD is the target for a new class of drugs that have shown considerable promise in clinical trials. Abnormal metal homeostasis is also reflected in the periphery in AD, and may be the basis for predictive biomarkers. OVERVIEW OF MATERNAL SERUM SCREENING FOR DOWN SYNDROME Narelle Hadlow Department of Biochemistry, Western Diagnostic Pathology, Perth, and Department of Biochemistry, Pathwest Laboratory Medicine, Queen Elizabeth II Hospital, Perth, WA, Australia This presentation will cover the principles of Down syndrome screening and the progress of screening from the use of age, second trimester and later first trimester screening tests. Refinements of first trimester screening will be discussed, including the timing of blood and ultrasound components, accreditation of sonologists, addition of nasal bone and ductus venosus to risk assessments and progress towards measuring precision and bias in ultrasound. The benefits and disadvantages of first and second trimester screening tests will be compared. Newer developments assessing risk of neural tube defects at first trimester including loss of intracranial translucency, caudal midbrain displacement and first trimester AFP will be covered. Screening programs can also assess risk for other chromosomal abnormalities such as Edward, Pataus and sex chromosomal anomalies. Prediction of other adverse outcomes such as preterm birth, low birth weight and pre-eclampsia have also been studied. Practical issues in a screening program, such as interferences and confounding factors are important to recognise and will be briefly discussed. The lecture will conclude with recognition that screening is an individual ethical choice. Pre-test information and counselling are important and the implications of the follow-up diagnostic tests should be understood. NON-INVASIVE PRENATAL DIAGNOSIS OF DOWN SYNDROME: A DREAM COME TRUE Rossa W. K. Chiu Li Ka Shing Institute of Health Sciences and Department of Chemical Pathology, The Chinese University of Hong Kong Our group discovered the presence of cell-free fetal DNA in plasma of pregnant women. This finding offered opportunities for the development of non-invasive approaches for prenatal diagnosis. However, fetal DNA co-exists with a large background of maternal DNA and amounts to just some 10% of the total DNA in maternal plasma. Despite the technical challenges, we developed an approach based on massively parallel sequencing for the
2012 Royal College of Pathologists of Australasia
Copyright © Royal College of pathologists of Australasia. Unauthorized reproduction of this article is prohibited.
Chemical Pathology
DIAGNOSTIC AND THERAPEUTIC APPROACHES TO ALZHEIMER’S DISEASE Simon M. Laws1,2, Giuseppe Verdile1,2, James Doecke3,4,5, Ralph N. Martins,1,2 and the AIBL research group6 1 Centre of Excellence for Alzheimer’s Disease Research and Care, School of Medical Sciences, Edith Cowan University, Joondalup, WA, 2Sir James McCusker Alzheimer’s Disease Research Unit (Hollywood Private Hospital), Perth, WA, 3The Australian E-Health Research Centre, Royal Brisbane and Women’s Hospital, Herston, Qld, 4CSIRO Preventative Health Flagship, Parkville, Vic, 5CSIRO Mathematics and Information Sciences, Macquarie University, Sydney, NSW, Australia, 6http://www.aibl.csiro.au/ Background: The definitive diagnosis of Alzheimer’s disease (AD) is currently only possible following post-mortem examination of the brain for the disease’s characteristic neuropathology. The successful implementation of disease interventions makes the discovery of biomarkers for early diagnosis and response to treatment paramount. Here we present results from two studies that have implications for AD diagnosis and treatment. Methods: The Australian Imaging Biomarker and Lifestyle (AIBL) study of ageing provided the cohorts and data studied. The first study aimed to identify plasma biomarkers for the diagnosis of disease through the screening of 224 plasma analytes. The second study investigated the impact of testosterone and gonadotropins on AD biomarkers. Results: A panel of eight biomarkers was identified that obtained sensitivity and specificity of 83% and an AUC of 87%. Testosterone and luteinizing hormone were both found to be associated with plasma and cerebral amyloid-beta levels. Conclusions: The identification and validation of a short panel of biomarkers has significant implications for the future diagnosis, prediction and monitoring of AD. The close association of hormones with AD pathology likewise has significant implications on future treatments of the disease, with a clinical trial being the next stage in assessing the efficacy of this approach. METALS IN ALZHEIMER’S DISEASE Ashley Bush Department of Pathology, and Mental Health Research Institute, The University of Melbourne, Vic, Australia The brain houses high concentrations of transition metals zinc, copper and iron, which it uses for specialised neurochemistry and the synthesis of heme. It is in this high flux environment that several of the culprit proteins of Alzheimer’s disease (AD) aggregate, losing function and possibly becoming toxic. These include amyloid (Ab) that aggregates outside of the cell forming plaques, and tau, which aggregates inside the neurons forming tangles. Both pathologies recruit high concentrations of metal ions. Presenilins, whose mutations cause aggressive familial AD, play a major role in metal uptake. The levels of iron in the brain rise with aging and rise even more with AD. This is caused by dissociating zinc within Print ISSN 0031-3025/Online ISSN 1465-3931
#
amyloid deposits inhibiting the iron-export activity of the Ab precursor protein (APP), which is a major component of neuronal iron efflux. We have recently found that tau plays a major role in neuronal iron homeostasis by mediating APP trafficking. The metal-centred neuropathology of AD is the target for a new class of drugs that have shown considerable promise in clinical trials. Abnormal metal homeostasis is also reflected in the periphery in AD, and may be the basis for predictive biomarkers. OVERVIEW OF MATERNAL SERUM SCREENING FOR DOWN SYNDROME Narelle Hadlow Department of Biochemistry, Western Diagnostic Pathology, Perth, and Department of Biochemistry, Pathwest Laboratory Medicine, Queen Elizabeth II Hospital, Perth, WA, Australia This presentation will cover the principles of Down syndrome screening and the progress of screening from the use of age, second trimester and later first trimester screening tests. Refinements of first trimester screening will be discussed, including the timing of blood and ultrasound components, accreditation of sonologists, addition of nasal bone and ductus venosus to risk assessments and progress towards measuring precision and bias in ultrasound. The benefits and disadvantages of first and second trimester screening tests will be compared. Newer developments assessing risk of neural tube defects at first trimester including loss of intracranial translucency, caudal midbrain displacement and first trimester AFP will be covered. Screening programs can also assess risk for other chromosomal abnormalities such as Edward, Pataus and sex chromosomal anomalies. Prediction of other adverse outcomes such as preterm birth, low birth weight and pre-eclampsia have also been studied. Practical issues in a screening program, such as interferences and confounding factors are important to recognise and will be briefly discussed. The lecture will conclude with recognition that screening is an individual ethical choice. Pre-test information and counselling are important and the implications of the follow-up diagnostic tests should be understood. NON-INVASIVE PRENATAL DIAGNOSIS OF DOWN SYNDROME: A DREAM COME TRUE Rossa W. K. Chiu Li Ka Shing Institute of Health Sciences and Department of Chemical Pathology, The Chinese University of Hong Kong Our group discovered the presence of cell-free fetal DNA in plasma of pregnant women. This finding offered opportunities for the development of non-invasive approaches for prenatal diagnosis. However, fetal DNA co-exists with a large background of maternal DNA and amounts to just some 10% of the total DNA in maternal plasma. Despite the technical challenges, we developed an approach based on massively parallel sequencing for the
2012 Royal College of Pathologists of Australasia
Copyright © Royal College of pathologists of Australasia. Unauthorized reproduction of this article is prohibited.