Co operative Research Center for Mental Health

Perth, Australia

Co operative Research Center for Mental Health

Perth, Australia
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Gupta V.B.,Edith Cowan University | Gupta V.B.,Co operative Research Center for Mental Health | Hone E.,Edith Cowan University | Hone E.,Co operative Research Center for Mental Health | And 16 more authors.
Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring | Year: 2017

Introduction A blood-based biomarker panel to identify individuals with preclinical Alzheimer's disease (AD) would be an inexpensive and accessible first step for routine testing. Methods We analyzed 14 biomarkers that have previously been linked to AD in the Australian Imaging Biomarkers lifestyle longitudinal study of aging cohort. Results Levels of apolipoprotein J (apoJ) were higher in AD individuals compared with healthy controls at baseline and 18 months (P =.0003) and chemokine-309 (I-309) were increased in AD patients compared to mild cognitive impaired individuals over 36 months (P =.0008). Discussion These data suggest that apoJ may have potential in the context of use (COU) of AD diagnostics, I-309 may be specifically useful in the COU of identifying individuals at greatest risk for progressing toward AD. This work takes an initial step toward identifying blood biomarkers with potential use in the diagnosis and prognosis of AD and should be validated across other prospective cohorts. © 2017 The Authors

Lim Y.Y.,University of Melbourne | Rainey-Smith S.,Edith Cowan University | Lim Y.,University of South Australia | Laws S.M.,Edith Cowan University | And 20 more authors.
International Psychogeriatrics | Year: 2017

Background:: The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism Met allele exacerbates amyloid (Aβ) related decline in episodic memory (EM) and hippocampal volume (HV) over 36–54 months in preclinical Alzheimer's disease (AD). However, the extent to which Aβ+ and BDNF Val66Met is related to circulating markers of BDNF (e.g. serum) is unknown. We aimed to determine the effect of Aβ and the BDNF Val66Met polymorphism on levels of serum mBDNF, EM, and HV at baseline and over 18-months. Methods:: Non-demented older adults (n = 446) underwent Aβ neuroimaging and BDNF Val66Met genotyping. EM and HV were assessed at baseline and 18 months later. Fasted blood samples were obtained from each participant at baseline and at 18-month follow-up. Aβ PET neuroimaging was used to classify participants as Aβ– or Aβ+. Results:: At baseline, Aβ+ adults showed worse EM impairment and lower serum mBDNF levels relative to Aβ- adults. BDNF Val66Met polymorphism did not affect serum mBDNF, EM, or HV at baseline. When considered over 18-months, compared to Aβ– Val homozygotes, Aβ+ Val homozygotes showed significant decline in EM and HV but not serum mBDNF. Similarly, compared to Aβ+ Val homozygotes, Aβ+ Met carriers showed significant decline in EM and HV over 18-months but showed no change in serum mBDNF. Conclusion:: While allelic variation in BDNF Val66Met may influence Aβ+ related neurodegeneration and memory loss over the short term, this is not related to serum mBDNF. Longer follow-up intervals may be required to further determine any relationships between serum mBDNF, EM, and HV in preclinical AD. Copyright © International Psychogeriatric Association 2017

Lim Y.Y.,University of Melbourne | Williamson R.,University of Melbourne | Laws S.M.,Edith Cowan University | Laws S.M.,Co operative Research Center for Mental Health | And 13 more authors.
Journal of Alzheimer's Disease | Year: 2017

Background: The association between the apolipoprotein E (APOE) ϵ4 allele and high risk of developing Alzheimer's disease (AD) dementia before the age of 80 has been recognized for over 30 years. However, the timing and mode of action of APOE is not understood, nor has there been a detailed analysis of the effect of APOE genotype on memory, hippocampal volume, and amyloid-β (Aβ) levels in cognitively normal adults. Objective: Examine the effect of APOE allelic genotype on the relationship between Aβ levels, hippocampal volume, and memory in cognitively normal adults. Methods: This is a cross-sectional study of 989 cognitively normal older adults enrolled in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study, all of whom underwent APOE genotyping and memory assessment. A subset of this group underwent PET neuroimaging for Aβ (n = 585) and MRI for hippocampal volume (n = 303). Results: APOE ϵ4 homozygotes (ϵ4/ϵ4) showed significantly worse episodic memory and higher Aβ levels than ϵ4 heterozygotes. The relationship between increasing Aβ levels and worse episodic memory was significant for ϵ3 homozygotes (ϵ3/ϵ3), ϵ4 heterozygotes, and strongest for ϵ4 homozygotes. There were no differences in hippocampal volume between APOE groups; the relationship between smaller hippocampal volume and worse episodic memory was significant only for ϵ4 homozygotes. Conclusion: APOE acts in a co-dominant fashion on Aβ levels, episodic memory, and hippocampal volume in cognitively normal older adults. APOE ϵ4 is central to the events that lead to AD in cognitively normal older adults, likely through a quantitative role in the disruption of Aβ clearance. © 2017 - IOS Press and the authors. All rights reserved.

Lim Y.Y.,University of Melbourne | Lim Y.Y.,Brown University | Lim Y.Y.,Rhode Island Hospital | Villemagne V.L.,University of Melbourne | And 19 more authors.
Molecular Psychiatry | Year: 2015

Accumulation of β-amyloid (Aβ) in the brain is associated with memory decline in healthy individuals as a prelude to Alzheimer's disease (AD). Genetic factors may moderate this decline. We examined the role of apolipoprotein E (ε4 carrier ε4 + , ε4 non-carrier ε4) and brain-derived neurotrophic factor (BDNF Val/Val, BDNF Met) in the extent to which they moderate Aβ-related memory decline. Healthy adults (n=333, M age =70 years) enrolled in the Australian Imaging, Biomarkers and Lifestyle study underwent Aβ neuroimaging. Neuropsychological assessments were conducted at baseline, 18-, 36- and 54-month follow-ups. Aβ positron emission tomography neuroimaging was used to classify participants as Aβ - or Aβ +. Relative to Aβ - ε4 -, Aβ + ε4 + individuals showed significantly faster rates of cognitive decline over 54 months across all domains (d=0.40-1.22), while Aβ + ε4 - individuals showed significantly faster decline only on verbal episodic memory (EM). There were no differences in rates of cognitive change between Aβ - ε4 - and Aβ - ε4 + groups. Among Aβ + individuals, ε4 + /BDNF Met participants showed a significantly faster rate of decline on verbal and visual EM, and language over 54 months compared with ε4 - /BDNF Val/Val participants (d=0.90-1.02). At least two genetic loci affect the rate of Aβ-related cognitive decline. Aβ + ε4 + /BDNF Met individuals can expect to show clinically significant memory impairment after 3 years, whereas Aβ + ε4 + /BDNF Val/Val individuals can expect a similar degree of impairment after 10 years. Little decline over 54 months was observed in the Aβ - and Aβ + ε4 - groups, irrespective of BDNF status. These data raise important prognostic issues in managing preclinical AD, and should be considered in designing secondary preventative clinical trials. © 2015 Macmillan Publishers Limited Molecular Psychiatry.

Lim Y.Y.,University of Melbourne | Villemagne V.L.,University of Melbourne | Villemagne V.L.,Austin Health | Laws S.M.,Edith Cowan University | And 16 more authors.
Journal of Molecular Neuroscience | Year: 2016

In a group of older adults with very mild dementia, we aimed to characterize the nature and magnitude of cognitive decline as measured by the Cogstate Brief Battery, in relation to Aβ levels and hippocampal volume. Participants were characterized according to their status on the Clinical Dementia Rating (CDR) scale. A total of 308 individuals who were CDR 0 and had low cerebral Aβ levels (Aβ−), 32 individuals who were Aβ− and CDR 0.5, and 43 individuals who were Aβ+ and CDR 0.5 were included in this study. Participants completed the CogState brief battery at baseline, and at 18-, 36-, 54- and 72-month follow-up. Linear mixed model analyses indicated that relative to the Aβ− CDR 0 group, the Aβ+ CDR 0.5 group showed increased rates of memory decline and hippocampal volume loss. However, compared to the Aβ− CDR 0 group, the Aβ− CDR 0.5 group showed no changes in cognitive function or hippocampal volume over 72 months. The results of this study confirm that in individuals with very mild dementia, who also have biomarker confirmation of Aβ+, changes in cognitive function manifest primarily as deterioration in memory processing, and this is associated with hippocampal volume loss. Conversely, the absence of any cognitive decline or loss in hippocampal volume in individuals with very mild dementia but who are Aβ− suggests that some other non-AD disease process may underlie any static impairment in cognitive function. © 2016 Springer Science+Business Media New York

Lim Y.Y.,University of Melbourne | Villemagne V.L.,University of Melbourne | Villemagne V.L.,Austin Health | Laws S.M.,Edith Cowan University | And 17 more authors.
PLoS ONE | Year: 2014

Objective: Cross-sectional genetic association studies have reported equivocal results on the relationship between the brain-derived neurotrophic factor (BDNF) Val66Met and risk of Alzheimer's disease (AD). As AD is a neurodegenerative disease, genetic influences may become clearer from prospective study. We aimed to determine whether BDNF Val66Met polymorphism influences changes in memory performance, hippocampal volume, and Aβ accumulation in adults with amnestic mild cognitive impairment (aMCI) and high Aβ. Methods: Thirty-four adults with aMCI were recruited from the Australian, Imaging, Biomarkers and Lifestyle (AIBL) Study. Participants underwent PiB-PET and structural MRI neuroimaging, neuropsychological assessments and BDNF genotyping at baseline, 18 month, and 36 month assessments. Results: In individuals with aMCI and high Aβ, Met carriers showed significant and large decline in episodic memory (d = 0.90, p = .020) and hippocampal volume (d = 0.98, p = .035). BDNF Val66Met was unrelated to the rate of Aβ accumulation (d = -0.35, p = .401). Conclusions: Although preliminary due to the small sample size, results of this study suggest that high Aβ levels and Met carriage may be useful prognostic markers of accelerated decline in episodic memory, and reductions in hippocampal volume in individuals in the prodromal or MCI stage of AD. © 2014 Lim et al.

Verdile G.,Edith Cowan University | Verdile G.,Sir James McCusker Alzheimers Disease Research Unit Hollywood Private Hospital | Laws S.M.,Edith Cowan University | Laws S.M.,Sir James McCusker Alzheimers Disease Research Unit Hollywood Private Hospital | And 30 more authors.
Molecular Psychiatry | Year: 2014

Testosterone and gonadotropins have been associated with cognitive decline in men and the modulation of β amyloid (Aβ) metabolism. The relatively few studies that have investigated whether changes in one or a combination of these hormones influence Aβ levels have focused primarily on plasma Aβ 1-40 and not on the more pathogenic Aβ 1-42. Currently, no study has investigated whether these hormones are associated with an increase in brain amyloid deposition, ante mortem. Through the highly characterised Australian imaging, biomarkers and lifestyle study, we have determined the impact of these hormones on plasma Aβ levels and brain amyloid burden (Pittsburgh compound B (PiB) retention). Spearman's rank correlation and linear regression analysis was carried out across the cohort and within subclassifications. Luteinizing hormone (LH) was the only variable shown, in the total cohort, to have a significant impact on plasma Aβ 1-40 and Aβ 1-42 levels (beta=0.163, P<0.001; beta=0.446, P<0.001). This held in subjective memory complainers (SMC) (Aβ 1-40; beta=0.208, P=0.017; Aβ 1-42; beta=0.215, P=0.017) but was absent in mild cognitive impairment (MCI) and Alzheimer's disease (AD) groups. In SMC, increased frequency of the APOE-ε4 allele (beta=0.536, P<0.001) and increasing serum LH levels (beta=0.421, P=0.004) had a significant impact on PiB retention. Whereas in MCI, PiB retention was associated with increased APOE-ε4 allele copy number (beta=0.674, P<0.001) and decreasing calculated free testosterone (beta=-0.303, P=0.043). These findings suggest a potential progressive involvement of LH and testosterone in the early preclinical stages of AD. Furthermore, these hormones should be considered while attempting to predict AD at these earliest stages of the disease. © 2014 Macmillan Publishers Limited.

Stevens B.J.,University of Melbourne | Hare D.J.,University of Melbourne | Hare D.J.,University of Technology, Sydney | Volitakis I.,University of Melbourne | And 3 more authors.
Journal of Analytical Atomic Spectrometry | Year: 2017

High prevalence of zinc deficiency stemming from malnutrition, gastrointestinal diseases and low dietary intake accounts for detection of zinc in plasma being a frequently requested clinical pathology assay. Serum and plasma zinc determination by graphite furnace atomic absorption spectrometry (GFAAS) has previously been hampered by significant interfering species and intolerance to high pyrolysis temperatures. In this Technical Note, we report a GFAAS method developed to overcome these restrictions by employing two matrix modifiers and a high pyrolysis temperature. Serum and plasma samples were diluted twenty times with an Antifoam/Triton-X-100 diluent and measured against aqueous standards similarly diluted, without the use of Zeeman correction. Interference from chloride was eliminated using a combination of two matrix modifiers: a magnesium/palladium mixture combined with 1% (w/v) aqueous ethylenediaminetetraacetic acid (EDTA). This allowed a pyrolysis temperature of 1000 °C to be used, which resulted in the complete removal of chloride interference. The accuracy of the method was verified by direct comparison with inductively coupled plasma-mass spectrometry (ICP-MS) and flame atomic absorption spectrometry (FAAS); analysis of a commercial reference material (Seronorm); and by analytical recovery studies. © The Royal Society of Chemistry.

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