Co operative Research Center for Mental Health

Perth, Australia

Co operative Research Center for Mental Health

Perth, Australia
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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.


Thai C.,RMIT University | Lim Y.Y.,Florey Institute of Neuroscience and Mental Health | Lim Y.Y.,Brown University | Lim Y.Y.,Rhode Island Hospital | And 20 more authors.
PLoS ONE | Year: 2015

High levels of β-amyloid (Aβ) in the brain and carriage of the APOE ε4 allele have each been linked to cognitive impairment in cognitively normal (CN) older adults. However, the relationship between these two biomarkers and cognitive decline is unclear. The aim of this study was to investigate the relationship between cerebral Aβ level, APOE ε4 carrier status, and cognitive decline over 18 months, in 317 cognitively healthy (CN) older adults (47.6% males, 52.4%females) aged between 60 and 89 years (Mean = 69.9, SD = 6.8). Cognition was assessed using the Cogstate Brief Battery (CBB) and the California Verbal Learning Test, Second Edition (CVLT-II). Planned comparisons indicated that CN older adults with high Aβ who were also APOE ε4 carriers demonstrated the most pronounced decline in learning and working memory. In CN older adults who were APOE ε4 non-carriers, high Aβ was unrelated to cognitive decline in learning and working memory. Carriage of APOE ε4 in CN older adults with low Aβ was associated with a significantly increased rate of decline in learning and unexpectedly, improved cognitive performance on measures of verbal episodic memory over 18 months. These results suggest that Aβ and APOE ε4 interact to increase the rate of cognitive decline in CN older adults and provide further support for the use of Aβ and APOE ε4 as biomarkers of early Alzheimer's disease. © 2015 Thai et al.

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