166 results on '"Rowe, C.C."'
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2. Fifteen years of the Australian Imaging, Biomarkers and Lifestyle (AIBL) Study: Progress and observations from 2,359 older adults spanning the spectrum from cognitive normality to Alzheimer’s Disease
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Fowler, C., Rainey-Smith, S.R., Bird, S., Bomke, J., Bourgeat, P., Brown, B.M., Burnham, S.C., Bush, A.I., Chadunow, C., Collins, S., Doecke, J., Doré, V., Ellis, K.A., Evered, L., Fazlollahi, A., Fripp, J., Gardener, S.L., Gibson, S., Grenfell, R., Harrison, E., Head, R., Jin, L., Kamer, A., Lamb, F., Lautenschlager, N.T., Laws, S.M., Li, Q-X, Lim, L., Lim, Y.Y., Louey, A., Macaulay, S.L., Mackintosh, L., Martins, R.N., Maruff, P., Masters, C.L., McBride, S., Milicic, L., Peretti, M., Pertile, K., Porter, T., Radler, M., Rembach, A., Robertson, J., Rodrigues, M., Rowe, C.C., Rumble, R., Salvado, O., Savage, G., Silbert, B., Soh, M., Sohrabi, H.R., Taddei, K., Taddei, T., Thai, C., Trounson, B., Tyrrell, R., Vacher, M., Varghese, S., Villemagne, V.L., Weinborn, M., Woodward, M., Xia, Y., Ames, D., Fowler, C., Rainey-Smith, S.R., Bird, S., Bomke, J., Bourgeat, P., Brown, B.M., Burnham, S.C., Bush, A.I., Chadunow, C., Collins, S., Doecke, J., Doré, V., Ellis, K.A., Evered, L., Fazlollahi, A., Fripp, J., Gardener, S.L., Gibson, S., Grenfell, R., Harrison, E., Head, R., Jin, L., Kamer, A., Lamb, F., Lautenschlager, N.T., Laws, S.M., Li, Q-X, Lim, L., Lim, Y.Y., Louey, A., Macaulay, S.L., Mackintosh, L., Martins, R.N., Maruff, P., Masters, C.L., McBride, S., Milicic, L., Peretti, M., Pertile, K., Porter, T., Radler, M., Rembach, A., Robertson, J., Rodrigues, M., Rowe, C.C., Rumble, R., Salvado, O., Savage, G., Silbert, B., Soh, M., Sohrabi, H.R., Taddei, K., Taddei, T., Thai, C., Trounson, B., Tyrrell, R., Vacher, M., Varghese, S., Villemagne, V.L., Weinborn, M., Woodward, M., Xia, Y., and Ames, D.
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Background: The Australian Imaging, Biomarkers and Lifestyle (AIBL) Study commenced in 2006 as a prospective study of 1,112 individuals (768 cognitively normal (CN), 133 with mild cognitive impairment (MCI), and 211 with Alzheimer’s disease dementia (AD)) as an ‘Inception cohort’ who underwent detailed ssessments every 18 months. Over the past decade, an additional 1247 subjects have been added as an ‘Enrichment cohort’ (as of 10 April 2019). Objective: Here we provide an overview of these Inception and Enrichment cohorts of more than 8,500 person-years of investigation. Methods: Participants underwent reassessment every 18 months including comprehensive cognitive testing, neuroimaging (magnetic resonance imaging, MRI; positron emission tomography, PET), biofluid biomarkers and lifestyle evaluations. Results: AIBL has made major contributions to the understanding of the natural history of AD, with cognitive and biological definitions of its three major stages: preclinical, prodromal and clinical. Early deployment of Aβ-amyloid and tau molecular PET imaging and the development of more sensitive and specific blood tests have facilitated the assessment of genetic and environmental factors which affect age at onset and rates of progression. Conclusion: This fifteen-year study provides a large database of highly characterized individuals with longitudinal cognitive, imaging and lifestyle data and biofluid collections, to aid in the development of interventions to delay onset, prevent or treat AD. Harmonization with similar large longitudinal cohort studies is underway to further these aims.
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- 2021
3. Longitudinal trajectories in cortical thickness and volume atrophy: Superior cognitive performance does not protect against brain atrophy in older adults
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Gardener, S.L., Weinborn, M., Sohrabi, H.R., Doecke, J.D., Bourgeat, P., Rainey-Smith, S.R., Shen, K-K, Fripp, J., Taddei, K., Maruff, P., Salvado, O., Savage, G., Ames, D., Masters, C.L., Rowe, C.C., Martins, R.N., O’Bryant, S., Gardener, S.L., Weinborn, M., Sohrabi, H.R., Doecke, J.D., Bourgeat, P., Rainey-Smith, S.R., Shen, K-K, Fripp, J., Taddei, K., Maruff, P., Salvado, O., Savage, G., Ames, D., Masters, C.L., Rowe, C.C., Martins, R.N., and O’Bryant, S.
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Background: Previous research has identified a small subgroup of older adults that maintain a high level of cognitive functioning well into advanced age. Investigation of those with superior cognitive performance (SCP) for their age is important, as age-related decline has previously been thought to be inevitable. Objective: Preservation of cortical thickness and volume was evaluated in 76 older adults with SCP and 100 typical older adults (TOAs) assessed up to five times over six years. Methods: Regions of interest (ROIs) found to have been associated with super-aging status (a construct similar to SCP status) in previous literature were investigated, followed by a discovery phase analyses of additional regions. SCPs were aged 70 + at baseline, scoring at/above normative memory (CVLT-II) levels for demographically similar individuals aged 30–44 years old, and in the unimpaired range for all other cognitive domains over the course of the study. Results: In linear mixed models, following adjustment for multiple comparisons, there were no significant differences between rates of thinning or volume atrophy between SCPs and TOAs in previously identified ROIs, or the discovery phase analyses. With only amyloid-β negative individuals in the analyses, again there were no significant differences between SCPs and TOAs. Conclusion: The increased methodological rigor in classifying groups, together with the influence of cognitive reserve, are discussed as potential factors accounting for our findings as compared to the extant literature on those with superior cognitive performance for their age.
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- 2021
4. SPON1 Is associated with Amyloid-β and APOE ε4-Related cognitive decline in cognitively normal adults
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Fernandez, S., Burnham, S.C., Milicic, L., Savage, G., Maruff, P., Peretti, M., Sohrabi, H.R., Lim, Y.Y., Weinborn, M., Ames, D., Masters, C.L., Martins, R.N., Rainey-Smith, S., Rowe, C.C., Salvado, O., Groth, D., Verdile, G., Villemagne, V.L., Porter, T., Laws, S.M., Fernandez, S., Burnham, S.C., Milicic, L., Savage, G., Maruff, P., Peretti, M., Sohrabi, H.R., Lim, Y.Y., Weinborn, M., Ames, D., Masters, C.L., Martins, R.N., Rainey-Smith, S., Rowe, C.C., Salvado, O., Groth, D., Verdile, G., Villemagne, V.L., Porter, T., and Laws, S.M.
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Background: Genetic variation in Spondin-1, specifically rs11023139, has been associated with reduced rates of cognitive decline in individuals with Alzheimer’s disease. Objective: The aim of this study was to assess whether the association was present in cognitively normal older adults. Methods: Longitudinal cognitive decline was investigated using linear mixed modelling in a cohort of 590 cognitively normal older adults enrolled in the Australian Imaging, Biomarkers and Lifestyle Study. Results: No independent effect of Spondin-1 rs11023139 on cognitive decline was observed. However, significant associations were observed for the interaction between Apolipoprotein E (APOE) ɛ4 and rs11023139 in individuals with high amyloid-β burden. APOE ɛ4/rs11023139-A carriers declined significantly faster than APOE ɛ4/rs11023139-G_G carriers in measures of global cognition (p = 0.011) and verbal episodic memory (p = 0.020). Conclusion: These results suggest that carriage of the Spondin-1 rs11023139-A allele significantly contributes to a worsening of cognitive performance in APOE ɛ4 cognitively normal older adults with a high neocortical amyloid-β burden.
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- 2021
5. Androgen receptor CAG repeat length as a moderator of the relationship between free testosterone levels and cognition
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Tan, S., Porter, T., Bucks, R.S., Weinborn, M., Milicic, L., Brown, A., Rainey-Smith, S.R., Taddei, K., Ames, D., Masters, C.L., Maruff, P., Savage, G., Rowe, C.C., Villemagne, V.L., Brown, B., Sohrabi, H.R., Laws, S.M., Martins, R.N., Tan, S., Porter, T., Bucks, R.S., Weinborn, M., Milicic, L., Brown, A., Rainey-Smith, S.R., Taddei, K., Ames, D., Masters, C.L., Maruff, P., Savage, G., Rowe, C.C., Villemagne, V.L., Brown, B., Sohrabi, H.R., Laws, S.M., and Martins, R.N.
- Abstract
Age-related decrease in testosterone levels is a potential risk factor for cognitive decline in older men. However, observational studies and clinical trials have reported inconsistent results on the effects of testosterone on individual cognitive domains. Null findings may be attributed to factors that studies have yet to consider. In particular, individual variations in polyglutamine (CAG) length in the androgen receptor (AR) gene could alter androgenic activity in brain regions associated with cognitive processes including memory and executive functions. However, the role of AR CAG repeat length as a moderator of the relationship between testosterone levels and cognition has not been investigated. Therefore, we aimed to examine the relationship between baseline calculated free testosterone (cFT) levels, change in cFT levels over 18 months and CAG repeat length on cognitive performance in memory, executive function, language, attention and processing speed domains. These relationships were examined in 304 cognitively normal older male participants of the Australian Imaging, Biomarkers and Lifestyle (AIBL) Study of Ageing. In the attention and processing speed domain, a short CAG repeat length appears to exacerbate the effects of low baseline cFT levels that are also lower than expected at follow-up. These results highlight that individual variations in AR CAG repeat length should be considered in future studies and clinical trials that examine the complex relationship between testosterone and cognition.
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- 2021
6. Relationship between nicotinic receptors and cognitive function in early Alzheimer’s disease: A 2-[ 18F]fluoro-A-85380 PET study
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Ellis, J.R., Villemagne, V.L., Nathan, P.J., Mulligan, R.S., Gong, S.J., Chan, J.G., Sachinidis, J., O’Keefe, G.J., Pathmaraj, K., Wesnes, K.A., Savage, G., and Rowe, C.C.
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- 2008
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7. Aβ deposits in older non-demented individuals with cognitive decline are indicative of preclinical Alzheimer's disease
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Villemagne, V.L., Pike, K.E., Darby, D., Maruff, P., Savage, G., Ng, S., Ackermann, U., Cowie, T.F., Currie, J., Chan, S.G., Jones, G., Tochon-Danguy, H., O’Keefe, G., Masters, C.L., and Rowe, C.C.
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- 2008
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8. 11C-PiB PET studies in typical sporadic Creutzfeldt-Jakob disease
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Villemagne, V.L., McLean, C.A., Reardon, K., Boyd, A., Lewis, V., Klug, G., Jones, G., Baxendale, D., Masters, C.L., Rowe, C.C., and Collins, S.J.
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Creutzfeldt-Jakob disease -- Development and progression ,Creutzfeldt-Jakob disease -- Diagnosis ,Creutzfeldt-Jakob disease -- Research ,PET imaging -- Analysis ,Biological markers -- Research ,Health ,Psychology and mental health - Published
- 2009
9. Amyloid load in Parkinson's disease dementia and Lewy body dementia measured with [11C]PIB positron emission tomography
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Edison, P., Rowe, C.C., Rinne, J.O., Ng, S., Ahmed, I., Kemppainen, N., Villemagne, V.L., O'Keefe, G., Nagren, K., Chaudhury, K.R., Masters, C.L., and Brooks, D.J.
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Parkinson's disease -- Diagnosis ,Parkinson's disease -- Research ,Lewy body disease -- Diagnosis ,Lewy body disease -- Research ,PET imaging -- Usage ,Glycoproteins -- Measurement ,Health ,Psychology and mental health - Published
- 2008
10. Plasma high density lipoprotein small subclass is reduced in Alzheimer’s disease patients and correlates with cognitive performance
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Pedrini, S., Hone, E., Gupta, V.B., James, I., Teimouri, E., Bush, A.I., Rowe, C.C., Villemagne, V.L., Ames, D., Masters, C.L., Rainey-Smith, S., Verdile, G., Sohrabi, H.R., Raida, M.R., Wenk, M.R., Taddei, K., Chatterjee, P., Martins, I., Laws, S.M., Martins, R.N., Pasinetti, G., Pedrini, S., Hone, E., Gupta, V.B., James, I., Teimouri, E., Bush, A.I., Rowe, C.C., Villemagne, V.L., Ames, D., Masters, C.L., Rainey-Smith, S., Verdile, G., Sohrabi, H.R., Raida, M.R., Wenk, M.R., Taddei, K., Chatterjee, P., Martins, I., Laws, S.M., Martins, R.N., and Pasinetti, G.
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Background: The link between cholesterol and Alzheimer’s disease (AD) has received much attention, as evidence suggests high levels of cholesterol might be an AD risk factor. The carriage of cholesterol and lipids through the body is mediated via lipoproteins, some of which, particularly apolipoprotein E (ApoE), are intimately linked with AD. In humans, high density lipoprotein (HDL) is regarded as a “good” lipid complex due to its ability to enable clearance of excess cholesterol via ‘cholesterol reverse transport’, although its activities in the pathogenesis of AD are poorly understood. There are several subclasses of HDL; these range from the newly formed small HDL, to much larger HDL. Objective: We examined the major subclasses of HDL in healthy controls, mild cognitively impaired, and AD patients who were not taking statins to determine whether there were HDL profile differences between the groups, and whether HDL subclass levels correlated with plasma amyloid-β (Aβ) levels or brain Aβ deposition. Methods: Samples from AIBL cohort were used in this study. HDL subclass levels were assessed by Lipoprint while Aβ1–42 levels were assessed by ELISA. Brain Aβ deposition was assessed by PET scan. Statistical analysis was performed using parametric and non-parametric tests. Results: We found that small HDL subclass is reduced in AD patients and it correlates with cognitive performance while plasma Aβ concentrations do not correlate with lipid profile or HDL subfraction levels. Conclusion: Our data indicate that AD patients exhibit altered plasma HDL profile and that HDL subclasses correlate with cognitive performances.
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- 2020
11. Comorbidity of cerebrovascular and Alzheimer’s disease in aging
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Xia, Y., Yassi, N., Raniga, P., Bourgeat, P., Desmond, P., Doecke, J., Ames, D., Laws, S.M., Fowler, C., Rainey-Smith, S.R., Martins, R., Maruff, P., Villemagne, V.L., Masters, C.L., Rowe, C.C., Fripp, J., Salvado, O., Xia, Y., Yassi, N., Raniga, P., Bourgeat, P., Desmond, P., Doecke, J., Ames, D., Laws, S.M., Fowler, C., Rainey-Smith, S.R., Martins, R., Maruff, P., Villemagne, V.L., Masters, C.L., Rowe, C.C., Fripp, J., and Salvado, O.
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Background:Cerebrovascular disease often coexists with Alzheimer’s disease (AD). While both diseases share common risk factors, their interrelationship remains unclear. Increasing the understanding of how cerebrovascular changes interact with AD is essential to develop therapeutic strategies and refine biomarkers for early diagnosis. Objective:We investigate the prevalence and risk factors for the comorbidity of amyloid-β (Aβ) and cerebrovascular disease in the Australian Imaging, Biomarkers and Lifestyle Study of Ageing, and further examine their cross-sectional association. Methods:A total of 598 participants (422 cognitively normal, 89 with mild cognitive impairment, 87 with AD) underwent positron emission tomography and structural magnetic resonance imaging for assessment of Aβ deposition and cerebrovascular disease. Individuals were categorized based on the comorbidity status of Aβ and cerebrovascular disease (V) as Aβ–V–, Aβ–V+, Aβ+V–, or Aβ+V+. Results:Advancing age was associated with greater likelihood of cerebrovascular disease, high Aβ load and their comorbidity. Apolipoprotein E ɛ4 carriage was only associated with Aβ positivity. Greater total and regional WMH burden were observed in participants with AD. However, no association were observed between Aβ and WMH measures after stratification by clinical classification, suggesting that the observed association between AD and cerebrovascular disease was driven by the common risk factor of age. Conclusion:Our observations demonstrate common comorbid condition of Aβ and cerebrovascular disease in later life. While our study did not demonstrate a convincing cross-sectional association between Aβ and WMH burden, future longitudinal studies are required to further confirm this.
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- 2020
12. Evaluation of GammaH2AX in Buccal Cells as a molecular biomarker of DNA damage in Alzheimer’s Disease in the AIBL study of ageing
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Siddiqui, M.S., François, M., Rainey-Smith, S., Martins, R., Masters, C.L., Ames, D., Rowe, C.C., Macaulay, L.S., Fenech, M.F., Leifert, W.R., Siddiqui, M.S., François, M., Rainey-Smith, S., Martins, R., Masters, C.L., Ames, D., Rowe, C.C., Macaulay, L.S., Fenech, M.F., and Leifert, W.R.
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In response to double-stranded breaks (DSBs) in chromosomal DNA, H2AX (a member of histone H2A family) becomes phosphorylated to form γH2AX. Although increased levels of γH2AX have been reported in the neuronal nuclei of Alzheimer’s disease (AD) patients, the understanding of γH2AX responses in buccal nuclei of individuals with mild cognitive impairment (MCI) and AD remain unexplored. In the current study, endogenous γH2AX was measured in buccal cell nuclei from MCI (n = 18) or AD (n = 16) patients and in healthy controls (n = 17) using laser scanning cytometry (LSC). The γH2AX level was significantly elevated in nuclei of the AD group compared to the MCI and control group, and there was a concomitant increase in P-trend for γH2AX from the control group through MCI to the AD group. Receiver-operating characteristic curves were carried out for different γH2AX parameters; γH2AX in nuclei resulted in the greatest area under the curve value of 0.7794 (p = 0.0062) with 75% sensitivity and 70% specificity for the identification of AD patients from control. In addition, nuclear circularity (a measure of irregular nuclear shape) was significantly higher in the buccal cell nuclei from the AD group compared with the MCI and control groups. Additionally, there was a positive correlation between the nuclear circularity and γH2AX signals. The results indicated that increased DNA damage is associated with AD.
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- 2020
13. Association of β-amyloid level, clinical progression and longitudinal cognitive change in normal older individuals
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van der Kall, L.M., Truong, T., Burnham, S.C., Doré, V., Mulligan, R.S., Bozinovski, S., Lamb, F., Bourgeat, P., Fripp, J., Schultz, S., Lim, Y.Y., Laws, S.M., Ames, D., Fowler, C., Rainey-Smith, S.R., Martins, R.N., Salvado, O., Robertson, J., Maruff, P., Masters, C.L., Villemagne, V.L., Rowe, C.C., van der Kall, L.M., Truong, T., Burnham, S.C., Doré, V., Mulligan, R.S., Bozinovski, S., Lamb, F., Bourgeat, P., Fripp, J., Schultz, S., Lim, Y.Y., Laws, S.M., Ames, D., Fowler, C., Rainey-Smith, S.R., Martins, R.N., Salvado, O., Robertson, J., Maruff, P., Masters, C.L., Villemagne, V.L., and Rowe, C.C.
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Objective To determine the effect of β-amyloid (Aβ) level on progression risk to mild cognitive impairment (MCI) or dementia and longitudinal cognitive change in cognitively normal (CN) older individuals. Methods All CN from the Australian Imaging Biomarkers and Lifestyle study with Aβ PET and ≥3 years follow-up were included (n = 534; age 72 ± 6 years; 27% Aβ positive; follow-up 5.3 ± 1.7 years). Aβ level was divided using the standardized 0–100 Centiloid scale: <15 CL negative, 15–25 CL uncertain, 26–50 CL moderate, 51–100 CL high, >100 CL very high, noting >25 CL approximates a positive scan. Cox proportional hazards analysis and linear mixed effect models were used to assess risk of progression and cognitive decline. Results Aβ levels in 63% were negative, 10% uncertain, 10% moderate, 14% high, and 3% very high. Fifty-seven (11%) progressed to MCI or dementia. Compared to negative Aβ, the hazard ratio for progression for moderate Aβ was 3.2 (95% confidence interval [CI] 1.3–7.6; p < 0.05), for high was 7.0 (95% CI 3.7–13.3; p < 0.001), and for very high was 11.4 (95% CI 5.1–25.8; p < 0.001). Decline in cognitive composite score was minimal in the moderate group (−0.02 SD/year, p = 0.05), while the high and very high declined substantially (high −0.08 SD/year, p < 0.001; very high −0.35 SD/year, p < 0.001). Conclusion The risk of MCI or dementia over 5 years in older CN is related to Aβ level on PET, 5% if negative vs 25% if positive but ranging from 12% if 26–50 CL to 28% if 51–100 CL and 50% if >100 CL. This information may be useful for dementia risk counseling and aid design of preclinical AD trials.
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- 2020
14. Reduced posterior cingulate binding of I-123 iodo-dexetimide to muscarinic receptors in mild Alzheimer’s disease
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Boundy, K.L., Barnden, L.R., Katsifis, A.G., and Rowe, C.C.
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- 2005
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15. Imaginem oblivionis: the prospects of neuroimaging for early detection of Alzheimer's disease
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Villemagne, Victor L., Rowe, C.C., Macfarlane, S., Novakovic, K.E., and Masters, C.L.
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- 2005
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16. COMT val158met is not associated with Aβ-amyloid and APOE ε4 related cognitive decline in cognitively normal older adults
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Porter, T., Burnham, S.C., Milicic, L., Savage, G., Maruff, P., Sohrabi, H.R., Peretti, M., Lim, Y.Y., Weinborn, M., Ames, D., Masters, C.L., Martins, R.N., Rainey-Smith, S., Rowe, C.C., Salvado, O., Groth, D., Verdile, G., Villemagne, V.L., Laws, S.M., Porter, T., Burnham, S.C., Milicic, L., Savage, G., Maruff, P., Sohrabi, H.R., Peretti, M., Lim, Y.Y., Weinborn, M., Ames, D., Masters, C.L., Martins, R.N., Rainey-Smith, S., Rowe, C.C., Salvado, O., Groth, D., Verdile, G., Villemagne, V.L., and Laws, S.M.
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The non-synonymous single nucleotide polymorphism (SNP), Val158Met within the Catechol-O-methyltransferase (COMT) gene has been associated with altered levels of cognition and memory performance in cognitively normal adults. This study aimed to investigate the independent and interactional effects of COMT Val158Met on cognitive performance. In particular, it was hypothesised that COMT Val158Met would modify the effect of neocortical Aβ-amyloid (Aβ) accumulation and carriage of the apolipoprotein E (APOE) ε4 allele on cognition in preclinical Alzheimer’s disease (AD). In 598 cognitively normal older adults with known neocortical Aβ levels, linear mixed modelling revealed no significant independent or interactional associations between COMT Val158Met and cognitive decline. These findings do not support previous associations between COMT Val158Met and cognitive performance and suggest this variant does not influence Aβ-amyloid or APOE ε4 driven cognitive decline in a well characterised cohort of cognitively normal older adults.
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- 2019
17. Rates of age‐ and amyloid β‐associated cortical atrophy in older adults with superior memory performance
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Dang, C., Yassi, N., Harrington, K.D., Xia, Y., Lim, Y.Y., Ames, D., Laws, S.M., Hickey, M., Rainey‐Smith, S., Sohrabi, H.R., Doecke, J.D., Fripp, J., Salvado, O., Snyder, P.J., Weinborn, M., Villemagne, V.L., Rowe, C.C., Masters, C.L., Maruff, P., Chambers, B., Chiu, E., Clarnette, R., Darby, D., Davison, M., Drago, J., Drysdale, P., Gilbert, J., Lim, K., Lautenschlager, N., LoGiudice, D., McCardle, P., McFarlane, S., Mander, A., Merory, J., O'Connor, D., Scholes, R., Samuel, M., Trivedi, D., Woodward, M., Dang, C., Yassi, N., Harrington, K.D., Xia, Y., Lim, Y.Y., Ames, D., Laws, S.M., Hickey, M., Rainey‐Smith, S., Sohrabi, H.R., Doecke, J.D., Fripp, J., Salvado, O., Snyder, P.J., Weinborn, M., Villemagne, V.L., Rowe, C.C., Masters, C.L., Maruff, P., Chambers, B., Chiu, E., Clarnette, R., Darby, D., Davison, M., Drago, J., Drysdale, P., Gilbert, J., Lim, K., Lautenschlager, N., LoGiudice, D., McCardle, P., McFarlane, S., Mander, A., Merory, J., O'Connor, D., Scholes, R., Samuel, M., Trivedi, D., and Woodward, M.
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Introduction Superior cognitive performance in older adults may reflect underlying resistance to age‐associated neurodegeneration. While elevated amyloid β (Aβ) deposition (Aβ+) has been associated with increased cortical atrophy, it remains unknown whether “SuperAgers” may be protected from Aβ‐associated neurodegeneration. Methods Neuropsychologically defined SuperAgers (n = 172) and cognitively normal for age (n = 172) older adults from the Australian Imaging, Biomarkers and Lifestyle study were case matched. Rates of cortical atrophy over 8 years were examined by SuperAger classification and Aβ status. Results Of the case‐matched SuperAgers and cognitively normal for age older adults, 40.7% and 40.1%, respectively, were Aβ+. Rates of age‐ and Aβ‐associated atrophy did not differ between the groups on any measure. Aβ− individuals displayed the slowest rates of atrophy. Discussion Maintenance of superior memory in late life does not reflect resistance to age‐ or Aβ‐associated atrophy. However, those individuals who reached old age without cognitive impairment nor elevated Aβ deposition (i.e. Aβ−) displayed reduced rates of cortical atrophy.
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- 2019
18. Klotho allele status is not associated with Aβ and APOE ε4–related cognitive decline in preclinical Alzheimer's disease
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Porter, T., Burnham, S.C., Milicic, L., Savage, G., Maruff, P., Lim, Y.Y., Ames, D., Masters, C.L., Martins, R.N., Rainey-Smith, S., Rowe, C.C., Salvado, O., Groth, D., Verdile, G., Villemagne, V.L., Laws, S.M., Porter, T., Burnham, S.C., Milicic, L., Savage, G., Maruff, P., Lim, Y.Y., Ames, D., Masters, C.L., Martins, R.N., Rainey-Smith, S., Rowe, C.C., Salvado, O., Groth, D., Verdile, G., Villemagne, V.L., and Laws, S.M.
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The longevity gene Klotho (KL), specifically the functional KL-VS variant, has previously been associated with cognition and rates of cognitive decline. This study aimed to determine whether KL-VS associations with cognition were observable in preclinical Alzheimer's disease (AD). The study also aimed to determine whether there was a combined influence of KL-VS, neocortical amyloid-β (Aβ) burden, and carriage of the apolipoprotein E (APOE) ε4 allele on cognitive decline. This study involved 581 Aβ-imaged, cognitively normal older adults, enrolled in the Australian Imaging, Biomarkers and Lifestyle Study of Aging. Linear mixed effects models revealed no significant associations between KL-VS and cognitive decline independently or in combination with Aβ burden and APOE ε4 genotype. Overall, previous associations reported between KL-VS and cognitive decline are not observed at the preclinical stages of AD. Furthermore, the results do not support the hypothesis that KL-VS has a modifying effect on Aβ burden and APOE ε4–driven cognitive decline in preclinical AD.
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- 2019
19. Validation of a priori candidate Alzheimer’s disease SNPs with brain amyloid-beta deposition
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Vacher, M., Porter, T., Villemagne, V.L., Milicic, L., Peretti, M., Fowler, C., Martins, R., Rainey-Smith, S., Ames, D., Masters, C.L., Rowe, C.C., Doecke, J.D., Laws, S.M., Vacher, M., Porter, T., Villemagne, V.L., Milicic, L., Peretti, M., Fowler, C., Martins, R., Rainey-Smith, S., Ames, D., Masters, C.L., Rowe, C.C., Doecke, J.D., and Laws, S.M.
- Abstract
The accumulation of brain amyloid β (Aβ) is one of the main pathological hallmarks of Alzheimer’s disease (AD). However, the role of brain amyloid deposition in the development of AD and the genetic variants associated with this process remain unclear. In this study, we sought to identify associations between Aβ deposition and an a priori evidence based set of 1610 genetic markers, genotyped from 505 unrelated individuals (258 Aβ+ and 247 Aβ−) enrolled in the Australian Imaging, Biomarker & Lifestyle (AIBL) study. We found statistically significant associations for 6 markers located within intronic regions of 6 genes, including AC103796.1-BDNF, PPP3R1, NGFR, KL, ABCA7 & CALHM1. Although functional studies are required to elucidate the role of these genes in the accumulation of Aβ and their potential implication in AD pathophysiology, our findings are consistent with results obtained in previous GWAS efforts.
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- 2019
20. Patterns of postictal cerebral blood flow in temporal lobe epilepsy: Qualitative and quantitative analysis
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Rowe, C.C., Berkovic, S.F., Austin, M.C., McKay, W.J., and Bladin, P.F.
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Seizures (Medicine) -- Physiological aspects ,Cerebral circulation -- Measurement ,Temporal lobe epilepsy -- Physiological aspects ,Health ,Psychology and mental health - Abstract
When epilepsy is both severe and unresponsive to medication, the last resort for treatment may be the surgical removal of the focus, the part of the brain where the epileptic seizure originates. Of course, the success of the method requires a precise determination of the location of the focus. The preliminary evaluation of the patient invariably includes electroencephalography (EEG). In many cases, electrophysiological abnormalities found by the EEG indicate a spot likely to be an epileptic focus. In some cases, however, the EEG findings are not conclusive. It is often necessary, therefore, to surgically implant electrodes for more precise evaluation before the surgical treatment itself can be planned. Researchers have now shown that some patients may be spared the implantation of electrodes in the brain by using the SPECT imaging technique. SPECT, or single-photon emission tomography, creates images of the distribution of radioactive tracer molecules in the brain. Radioactive tracer molecules may be chosen which reflect the circulation of blood within the brain. Since the brain is constantly altering its own circulation to meet the changing needs of different parts, the location of an epileptic focus may be visualized by observing corresponding changes in blood flow. In 83 percent of the 78 epileptic patients studied, an specific increase in blood flow could be observed during or shortly after a seizure. In 80 percent of the patients, there was also a depression of blood flow in much of the temporal lobe outside of the actual focus itself. This may provide a trap for the unwary; a quick look at the SPECT image might suggest that the opposite side of the brain is experiencing an increase in blood flow, but this illusion is created by the depression of blood flow on the same side as the focus. SPECT data is, in itself, inadequate for the determination of the location of an epileptic focus. However, if the determination made by SPECT coincides with the determination made by EEG, it may be possible to spare the patient the implantation of electrodes. It is thought that as many as half of all temporal lobe epilepsy patients facing surgery may be spared the implantation of electrodes using this procedure. (Consumer Summary produced by Reliance Medical Information, Inc.)
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- 1991
21. Mediterranean diet adherence and rate of cerebral Aβ-amyloid accumulation: Data from the Australian Imaging, Biomarkers and Lifestyle Study of Ageing
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Rainey-Smith, S.R. Gu, Y. Gardener, S.L. Doecke, J.D. Villemagne, V.L. Brown, B.M. Taddei, K. Laws, S.M. Sohrabi, H.R. Weinborn, M. Ames, D. Fowler, C. Macaulay, S.L. Maruff, P. Masters, C.L. Salvado, O. Rowe, C.C. Scarmeas, N. Martins, R.N.
- Abstract
Accumulating research has linked Mediterranean diet (MeDi) adherence with slower cognitive decline and reduced Alzheimer’s disease (AD) risk. However, no study to-date has examined the relationship between MeDi adherence and accumulation of cerebral Aβ-amyloid (Aβ; a pathological hallmark of AD) in older adults. Cognitively normal healthy control participants of the Australian Imaging, Biomarkers and Lifestyle (AIBL) Study of Ageing completed the Cancer Council of Victoria Food Frequency Questionnaire at baseline, which was used to construct a MeDi score for each participant (score range 0–9; higher score indicating higher adherence). Cerebral Aβ load was quantified by Pittsburgh Compound B positron emission tomography at baseline, 18 and 36 months: Only individuals categorised as “Aβ accumulators”, and thus considered to be on the AD pathway, were included in the analysis (N = 77). The relationship between MeDi adherence, MeDi components, and change in cerebral Aβ load (baseline to 36 months) was evaluated using Generalised Linear Modelling, accounting for age, gender, education, Apolipoprotein E ε4 allele status, body mass index and total energy intake. Higher MeDi score was associated with less Aβ accumulation in our cohort (β = −0.01 ± 0.004, p = 0.0070). Of the individual MeDi score components, a high intake of fruit was associated with less accumulation of Aβ (β = −0.04 ± 0.01, p = 0.00036). Our results suggest MeDi adherence is associated with reduced cerebral AD pathology accumulation over time. When our results are considered collectively with previous data linking the MeDi to slower cognitive decline, it is apparent that MeDi adherence warrants further investigation in the quest to delay AD onset. © 2018, The Author(s).
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- 2018
22. Association of cerebral amyloid-β Aggregation with cognitive functioning in persons without dementia
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Jansen, W.J. Ossenkoppele, R. Tijms, B.M. Fagan, A.M. Hansson, O. Klunk, W.E. Van Der Flier, W.M. Villemagne, V.L. Frisoni, G.B. Fleisher, A.S. Lleó, A. Mintun, M.A. Wallin, A. Engelborghs, S. Na, D.L. Chételat, G. Molinuevo, J.L. Landau, S.M. Mattsson, N. Kornhuber, J. Sabri, O. Rowe, C.C. Parnetti, L. Popp, J. Fladby, T. Jagust, W.J. Aalten, P. Lee, D.Y. Vandenberghe, R. De Oliveira, C.R. Kapaki, E. Froelich, L. Ivanoiu, A. Gabryelewicz, T. Verbeek, M.M. Sanchez-Juan, P. Hildebrandt, H. Camus, V. Zboch, M. Brooks, D.J. Drzezga, A. Rinne, J.O. Newberg, A. De Mendonça, A. Sarazin, M. Rabinovici, G.D. Madsen, K. Kramberger, M.G. Nordberg, A. Mok, V. Mroczko, B. Wolk, D.A. Meyer, P.T. Tsolaki, M. Scheltens, P. Verhey, F.R.J. Visser, P.J. Aarsland, D. Alcolea, D. Alexander, M. Almdahl, I.S. Arnold, S.E. Baldeiras, I. Barthel, H. Van Berckel, B.N.M. Blennow, K. Van Buchem, M.A. Cavedo, E. Chen, K. Chipi, E. Cohen, A.D. Förster, S. Fortea, J. Frederiksen, K.S. Freund-Levi, Y. Gkatzima, O. Gordon, M.F. Grimmer, T. Hampel, H. Hausner, L. Hellwig, S. Herukka, S.-K. Johannsen, P. Klimkowicz-Mrowiec, A. Köhler, S. Koglin, N. Van Laere, K. De Leon, M. Lisetti, V. Maier, W. Marcusson, J. Meulenbroek, O. Møllergård, H.M. Morris, J.C. Nordlund, A. Novak, G.P. Paraskevas, G.P. Perera, G. Peters, O. Ramakers, I.H.G.B. Rami, L. Rodríguez-Rodríguez, E. Roe, C.M. Rot, U. Rüther, E. Santana, I. Schröder, J. Seo, S.W. Sorininen, H. Spiru, L. Stomrud, E. Struyfs, H. Teunissen, C.E. Vos, S.J.B. Van Waalwijk Van Doorn, L.J.C. Waldemar, G. Wallin, Å.K. Wiltfang, J. Zetterberg, H. Amyloid Biomarker Study Group
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mental disorders - Abstract
IMPORTANCE Cerebral amyloid-β aggregation is an early event in Alzheimer disease (AD). Understanding the association between amyloid aggregation and cognitive manifestation in persons without dementia is important for a better understanding of the course of AD and for the design of prevention trials. OBJECTIVE To investigate whether amyloid-β aggregation is associated with cognitive functioning in persons without dementia. DESIGN, SETTING, AND PARTICIPANTS This cross-sectional study included 2908 participants with normal cognition and 4133 with mild cognitive impairment (MCI) from 53 studies in the multicenter Amyloid Biomarker Study. Normal cognition was defined as having no cognitive concerns for which medical help was sought and scores within the normal range on cognitive tests. Mild cognitive impairment was diagnosed according to published criteria. Study inclusion began in 2013 and is ongoing. Data analysis was performed in January 2017. MAIN OUTCOMES AND MEASURES Global cognitive performance as assessed by the Mini-Mental State Examination (MMSE) and episodic memory performance as assessed by a verbal word learning test. Amyloid aggregation was measured with positron emission tomography or cerebrospinal fluid biomarkers and dichotomized as negative (normal) or positive (abnormal) according to study-specific cutoffs. Generalized estimating equations were used to examine the association between amyloid aggregation and low cognitive scores (MMSE score≤27 or memory z score≤-1.28) and to assess whether this association was moderated by age, sex, educational level, or apolipoprotein E genotype. RESULTS Among 2908 persons with normal cognition (mean [SD] age, 67.4 [12.8] years), amyloid positivity was associated with low memory scores after age 70 years (mean difference in amyloid positive vs negative, 4%[95%CI, 0%-7%] at 72 years and 21% [95%CI, 10%-33%] at 90 years) but was not associated with low MMSE scores (mean difference, 3%[95%CI, -1%to 6%], P = .16). Among 4133 patients with MCI (mean [SD] age, 70.2 [8.5] years), amyloid positivity was associated with low memory (mean difference, 16%[95%CI, 12%-20%], P < .001) and low MMSE (mean difference, 14%[95%CI, 12%-17%], P < .001) scores, and this association decreased with age. Low cognitive scores had limited utility for screening of amyloid positivity in persons with normal cognition and those with MCI. In persons with normal cognition, the age-related increase in low memory score paralleled the age-related increase in amyloid positivity with an intervening period of 10 to 15 years. CONCLUSIONS AND RELEVANCE Although low memory scores are an early marker of amyloid positivity, their value as a screening measure for early AD among persons without dementia is limited.
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- 2018
23. Three probiotic strains exert different effects on plasma bile acid profiles in healthy obese adults: randomised, double-blind placebo-controlled crossover study
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Culpepper, T., primary, Rowe, C.C., additional, Rusch, C.T., additional, Burns, A.M., additional, Federico, A.P., additional, Girard, S.-A., additional, Tompkins, T.A., additional, Nieves, C., additional, Dennis-Wall, J.C., additional, Christman, M.C., additional, and Langkamp-Henken, B., additional
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- 2019
- Full Text
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24. APPLICATION OF THE NIA-AA RESEARCH FRAMEWORK: TOWARDS A BIOLOGICAL DEFINITION OF ALZHEIMER’S DISEASE USING CEREBROSPINAL FLUID BIOMARKERS IN THE AIBL STUDY
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Burnham, S.C, primary, Coloma, P.M., additional, Li, Q.-X., additional, Collins, S., additional, Savage, G., additional, Laws, S., additional, Doecke, J., additional, Maruff, P., additional, Martins, R.N., additional, Ames, D., additional, Rowe, C.C., additional, Masters, C.L., additional, and Villemagne, V.L., additional
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- 2019
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25. Mediterranean diet adherence and rate of cerebral Aβ-amyloid accumulation: Data from the Australian Imaging, Biomarkers and Lifestyle Study of Ageing
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Rainey-Smith, S.R., Gu, Y., Gardener, S.L., Doecke, J.D., Villemagne, V.L., Brown, B.M., Taddei, K., Laws, S.M., Sohrabi, H.R., Weinborn, M., Ames, D., Fowler, C., Macaulay, S.L., Maruff, P., Masters, C.L., Salvado, O., Rowe, C.C., Scarmeas, N., Martins, R.N., Rainey-Smith, S.R., Gu, Y., Gardener, S.L., Doecke, J.D., Villemagne, V.L., Brown, B.M., Taddei, K., Laws, S.M., Sohrabi, H.R., Weinborn, M., Ames, D., Fowler, C., Macaulay, S.L., Maruff, P., Masters, C.L., Salvado, O., Rowe, C.C., Scarmeas, N., and Martins, R.N.
- Abstract
Accumulating research has linked Mediterranean diet (MeDi) adherence with slower cognitive decline and reduced Alzheimer's disease (AD) risk. However, no study to-date has examined the relationship between MeDi adherence and accumulation of cerebral Aβ-amyloid (Aβ; a pathological hallmark of AD) in older adults. Cognitively normal healthy control participants of the Australian Imaging, Biomarkers and Lifestyle (AIBL) Study of Ageing completed the Cancer Council of Victoria Food Frequency Questionnaire at baseline, which was used to construct a MeDi score for each participant (score range 0-9; higher score indicating higher adherence). Cerebral Aβ load was quantified by Pittsburgh Compound B positron emission tomography at baseline, 18 and 36 months: Only individuals categorised as "Aβ accumulators", and thus considered to be on the AD pathway, were included in the analysis (N = 77). The relationship between MeDi adherence, MeDi components, and change in cerebral Aβ load (baseline to 36 months) was evaluated using Generalised Linear Modelling, accounting for age, gender, education, Apolipoprotein E ε4 allele status, body mass index and total energy intake. Higher MeDi score was associated with less Aβ accumulation in our cohort (β = -0.01 ± 0.004, p = 0.0070). Of the individual MeDi score components, a high intake of fruit was associated with less accumulation of Aβ (β = -0.04 ± 0.01, p = 0.00036). Our results suggest MeDi adherence is associated with reduced cerebral AD pathology accumulation over time. When our results are considered collectively with previous data linking the MeDi to slower cognitive decline, it is apparent that MeDi adherence warrants further investigation in the quest to delay AD onset.
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- 2018
26. Self-reported physical activity is associated with Tau Burden measured by Positron Emission Tomography
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Brown, B.M., Rainey-Smith, S.R., Dore, V., Peiffer, J.J., Burnham, S.C., Laws, S.M., Taddei, K., Ames, D., Masters, C.L., Rowe, C.C., Martins, R.N., Villemagne, V.L., Cristina Polidori, M., Brown, B.M., Rainey-Smith, S.R., Dore, V., Peiffer, J.J., Burnham, S.C., Laws, S.M., Taddei, K., Ames, D., Masters, C.L., Rowe, C.C., Martins, R.N., Villemagne, V.L., and Cristina Polidori, M.
- Abstract
Numerous animal studies have reported exercise reduces the accumulation of Alzheimer’s disease pathology, including amyloid-β (Aβ) and tau. Furthermore, we previously reported a relationship between higher levels of physical activity (PA) and lower brain Aβ burden in a human population. The recent advent of tau positron emission tomography (PET) tracers enables us to extend our investigations into the evaluation of the relationship between PA and brain tau burden. Utilizing data from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study, we have examined the cross-sectional relationship between habitual PA and PET-quantified tau burden. Forty-three cognitively healthy older adults were categorized into low-moderate PA (LMPA; n = 16) or high PA (HPA; n = 27), based on self-reported PA levels. Tau PET imaging with the AV1451 tracer was conducted on all participants. The LMPA group had significantly higher neocortical tau burden (presented as a z-score; 1.22±1.98), compared to the HPA group (z-score: – 0.28±1.18). The difference between the LMPA and HPA groups was also evident when examining regional tau burden in the temporoparietal cortex and the prefrontal cortex. Our results suggest an association between self-reported PA level and brain tau burden. Future longitudinal and interventional studies utilizing larger samples sizes are vital to further investigate the nature of the relationship between tau and PA.
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- 2018
27. Alzheimer’s disease: A journey from amyloid peptides and oxidative stress, to biomarker technologies and disease prevention strategies—gains from AIBL and DIAN cohort studies
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Martins, R.N., Villemagne, V., Sohrabi, H.R., Chatterjee, P., Shah, T.M., Verdile, G., Fraser, P., Taddei, K., Gupta, V.B., Rainey-Smith, S.R., Hone, E., Pedrini, S., Lim, W.L., Martins, I., Frost, S., Gupta, S., O’Bryant, S., Rembach, A., Ames, D., Ellis, K., Fuller, S.J., Brown, B., Gardener, S.L., Fernando, B., Bharadwaj, P., Burnham, S., Laws, S.M., Barron, A.M., Goozee, K., Wahjoepramono, E.J., Asih, P.R., Doecke, J.D., Salvado, O., Bush, A.I., Rowe, C.C., Gandy, S.E., Masters, C.L., Perry, G., Avila, J., Zhu, X., Martins, R.N., Villemagne, V., Sohrabi, H.R., Chatterjee, P., Shah, T.M., Verdile, G., Fraser, P., Taddei, K., Gupta, V.B., Rainey-Smith, S.R., Hone, E., Pedrini, S., Lim, W.L., Martins, I., Frost, S., Gupta, S., O’Bryant, S., Rembach, A., Ames, D., Ellis, K., Fuller, S.J., Brown, B., Gardener, S.L., Fernando, B., Bharadwaj, P., Burnham, S., Laws, S.M., Barron, A.M., Goozee, K., Wahjoepramono, E.J., Asih, P.R., Doecke, J.D., Salvado, O., Bush, A.I., Rowe, C.C., Gandy, S.E., Masters, C.L., Perry, G., Avila, J., and Zhu, X.
- Abstract
Worldwide there are over 46 million people living with dementia, and this number is expected to double every 20 years reaching about 131 million by 2050. The cost to the community and government health systems, as well as the stress on families and carers is incalculable. Over three decades of research into this disease have been undertaken by several research groups in Australia, including work by our original research group in Western Australia which was involved in the discovery and sequencing of the amyloid-β peptide (also known as Aβ or A4 peptide) extracted from cerebral amyloid plaques. This review discusses the journey from the discovery of the Aβ peptide in Alzheimer’s disease (AD) brain to the establishment of pre-clinical AD using PET amyloid tracers, a method now serving as the gold standard for developing peripheral diagnostic approaches in the blood and the eye. The latter developments for early diagnosis have been largely achieved through the establishment of the Australian Imaging Biomarker and Lifestyle research group that has followed 1,100 Australians for 11 years. AIBL has also been instrumental in providing insight into the role of the major genetic risk factor apolipoprotein E ɛ4, as well as better understanding the role of lifestyle factors particularly diet, physical activity and sleep to cognitive decline and the accumulation of cerebral Aβ.
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- 2018
28. Genetic variation in Aquaporin-4 moderates the relationship between sleep and brain Aβ-amyloid burden
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Rainey-Smith, S.R., Mazzucchelli, G.N., Villemagne, V.L., Brown, B.M., Porter, T., Weinborn, M., Bucks, R.S., Milicic, L., Sohrabi, H.R., Taddei, K., Ames, D., Maruff, P., Masters, C.L., Rowe, C.C., Salvado, O., Martins, R.N., Laws, S.M., Rainey-Smith, S.R., Mazzucchelli, G.N., Villemagne, V.L., Brown, B.M., Porter, T., Weinborn, M., Bucks, R.S., Milicic, L., Sohrabi, H.R., Taddei, K., Ames, D., Maruff, P., Masters, C.L., Rowe, C.C., Salvado, O., Martins, R.N., and Laws, S.M.
- Abstract
The glymphatic system is postulated to be a mechanism of brain Aβ-amyloid clearance and to be most effective during sleep. Ablation of the astrocytic end-feet expressed water-channel protein, Aquaporin-4, in mice, results in impairment of this clearance mechanism and increased brain Aβ-amyloid deposition, suggesting that Aquaporin-4 plays a pivotal role in glymphatic function. Currently there is a paucity of literature regarding the impact of AQP4 genetic variation on sleep, brain Aβ-amyloid burden and their relationship to each other in humans. To address this a cross-sectional observational study was undertaken in cognitively normal older adults from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. Genetic variants in AQP4 were investigated with respect to self-reported Pittsburgh Sleep Quality Index sleep parameters, positron emission tomography derived brain Aβ-amyloid burden and whether these genetic variants moderated the sleep-Aβ-amyloid burden relationship. One AQP4 variant, rs72878776, was associated with poorer overall sleep quality, while several SNPs moderated the effect of sleep latency (rs491148, rs9951307, rs7135406, rs3875089, rs151246) and duration (rs72878776, rs491148 and rs2339214) on brain Aβ-amyloid burden. This study suggests that AQP4 genetic variation moderates the relationship between sleep and brain Aβ-amyloid burden, which adds weight to the proposed glymphatic system being a potential Aβ-amyloid clearance mechanism and suggests that AQP4 genetic variation may impair this function. Further, AQP4 genetic variation should be considered when interpreting sleep-Aβ relationships.
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- 2018
29. Associations of dietary protein and fiber intake with brain and blood amyloid-β
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Fernando, W.M.A.D.B., Rainey-Smith, S.R., Gardener, S.L., Villemagne, V.L., Burnham, S.C., Macaulay, S.L., Brown, B.M., Gupta, V.B., Sohrabi, H.R., Weinborn, M., Taddei, K., Laws, S.M., Goozee, K., Ames, D., Fowler, C., Maruff, P., Masters, C.L., Salvado, O., Rowe, C.C., Martins, R.N., Fernando, W.M.A.D.B., Rainey-Smith, S.R., Gardener, S.L., Villemagne, V.L., Burnham, S.C., Macaulay, S.L., Brown, B.M., Gupta, V.B., Sohrabi, H.R., Weinborn, M., Taddei, K., Laws, S.M., Goozee, K., Ames, D., Fowler, C., Maruff, P., Masters, C.L., Salvado, O., Rowe, C.C., and Martins, R.N.
- Abstract
Accumulating evidence suggests a diet high in protein and fiber may confer some protection against Alzheimer’s disease (AD). However, no human studies to-date have assessed the relationship between protein and fiber intake, and plasma and brain amyloid-β (Aβ). Consequently, this cross-sectional study, investigated the association of self-reported dietary intakes of protein and fiber, with plasma and brain Aβ burden (n = 541, and n = 162 respectively), in a well-characterized cohort of cognitively normal older adults, drawn from the larger Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging. We observed 12.59 and 8.43 higher odds of ‘high’ brain Aβ burden (PiB PET SUVR≥1.5) if protein intake fell in the lowest and middle tertile, respectively, compared to the highest tertile (p = 0.008; p = 0.013). Thus, in this cohort, the more protein consumed, the less likelihood of ‘high’ Aβ burden in the brain. No other significant associations were observed. The results of this study highlight the potentially protective impact of high dietary protein intake on brain Aβ burden in older adults, before objective memory decline is apparent. While longitudinal validation is required, these findings may assist in the development of dietary approaches aimed at preventing or delaying AD onset.
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- 2018
30. Estimates of age-related memory decline are inflated by unrecognized Alzheimer's disease
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Harrington, K.D., Schembri, A., Lim, Y.Y., Dang, C., Ames, D., Hassenstab, J., Laws, S.M., Rainey-Smith, S., Robertson, J., Rowe, C.C., Sohrabi, H.R., Salvado, O., Weinborn, M., Villemagne, V.L., Masters, C.L., Maruff, P., Harrington, K.D., Schembri, A., Lim, Y.Y., Dang, C., Ames, D., Hassenstab, J., Laws, S.M., Rainey-Smith, S., Robertson, J., Rowe, C.C., Sohrabi, H.R., Salvado, O., Weinborn, M., Villemagne, V.L., Masters, C.L., and Maruff, P.
- Abstract
Cognitive decline is considered an inevitable consequence of aging; however, estimates of cognitive aging may be influenced negatively by undetected preclinical Alzheimer's disease (AD). This study aimed to determine the extent to which estimates of cognitive aging were biased by preclinical AD. Cognitively normal older adults (n = 494) with amyloid-β status determined from positron emission tomography neuroimaging underwent serial neuropsychological assessment at 18-month intervals over 72 months. Estimates of the effects of age on verbal memory, working memory, executive function, and processing speed were derived using linear mixed models. The presence of preclinical AD and clinical progression to mild cognitive impairment or dementia during the study were then added to these models as covariates. Initially, age was associated with decline across all 4 cognitive domains. With the effects of elevated amyloid-β and clinical progression controlled, age was no longer associated with decline in verbal or working memory. However, the magnitude of decline was reduced only slightly for executive function and was unchanged for processing speed. Thus, considered together, the results of the study indicate that undetected preclinical AD negatively biases estimates of age-related cognitive decline for verbal and working memory.
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- 2018
31. Superior memory reduces 8-year risk of mild cognitive impairment and dementia but not amyloid β-associated cognitive decline in older adults
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Dang, C., Harrington, K.D., Lim, Y.Y., Ames, D., Hassenstab, J., Laws, S.M., Yassi, N., Hickey, M., Rainey-Smith, S.R., Robertson, J., Rowe, C.C., Sohrabi, H.R., Salvado, O., Weinborn, M., Villemagne, V.L., Masters, C.L., Maruff, P., Dang, C., Harrington, K.D., Lim, Y.Y., Ames, D., Hassenstab, J., Laws, S.M., Yassi, N., Hickey, M., Rainey-Smith, S.R., Robertson, J., Rowe, C.C., Sohrabi, H.R., Salvado, O., Weinborn, M., Villemagne, V.L., Masters, C.L., and Maruff, P.
- Abstract
Objective To prospectively examine 8-year risk of clinical disease progression to mild cognitive impairment (MCI)/dementia in older adults ≥60 with superior episodic memory (SuperAgers) compared to those cognitively normal for their age (CNFA). Additionally, to determine the extent to which SuperAgers were resilient to the negative effects of elevated amyloid-beta (Aβ+) on cognition. Method Participants were classified as SuperAgers based on episodic memory performance consistent with younger adults aged 30–44 and no impairment on non-memory tests (n = 179), and were matched with CNFA on age, sex, education, and follow-up time (n = 179). Subdistribution hazard models examined risk of clinical progression to MCI/dementia. Linear mixed models assessed the effect of Aβ on cognition over time. Results Prevalence of Aβ+ and APOE ε4 was equivalent between SuperAgers and CNFA. SuperAgers had 69%–73% reduced risk of clinical progression to MCI/dementia compared to CNFA (HR: 0.27–0.31, 95% CI: 0.11–0.73, p < .001). Aβ+ was associated with cognitive decline in verbal memory and executive function, regardless of SuperAger/CNFA classification. In the absence of Aβ+, equivalent age-related changes in cognition were observed between SuperAgers and CNFA. Conclusions SuperAgers displayed resilience against clinical progression to MCI/dementia compared to CNFA despite equivalent risk for Alzheimer’s disease (AD); however, SuperAgers had no greater protection from Aβ+ than CNFA. The deleterious effects of Aβ on cognition persist regardless of baseline cognitive ability. Thus, superior cognitive performance does not reflect resistance against the neuropathological processes associated with AD, and the observed resilience for SuperAgers may instead reflect neuropsychological criteria for cognitive impairment.
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- 2018
32. Relationship between amyloid-β positivity and progression to mild cognitive impairment or dementia over 8 years in cognitively normal older adults
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Dang, C., Harrington, K.D., Lim, Y.Y., Ames, D., Hassenstab, J., Laws, S.M., Yassi, N., Hickey, M., Rainey-Smith, S., Robertson, J., Sohrabi, H.R., Salvado, O., Weinborn, M., Villemagne, V.L., Rowe, C.C., Masters, C.L., Maruff, Paul, Dang, C., Harrington, K.D., Lim, Y.Y., Ames, D., Hassenstab, J., Laws, S.M., Yassi, N., Hickey, M., Rainey-Smith, S., Robertson, J., Sohrabi, H.R., Salvado, O., Weinborn, M., Villemagne, V.L., Rowe, C.C., Masters, C.L., and Maruff, Paul
- Abstract
Background: Preclinical Alzheimer’s disease (AD) is defined by cerebral amyloid-β positivity (Aβ+) in cognitively normal (CN) older adults. Objective:To estimate the risk of progression to the symptomatic stages of AD due to PET Aβ+ and the extent that progression was influenced by other demographic, genetic, and clinical characteristics in a large prospective study. Methods: Fine-Gray subdistribution modeling was used to examine the risk of progression from CN to MCI/dementia due to Aβ+, APOE ɛ4 carriage, and their interaction in the Australian Imaging, Biomarkers and Lifestyle (AIBL) flagship study of aging CN cohort (n = 599) over 8 years. Results: 17.7% Aβ+ and 8.1% Aβ–progressed over 8 years (OR: 2.43). Risk of progression for Aβ+ was 65–104% greater than Aβ–. Aβ+ APOE ɛ4 carriers were at 348% greater risk than all other participants. Significant risk factors of progression in Aβ+ were age (HR: 1.05), PET SUVR (HR: 2.49) and APOE ɛ4 carriage (HR: 2.63); only age was a significant risk factor in Aβ–(HR: 1.09). Aβ–progressors were not near the threshold for Aβ+. These relationships were not moderated by hypertension, diabetes, obesity, or stroke/TIA. Conclusion: Aβ+ is an important prognostic marker for progression from CN to MCI/dementia in older adults and APOE ɛ4 carriage provides further predictive value in the presence of Aβ+. These data suggest that Aβ-associated clinical progression is consistent with clinical-pathological models of AD, whereas progression in the absence of elevated Aβ deposition may be the result of neuropathological processes other than AD that accumulate with age.
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- 2018
33. Amyloid burden and incident depressive symptoms in preclinical Alzheimer’s disease
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Perin, S., Harrington, K.D., Lim, Y.Y., Ellis, K., Ames, D., Pietrzak, R.H., Schembri, A., Rainey-Smith, S., Salvado, O., Laws, S.M., Martins, R.N., Villemagne, V.L., Rowe, C.C., Masters, C.L., Maruff, P., Perin, S., Harrington, K.D., Lim, Y.Y., Ellis, K., Ames, D., Pietrzak, R.H., Schembri, A., Rainey-Smith, S., Salvado, O., Laws, S.M., Martins, R.N., Villemagne, V.L., Rowe, C.C., Masters, C.L., and Maruff, P.
- Abstract
Background Relationships between depression and Alzheimer's disease (AD) may become clearer if studied in preclinical AD where dementia is not present. Method The aim of this study was to evaluate prospectively, relationships between brain amyloid-β (Aβ), depressive symptoms and screen positive depression in cognitively normal (CN) older adults. Depressive symptoms were measured with the Geriatric Depression Inventory (GDS-15) in CN adults from the Australian Imaging Biomarkers and Lifestyle (AIBL) study without depression at baseline and classified as having abnormally high (Aβ+; n = 136) or low (Aβ−; n = 449) Aβ according to positron emission tomography at 18-month intervals over 72 months. Results Incident cases of screen positive depression were not increased in Aβ+ CN adults although small increases in overall depressive symptoms severity (d = − 0.25; 95% CI, − 0.45, − 0.05) and apathy-anxiety symptoms (d = − 0.28; 95% CI − 0.48, − 0.08) were. Limitations As the AIBL sample is an experimental sample, no individuals had severe medical illnesses or significant psychiatric disorders. Additionally, individuals who had evidence of screen-positive depression at screening were excluded from enrolment in the AIBL study. Thus, the current data can be considered only as providing a foundation for understanding relationships between Aβ and depression in preclinical AD. Conclusions These results suggest that the presence of a depressive disorder or even increased depressive symptoms are themselves unlikely to be a direct consequence of increasing Aβ. New depressive disorders presenting in CN older adults could therefore be investigated for aetiologies beyond AD.
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- 2018
34. Association of β-Amyloid and Apolipoprotein E ε4 with memory decline in preclinical Alzheimer disease
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Lim, Y.Y., Kalinowski, P., Pietrzak, R.H., Laws, S.M., Burnham, S.C., Ames, D., Villemagne, V.L., Fowler, C.J., Rainey-Smith, S.R., Martins, R.N., Rowe, C.C., Masters, C.L., Maruff, P.T., Lim, Y.Y., Kalinowski, P., Pietrzak, R.H., Laws, S.M., Burnham, S.C., Ames, D., Villemagne, V.L., Fowler, C.J., Rainey-Smith, S.R., Martins, R.N., Rowe, C.C., Masters, C.L., and Maruff, P.T.
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Importance: Older age, high levels of β-amyloid (Aβ), and the presence of the apolipoprotein E (APOE) ε4 allele are risk factors for Alzheimer disease (AD). However, the extent to which increasing age, Aβ, and ε4 are associated with memory decline remains unclear, and the age at which memory decline begins for Aβ-positive ε4 carriers and noncarriers has not been determined. Objective: To determine the association of age, Aβ level, and APOE ε4 with memory decline in a large group of cognitively healthy older adults. Design, setting, and participants: This longitudinal observational study included cognitively healthy older adults (age >60 years) enrolled in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study from March 31, 2006, through March 31, 2017; of 1583 individuals enrolled, 1136 refused or were excluded owing to other criteria (eg, having mild cognitive impairment or AD). Participants underwent Aβ imaging in research clinics in Perth and Melbourne and more than 72 months of follow-up (at 18-month intervals). The association of age with memory was fitted to a quadratic model. Age was treated as a continuous, time-dependent variable. Exposures: β-Amyloid imaging using positron emission tomography, genotyping for APOE ɛ4, and longitudinal neuropsychological assessments of episodic memory during the 72-month follow-up. Main outcomes and measures: Episodic memory composite score. Results: Of the 447 participants, 203 (45.4%) were men and 244 (54.6%) were women; mean (SD) age was 72.5 (6.6) years. Equal proportions of female participants were observed in each Aβ-ɛ4 group (24 of 51 Aβ-positive ε4 noncarriers [47.1%] ; 35 of 64 Aβ-negative ε4 carriers [54.7%]; 40 of 72 Aβ-positive ε4 carriers [55.6%]; and 145 of 260 Aβ-negative ε4 noncarriers [55.8%]). Adults with Aβ findings (mean [SD] age, 74.4 [6.8] years) were approximately 4 years older than those negative for Aβ (mean [SD] age, 69.8 [6.1] years). Memory decline diverged significantly from Aβ-negative ɛ
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- 2018
35. Cognitive gene risk profile for the prediction of cognitive decline in presymptomatic Alzheimer’s disease
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Porter, T., Villemagne, V.L., Savage, G., Milicic, L., Ying Lim, Y.Y., Maruff, P., Masters, C.L., Ames, D., Bush, A.I., Martins, R.N., Rainey-Smith, S., Rowe, C.C., Taddei, K., Groth, D., Verdile, G., Burnham, S.C., Laws, S.M., Porter, T., Villemagne, V.L., Savage, G., Milicic, L., Ying Lim, Y.Y., Maruff, P., Masters, C.L., Ames, D., Bush, A.I., Martins, R.N., Rainey-Smith, S., Rowe, C.C., Taddei, K., Groth, D., Verdile, G., Burnham, S.C., and Laws, S.M.
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Introduction In cognitively normal (CN) older adults, high levels of Aβ-amyloid are associated with significant decline in cognition, especially episodic memory. Several genes have previously been associated with cognition, including APOE, KIBRA, KLOTHO, BDNF, COMT, SPON1 and CSMD1. While some of this variation has been attributed to some of these genes individually, the combined effects of these genes on rates of cognitive decline, particularly in preclinical Alzheimer’s Disease remain largely unknown. Methods To elucidate if risk alleles within these genes can be suitably combined to predict cognitive decline 127 CN older adults with elevated PET-ascertained Aβ-amyloid were included in a decision tree analysis to define a “Cognitive Gene Risk Profile” for decline in a verbal episodic memory composite. Results The episodic memory-derived Cognitive Gene Risk Profile defined four groups: APOE ε4+ Risk, ε4+ Resilient, ε4− Risk, ε4− Resilient, with the ε4+ Risk group declining significantly faster than all other groups (ε4+ Resilient, p = 0.0008; ε4− Risk, p = 0.025; ε4− Resilient, p = 0.0006). The ε4+ Risk group also declined significantly faster than all other groups on Global, Clinical Progression and Pre-Alzheimer’s cognitive composites. Discussion The defined Cognitive Gene Risk Profile has potential utility in participant selection/stratification for preclinical AD trials that incorporate Aβ-amyloid and where decline in cognition is essential to determine therapeutic effectiveness.
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- 2018
36. The effect of preclinical Alzheimer's disease on age-related changes in intelligence in cognitively normal older adults
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Harrington, K.D., Dang, C., Lim, Y.Y., Ames, D., Laws, S.M., Pietrzak, R.H., Rainey-Smith, S., Robertson, J., Rowe, C.C., Salvado, O., Villemagne, V.L., Masters, C.L., Maruff, P., Harrington, K.D., Dang, C., Lim, Y.Y., Ames, D., Laws, S.M., Pietrzak, R.H., Rainey-Smith, S., Robertson, J., Rowe, C.C., Salvado, O., Villemagne, V.L., Masters, C.L., and Maruff, P.
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Background It is possible that estimates of normal age-related decline in intellectual function have been biased negatively by undetected preclinical Alzheimer's disease (AD). This prospective study aimed to determine the nature and magnitude of changes in crystallized and fluid intelligence, as well as their relationship to one another, in normal aging, taking into account the effects of preclinical AD. Methods Cognitively normal older adults (n = 494) aged between 60 and 84 years underwent serial assessment of fluid and crystallized intelligence at 18-month intervals over 72 months and PET neuroimaging for the presence of abnormal amyloid-β (Aβ+; n = 184). The effects of age and Aβ + on changes in fluid and crystallized intelligence were analysed using linear mixed models. An intelligence discrepancy score was developed from linear regression analysis of the extent to which fluid intelligence could be predicted from crystallized intelligence. The predictive validity of the intelligence discrepancy score for Aβ status or clinical disease progression was evaluated. Results Relative to the Aβ- group, the Aβ + group showed greater age-related decline on fluid, but not crystallized, intelligence. The intelligence discrepancy score predicted progression to clinically recognized disease (i.e., mild cognitive impairment or dementia), but was unrelated to Aβ status. Conclusions Preclinical AD is associated with more rapid age-related decline in fluid, but not crystallized, intelligence. Accordingly, a discrepancy between fluid and crystallized intelligence does indicate risk of progression to early AD.
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- 2018
37. KIBRA is associated with accelerated cognitive decline and hippocampal atrophy in APOE ε4-positive cognitively normal adults with high Aβ-amyloid burden
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Porter, T., Burnham, S.C., Doré, V., Savage, G., Bourgeat, P., Begemann, K., Milicic, L., Ames, D., Bush, A.I., Maruff, P., Masters, C.L., Rowe, C.C., Rainey-Smith, S., Martins, R.N., Groth, D., Verdile, G., Villemagne, V.L., Laws, S.M., Porter, T., Burnham, S.C., Doré, V., Savage, G., Bourgeat, P., Begemann, K., Milicic, L., Ames, D., Bush, A.I., Maruff, P., Masters, C.L., Rowe, C.C., Rainey-Smith, S., Martins, R.N., Groth, D., Verdile, G., Villemagne, V.L., and Laws, S.M.
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A single nucleotide polymorphism, rs17070145, in the KIdney and BRAin expressed protein (KIBRA) gene has been associated with cognition and hippocampal volume in cognitively normal (CN) individuals. However, the impact of rs17070145 on longitudinal cognitive decline and hippocampal atrophy in CN adults at greatest risk of developing Alzheimer’s disease is unknown. We investigated the impact rs17070145 has on the rate of cognitive decline and hippocampal atrophy over six years in 602 CN adults, with known brain Aβ-amyloid levels and whether there is an interactive effect with APOE genotype. We reveal that whilst limited independent effects of KIBRA genotype were observed, there was an interaction with APOE in CN adults who presented with high Aβ-amyloid levels across study duration. In comparison to APOE ε4-ve individuals carrying the rs17070145-T allele, significantly faster rates of cognitive decline (global, p = 0.006; verbal episodic memory, p = 0.004), and hippocampal atrophy (p = 0.04) were observed in individuals who were APOE ε4 + ve and did not carry the rs17070145-T allele. The observation of APOE effects in only non-carriers of the rs17070145-T allele, in the presence of high Aβ-amyloid suggest that carriers of the rs17070145-T allele are conferred a level of resilience to the detrimental effects of high Aβ-amyloid and APOE ε4.
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- 2018
38. Utility of an Alzheimer’s disease risk-weighted polygenic risk score for predicting rates of cognitive decline in preclinical Alzheimer’s disease: A prospective longitudinal study
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Porter, T., Burnham, S.C., Milicic, L., Savage, G., Maruff, P., Lim, Y.Y., Li, Q-X, Ames, D., Masters, C.L., Rainey-Smith, S., Rowe, C.C., Salvado, O., Groth, D., Verdile, G., Villemagne, V.L., Laws, S.M., Porter, T., Burnham, S.C., Milicic, L., Savage, G., Maruff, P., Lim, Y.Y., Li, Q-X, Ames, D., Masters, C.L., Rainey-Smith, S., Rowe, C.C., Salvado, O., Groth, D., Verdile, G., Villemagne, V.L., and Laws, S.M.
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Background:With the exception of APOE, genetic variants associated with increased Alzheimer’s disease (AD) risk are characterized by small effect sizes. Polygenic risk scores (PRS) have shown utility in predicting AD risk; however, their utility for predicting decline in cognition at preclinical stages of AD is poorly understood. Objective:To validate associations of a 22-variant AD-risk-weighted PRS with AD risk and related biomarkers and to assess its utility to predict cognitive decline. Methods:The PRS was evaluated with respect to brain amyloid-β (Aβ) burden, cerebrospinal fluid (CSF) Aβ42, total-tau, and phospho-tau, and decline in cognition in 643 (570 cognitively normal (CN), 73 AD) PET-imaged participants from the longitudinal Australian Imaging, Biomarkers and Lifestyle (AIBL) Study of Ageing. Cognition was assessed using three composite measures; global cognition, verbal episodic memory, and a Pre-Alzheimer’s Cognitive Composite (PACC). Results:PRS, both with and without APOE, were positively correlated with brain Aβ burden, CSF total-tau, and phospho-tau in CN older adults. Further, in CN biomarker positive (Aβhigh) participants, significant associations were observed with baseline and longitudinal cognition. However, this association was not observed after the removal of APOE. Partitioning the PRS into quartiles revealed that the PRS associations with cognitive decline in Aβhigh CN older adults is due to a saturating effect of APOE genotype. Conclusions:An AD-risk-weighted PRS is associated with cognitive decline in CN older adults. However, this association is absent when APOE genotype is excluded from the PRS, suggesting that associations with cognitive decline in this model of polygenic risk are driven by APOE genotype alone. Further research is needed to define appropriate PRSs with greater utility for predicting preclinical AD cognitive decline.
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- 2018
39. A polygenic risk score derived from episodic memory weighted genetic variants is associated with cognitive decline in preclinical Alzheimer’s disease
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Porter, T., Burnham, S.C., Savage, G., Lim, Y.Y., Maruff, P., Milicic, L., Peretti, M., Ames, D., Masters, C.L., Martins, R.N., Rainey-Smith, S., Rowe, C.C., Salvado, O., Taddei, K., Groth, D., Verdile, G., Villemagne, V.L., Laws, S.M., Porter, T., Burnham, S.C., Savage, G., Lim, Y.Y., Maruff, P., Milicic, L., Peretti, M., Ames, D., Masters, C.L., Martins, R.N., Rainey-Smith, S., Rowe, C.C., Salvado, O., Taddei, K., Groth, D., Verdile, G., Villemagne, V.L., and Laws, S.M.
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Studies of Alzheimer’s disease risk-weighted polygenic risk scores (PRSs) for cognitive performance have reported inconsistent associations. This inconsistency is particularly evident when PRSs are assessed independent of APOE genotype. As such, the development and assessment of phenotype-specific weightings to derive PRSs for cognitive decline in preclinical AD is warranted. To this end a episodic memory-weighted PRS (emPRS) was derived and assessed against decline in cognitive performance in 226 healthy cognitively normal older adults with high brain Aβ-amyloid burden participants from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. The effect size for decline in a verbal episodic memory was determined individually for 27 genetic variants in a reference sample (n = 151). These were then summed to generate a emPRS either including APOE (emPRSc¯APOE) or excluding APOE (emPRSs¯APOE). Resultant emPRS were then evaluated, in a test sample (n = 75), against decline in global cognition, verbal episodic memory and a pre-Alzheimer’s cognitive composite (AIBL-PACC) over 7.5 years. The mean (SD) age of the 226 participants was 72.2 (6.6) years and 116 (51.3%) were female. Reference and test samples did not differ significantly demographically. Whilst no association of emPRSs were observed with baseline cognition, the emPRSc¯APOE was associated with longitudinal global cognition (-0.237, P = 0.0002), verbal episodic memory (-0.259, P = 0.00003) and the AIBL-PACC (-0.381, P = 0.02). The emPRSs¯APOE was also associated with global cognition (-0.169, P = 0.021) and verbal episodic memory (-0.208, P = 0.004). Stratification by APOE ε4 revealed that the association between the emPRS and verbal episodic memory was limited to carriage of no ε4 or one ε4 allele. This was also observed for global cognition. The emPRS and rates of decline in AIBL-PACC were associated in those carrying one ε4 allele. Overall, the described novel emPRS has utility for the prediction of dec
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- 2018
40. Prevalence of the apolipoprotein E epsilon4 allele in amyloid beta positive subjects across the spectrum of Alzheimer's disease
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Mattsson, N., Groot, C. de, Jansen, W.J., Landau, S.M., Villemagne, V.L., Engelborghs, S., Mintun, M.M., Lleo, A., Molinuevo, J.L., Jagust, W.J., Frisoni, G.B., Ivanoiu, A., Chetelat, G., Oliveira, C. de, Rodrigue, K.M., Kornhuber, J., Wallin, A., Klimkowicz-Mrowiec, A., Kandimalla, R., Popp, J., Aalten, P.P., Aarsland, D., Alcolea, D., Almdahl, I.S., Baldeiras, I., Buchem, M.A. van, Cavedo, E., Chen, K., Cohen, A.D., Forster, S., Fortea, J., Frederiksen, K.S., Freund-Levi, Y., Gill, K.D., Gkatzima, O., Grimmer, T., Hampel, H., Herukka, S.K., Johannsen, P., Laere, K. Van, Leon, M.J. de, Maier, W., Marcusson, J., Meulenbroek, O.V., Mollergard, H.M., Morris, J.C., Mroczko, B., Nordlund, A., Prabhakar, S., Peters, O., Rami, L., Rodriguez-Rodriguez, E., Roe, C.M., Ruther, E., Santana, I., Schroder, J., Seo, S.W., Soininen, H., Spiru, L., Stomrud, E., Struyfs, H., Teunissen, C.E., Verhey, F.R.J., Vos, S.J.B., Waalwijk van Doorn, L.L.C. van, Waldemar, G., Wallin, A.K., Wiltfang, J., Vandenberghe, R., Brooks, D.J., Fladby, T., Rowe, C.C., Drzezga, A., Verbeek, M.M., Sarazin, M., Wolk, D.A., Fleisher, A.S., Klunk, W.E., Na, D.L., Sanchez-Juan, P., Lee, D.Y., Nordberg, A., Tsolaki, M., Camus, V., Rinne, J.O., Fagan, A.M., Zetterberg, H., Blennow, K., Rabinovici, G.D., Hansson, O., Berckel, B.N. van, Flier, W.M. van der, Scheltens, P., Visser, P.J., Ossenkoppele, R., Mattsson, N., Groot, C. de, Jansen, W.J., Landau, S.M., Villemagne, V.L., Engelborghs, S., Mintun, M.M., Lleo, A., Molinuevo, J.L., Jagust, W.J., Frisoni, G.B., Ivanoiu, A., Chetelat, G., Oliveira, C. de, Rodrigue, K.M., Kornhuber, J., Wallin, A., Klimkowicz-Mrowiec, A., Kandimalla, R., Popp, J., Aalten, P.P., Aarsland, D., Alcolea, D., Almdahl, I.S., Baldeiras, I., Buchem, M.A. van, Cavedo, E., Chen, K., Cohen, A.D., Forster, S., Fortea, J., Frederiksen, K.S., Freund-Levi, Y., Gill, K.D., Gkatzima, O., Grimmer, T., Hampel, H., Herukka, S.K., Johannsen, P., Laere, K. Van, Leon, M.J. de, Maier, W., Marcusson, J., Meulenbroek, O.V., Mollergard, H.M., Morris, J.C., Mroczko, B., Nordlund, A., Prabhakar, S., Peters, O., Rami, L., Rodriguez-Rodriguez, E., Roe, C.M., Ruther, E., Santana, I., Schroder, J., Seo, S.W., Soininen, H., Spiru, L., Stomrud, E., Struyfs, H., Teunissen, C.E., Verhey, F.R.J., Vos, S.J.B., Waalwijk van Doorn, L.L.C. van, Waldemar, G., Wallin, A.K., Wiltfang, J., Vandenberghe, R., Brooks, D.J., Fladby, T., Rowe, C.C., Drzezga, A., Verbeek, M.M., Sarazin, M., Wolk, D.A., Fleisher, A.S., Klunk, W.E., Na, D.L., Sanchez-Juan, P., Lee, D.Y., Nordberg, A., Tsolaki, M., Camus, V., Rinne, J.O., Fagan, A.M., Zetterberg, H., Blennow, K., Rabinovici, G.D., Hansson, O., Berckel, B.N. van, Flier, W.M. van der, Scheltens, P., Visser, P.J., and Ossenkoppele, R.
- Abstract
Item does not contain fulltext, INTRODUCTION: Apolipoprotein E (APOE) epsilon4 is the major genetic risk factor for Alzheimer's disease (AD), but its prevalence is unclear because earlier studies did not require biomarker evidence of amyloid beta (Abeta) pathology. METHODS: We included 3451 Abeta+ subjects (853 AD-type dementia, 1810 mild cognitive impairment, and 788 cognitively normal). Generalized estimating equation models were used to assess APOE epsilon4 prevalence in relation to age, sex, education, and geographical location. RESULTS: The APOE epsilon4 prevalence was 66% in AD-type dementia, 64% in mild cognitive impairment, and 51% in cognitively normal, and it decreased with advancing age in Abeta+ cognitively normal and Abeta+ mild cognitive impairment (P < .05) but not in Abeta+ AD dementia (P = .66). The prevalence was highest in Northern Europe but did not vary by sex or education. DISCUSSION: The APOE epsilon4 prevalence in AD was higher than that in previous studies, which did not require presence of Abeta pathology. Furthermore, our results highlight disease heterogeneity related to age and geographical location.
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- 2018
41. Association of Cerebral Amyloid-beta Aggregation With Cognitive Functioning in Persons Without Dementia
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Jansen, W.J., Ossenkoppele, R., Tijms, B.M., Fagan, A.M., Hansson, O., Klunk, W.E., Flier, W.M. van der, Villemagne, V.L., Frisoni, G.B., Fleisher, A.S., Lleo, A., Mintun, M.A., Wallin, A., Engelborghs, S., Na, D.L., Chetelat, G., Molinuevo, J.L., Landau, S.M., Mattsson, N., Kornhuber, J., Sabri, O., Rowe, C.C., Parnetti, L., Popp, J., Fladby, T., Jagust, W.J., Aalten, P., Lee, D.Y., Vandenberghe, R., Oliveira, C. de, Kapaki, E., Froelich, L., Ivanoiu, A., Gabryelewicz, T., Verbeek, M.M., Sanchez-Juan, P., Hildebrandt, H., Camus, V., Zboch, M., Brooks, D.J., Drzezga, A., Rinne, J.O., Newberg, A., Mendonca, A. de, Sarazin, M., Rabinovici, G.D., Madsen, K., Kramberger, M.G., Nordberg, A., Mok, V., Mroczko, B., Wolk, D.A., Meyer, P.T., Tsolaki, M., Scheltens, P., Verhey, F.R.J., Visser, P.J., Aarsland, D., Alcolea, D., Alexander, M., Almdahl, I.S., Arnold, S.E., Baldeiras, I., Barthel, H., Berckel, B.N. van, Blennow, K., Buchem, M.A. van, Cavedo, E., Chen, K., Chipi, E., Cohen, A.D., Forster, S., Fortea, J., Frederiksen, K.S., Freund-Levi, Y., Gkatzima, O., Gordon, M.F., Grimmer, T., Hampel, H., Hausner, L., Hellwig, S., Herukka, S.K., Johannsen, P., Klimkowicz-Mrowiec, A., Kohler, S., Koglin, N., Laere, K. Van, Leon, M., Lisetti, V., Maier, W., Marcusson, J., Meulenbroek, O., Mollergard, H.M., Morris, J.C., Nordlund, A., Novak, G.P., Paraskevas, G.P., Perera, G., Peters, O., Ramakers, I., et al., Jansen, W.J., Ossenkoppele, R., Tijms, B.M., Fagan, A.M., Hansson, O., Klunk, W.E., Flier, W.M. van der, Villemagne, V.L., Frisoni, G.B., Fleisher, A.S., Lleo, A., Mintun, M.A., Wallin, A., Engelborghs, S., Na, D.L., Chetelat, G., Molinuevo, J.L., Landau, S.M., Mattsson, N., Kornhuber, J., Sabri, O., Rowe, C.C., Parnetti, L., Popp, J., Fladby, T., Jagust, W.J., Aalten, P., Lee, D.Y., Vandenberghe, R., Oliveira, C. de, Kapaki, E., Froelich, L., Ivanoiu, A., Gabryelewicz, T., Verbeek, M.M., Sanchez-Juan, P., Hildebrandt, H., Camus, V., Zboch, M., Brooks, D.J., Drzezga, A., Rinne, J.O., Newberg, A., Mendonca, A. de, Sarazin, M., Rabinovici, G.D., Madsen, K., Kramberger, M.G., Nordberg, A., Mok, V., Mroczko, B., Wolk, D.A., Meyer, P.T., Tsolaki, M., Scheltens, P., Verhey, F.R.J., Visser, P.J., Aarsland, D., Alcolea, D., Alexander, M., Almdahl, I.S., Arnold, S.E., Baldeiras, I., Barthel, H., Berckel, B.N. van, Blennow, K., Buchem, M.A. van, Cavedo, E., Chen, K., Chipi, E., Cohen, A.D., Forster, S., Fortea, J., Frederiksen, K.S., Freund-Levi, Y., Gkatzima, O., Gordon, M.F., Grimmer, T., Hampel, H., Hausner, L., Hellwig, S., Herukka, S.K., Johannsen, P., Klimkowicz-Mrowiec, A., Kohler, S., Koglin, N., Laere, K. Van, Leon, M., Lisetti, V., Maier, W., Marcusson, J., Meulenbroek, O., Mollergard, H.M., Morris, J.C., Nordlund, A., Novak, G.P., Paraskevas, G.P., Perera, G., Peters, O., and Ramakers, I., et al.
- Abstract
Contains fulltext : 190311.pdf (Publisher’s version ) (Closed access), Importance: Cerebral amyloid-beta aggregation is an early event in Alzheimer disease (AD). Understanding the association between amyloid aggregation and cognitive manifestation in persons without dementia is important for a better understanding of the course of AD and for the design of prevention trials. Objective: To investigate whether amyloid-beta aggregation is associated with cognitive functioning in persons without dementia. Design, Setting, and Participants: This cross-sectional study included 2908 participants with normal cognition and 4133 with mild cognitive impairment (MCI) from 53 studies in the multicenter Amyloid Biomarker Study. Normal cognition was defined as having no cognitive concerns for which medical help was sought and scores within the normal range on cognitive tests. Mild cognitive impairment was diagnosed according to published criteria. Study inclusion began in 2013 and is ongoing. Data analysis was performed in January 2017. Main Outcomes and Measures: Global cognitive performance as assessed by the Mini-Mental State Examination (MMSE) and episodic memory performance as assessed by a verbal word learning test. Amyloid aggregation was measured with positron emission tomography or cerebrospinal fluid biomarkers and dichotomized as negative (normal) or positive (abnormal) according to study-specific cutoffs. Generalized estimating equations were used to examine the association between amyloid aggregation and low cognitive scores (MMSE score =27 or memory z score=-1.28) and to assess whether this association was moderated by age, sex, educational level, or apolipoprotein E genotype. Results: Among 2908 persons with normal cognition (mean [SD] age, 67.4 [12.8] years), amyloid positivity was associated with low memory scores after age 70 years (mean difference in amyloid positive vs negative, 4% [95% CI, 0%-7%] at 72 years and 21% [95% CI, 10%-33%] at 90 years) but was not associated with low MMSE scores (mean difference, 3% [95% CI, -1% to
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- 2018
42. Trajectories of irregular word reading ability as a proxy for premorbid intelligence in Alzheimer’s disease, mild cognitive impairment, and healthy aging: A longitudinal study
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Weinborn, M., Bucks, R.S., Sohrabi, H.R., Rainey-Smith, S.R., Brown, B.M., Gardener, S.L., Gozt, A., Christensen, D., Savage, G., Laws, S.M., Taddei, K., Maruff, P., Robertson, J.S., Ellis, K.A., Ames, D., Masters, C.L., Rowe, C.C., Martins, R.N., Weinborn, M., Bucks, R.S., Sohrabi, H.R., Rainey-Smith, S.R., Brown, B.M., Gardener, S.L., Gozt, A., Christensen, D., Savage, G., Laws, S.M., Taddei, K., Maruff, P., Robertson, J.S., Ellis, K.A., Ames, D., Masters, C.L., Rowe, C.C., and Martins, R.N.
- Abstract
The ability to read irregularly spelled words is commonly used to estimate premorbid intelligence, as this ability has been thought to be resistant to early effects of neurodegenerative disorders. However, studies evaluating decline of this skill in Alzheimer’s disease (AD) have produced conflicting results. Irregular word reading was assessed three times over 36 months in a large (N = 995) sample, including healthy control, AD, and Mild Cognitive Impairment (MCI) groups. At baseline, MCI and AD groups read correctly an average of 3.01 and 7.39 fewer words, respectively, than healthy controls. The MCI group’s performance remained stable during the study, but the AD group declined. Importantly, the observed decline was likely an underestimate, as significant numbers of the AD participants (42.6%) could not complete the task at follow-up. Use of alternate (e.g., demographics-based) methods is advised to augment or replace word pronunciation in estimating premorbid intelligence in individuals with even mild AD.
- Published
- 2018
43. [Accepted Manuscript] Presymptomatic atrophy in autosomal dominant Alzheimer's disease: A serial MRI study
- Author
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Kinnunen, K.M., Cash, D.M., Poole, T., Frost, C., Benzinger, T.L.S., Ahsan, R.L., Leung, K.K., Cardoso, M.J., Modat, M., Malone, I.B., Morris, J.C., Bateman, R.J., Marcus, D.S., Goate, A., Salloway, S., Correia, S., Sperling, R.A., Chhatwal, J.P., Mayeux, R., Brickman, A.M., Martins, R.N., Farlow, M.R., Ghetti, B., Saykin, A.J., Jack, C.R. Jr, Schofield, P.R., McDade, E., Weiner, M.W., Ringman, J.M., Thompson, P.M., Masters, C.L., Rowe, C.C., Rossor, M.N., Ourselin, S., Fox, N.C., and Dominantly Inherited Alzheimer Network (DIAN), .
- Subjects
sense organs ,skin and connective tissue diseases - Abstract
Identifying at what point atrophy rates first change in Alzheimer's disease is important for informing design of presymptomatic trials. Serial T1-weighed magnetic resonance imaging scans of 94 participants (28 noncarriers, 66 carriers) from the Dominantly Inherited Alzheimer Network were used to measure brain, ventricular, and hippocampal atrophy rates. For each structure, nonlinear mixed-effects models estimated the change-points when atrophy rates deviate from normal and the rates of change before and after this point. Atrophy increased after the change-point, which occurred 1-1.5 years (assuming a single step change in atrophy rate) or 3-8 years (assuming gradual acceleration of atrophy) before expected symptom onset. At expected symptom onset, estimated atrophy rates were at least 3.6 times than those before the change-point. Atrophy rates are pathologically increased up to seven years before "expected onset". During this period, atrophy rates may be useful for inclusion and tracking of disease progression.
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- 2017
44. A blood-based biomarker panel indicates IL-10 and IL-12/23p40 are jointly associated as predictors of β-amyloid load in an AD cohort
- Author
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Pedrini, S., Gupta, V.B., Hone, E., Doecke, J., O’Bryant, S., James, I., Bush, A.I., Rowe, C.C., Villemagne, V.L., Ames, D., Masters, C.L., Martins, R.N., Pedrini, S., Gupta, V.B., Hone, E., Doecke, J., O’Bryant, S., James, I., Bush, A.I., Rowe, C.C., Villemagne, V.L., Ames, D., Masters, C.L., and Martins, R.N.
- Abstract
Alzheimer’s Disease (AD) is the most common form of dementia, characterised by extracellular amyloid deposition as plaques and intracellular neurofibrillary tangles of tau protein. As no current clinical test can diagnose individuals at risk of developing AD, the aim of this project is to evaluate a blood-based biomarker panel to identify individuals who carry this risk. We analysed the levels of 22 biomarkers in clinically classified healthy controls (HC), mild cognitive impairment (MCI) and Alzheimer’s participants from the well characterised Australian Imaging, Biomarker and Lifestyle (AIBL) study of aging. High levels of IL-10 and IL-12/23p40 were significantly associated with amyloid deposition in HC, suggesting that these two biomarkers might be used to detect at risk individuals. Additionally, other biomarkers (Eotaxin-3, Leptin, PYY) exhibited altered levels in AD participants possessing the APOE ε4 allele. This suggests that the physiology of some potential biomarkers may be altered in AD due to the APOE ε4 allele, a major risk factor for AD. Taken together, these data highlight several potential biomarkers that can be used in a blood-based panel to allow earlier identification of individuals at risk of developing AD and/or early stage AD for which current therapies may be more beneficial.
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- 2017
45. Increased carbohydrate intake is associated with poorer performance in verbal memory and attention in an APOE genotype-dependent manner
- Author
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Gardener, S.L., Rainey-Smith, S.R., Sohrabi, H.R., Weinborn, M., Verdile, G., Fernando, W.M.A.D.B., Lim, Y.Y., Harrington, KaK.rra, Burnham, S., Taddei, K., Masters, C.L., Macaulay, S.L., Rowe, C.C., Ames, D., Maruff, P., Martins, R.N., O’Bryant, S., Gardener, S.L., Rainey-Smith, S.R., Sohrabi, H.R., Weinborn, M., Verdile, G., Fernando, W.M.A.D.B., Lim, Y.Y., Harrington, KaK.rra, Burnham, S., Taddei, K., Masters, C.L., Macaulay, S.L., Rowe, C.C., Ames, D., Maruff, P., Martins, R.N., and O’Bryant, S.
- Abstract
Evidence suggests that a diet low in carbohydrates can impact on cognitive performance among those with Alzheimer’s disease (AD). However, there is a lack of data assessing this relationship among cognitively normal (CN) older adults at increased future risk of developing AD due to carriage of the apolipoprotein E (APOE) ɛ4 allele. We assessed the cross-sectional association between carbohydrate intake, cognitive performance, and cerebral amyloid-β (Aβ) load in CN older adults, genotyped for APOE ɛ4 allele carrier status. Greater carbohydrate intake was associated with poorer performance in verbal memory in APOE ɛ4 allele non-carriers, and poorer performance in attention in APOE ɛ4 allele carriers. There were no associations between carbohydrate intake and cerebral Aβ load. These results provide support to the idea that decreasing carbohydrate intake may offer neurocognitive benefits, with specific cognitive domains affected in an APOE genotype-dependent manner. These findings warrant further investigation utilizing a longitudinal study design.
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- 2017
46. BDNF Val66Met in preclinical Alzheimer's disease is associated with short-term changes in episodic memory and hippocampal volume but not serum mBDNF
- Author
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Lim, Y.Y., Rainey-Smith, S., Lim, Y., Laws, S.M., Gupta, V., Porter, T., Bourgeat, P., Ames, D., Fowler, C., Salvado, O., Villemagne, V.L., Rowe, C.C., Masters, C.L., Zhou, X.F., Martins, R.N., Maruff, P., Lim, Y.Y., Rainey-Smith, S., Lim, Y., Laws, S.M., Gupta, V., Porter, T., Bourgeat, P., Ames, D., Fowler, C., Salvado, O., Villemagne, V.L., Rowe, C.C., Masters, C.L., Zhou, X.F., Martins, R.N., and Maruff, P.
- Abstract
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.
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- 2017
47. Plasma cortisol, brain Amyloid-β, and cognitive decline in preclinical Alzheimer’s disease: A 6-Year prospective cohort study
- Author
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Pietrzak, R.H., Laws, S.M., Lim, Y.Y., Bender, S. J., Porter, T., Doecke, J., Ames, D., Fowler, C., Masters, C.L., Milicic, L., Rainey-Smith, S., Villemagne, V.L., Rowe, C.C., Martins, R.N., Maruff, P., Pietrzak, R.H., Laws, S.M., Lim, Y.Y., Bender, S. J., Porter, T., Doecke, J., Ames, D., Fowler, C., Masters, C.L., Milicic, L., Rainey-Smith, S., Villemagne, V.L., Rowe, C.C., Martins, R.N., and Maruff, P.
- Abstract
Background Hypothalamic-pituitary-adrenal axis dysregulation, which is typically assessed by measuring cortisol levels, is associated with cognitive dysfunction, hippocampal atrophy, and increased risk for mild cognitive impairment and Alzheimer’s disease (AD). However, little is known about the role of hypothalamic-pituitary-adrenal axis dysregulation in moderating the effect of high levels of amyloid-β (Aβ+) on cognitive decline in the preclinical phase of AD, which is often protracted, and thus offers opportunities for prevention and early intervention. Methods Using data from a 6-year multicenter prospective cohort study, we evaluated the relation between Aβ level, plasma cortisol level, and cognitive decline in 416 cognitively normal older adults. Results Results revealed that Aβ+ older adults experienced faster decline than Aβ− older adults in all cognitive domains (Cohen’s d at 6-year assessment = 0.37–0.65). They further indicated a significant interaction between Aβ and cortisol levels for global cognition (d = 0.32), episodic memory (d = 0.50), and executive function (d = 0.59) scores, with Aβ+ older adults with high cortisol levels having significantly faster decline in these domains compared with Aβ+ older adults with low cortisol levels. These effects were independent of age, sex, APOE genotype, anxiety symptoms, and radiotracer type. Conclusions In cognitively healthy older adults, Aβ+ is associated with greater cognitive decline and high plasma cortisol levels may accelerate the effect of Aβ+ on decline in global cognition, episodic memory, and executive function. These results suggest that therapies targeted toward lowering plasma cortisol and Aβ levels may be helpful in mitigating cognitive decline in the preclinical phase of AD.
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- 2017
48. Amyloid β–associated cognitive decline in the absence of clinical disease progression and systemic illness
- Author
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Harrington, K.D., Lim, Y.Y., Ames, D., Hassenstab, J., Laws, S.M., Martins, R.N., Rainey‐Smith, S., Robertson, J., Rowe, C.C., Salvado, O., Doré, V., Villemagne, V.L., Snyder, P.J., Masters, C.L., Maruff, P., Harrington, K.D., Lim, Y.Y., Ames, D., Hassenstab, J., Laws, S.M., Martins, R.N., Rainey‐Smith, S., Robertson, J., Rowe, C.C., Salvado, O., Doré, V., Villemagne, V.L., Snyder, P.J., Masters, C.L., and Maruff, P.
- Abstract
Introduction High levels of amyloid β (Aβ) are associated with cognitive decline in cognitively normal (CN) older adults. This study investigated the nature of cognitive decline in healthy individuals who did not progress to mild cognitive impairment or dementia. Method Cognition was measured over 72 months and compared between low (Aβ−) and high (Aβ+) CN older adults (n = 335) who did not progress to mild cognitive impairment or dementia and who remained free of severe or uncontrolled systemic illness. Results Compared to the Aβ− group, the Aβ+ group showed no cognitive impairment at baseline but showed substantial decline in verbal learning, episodic memory, and attention over 72 months. Discussion Moderate cognitive decline, particularly for learning and memory, was associated with Aβ+ in CN older adults in the absence of clinical disease progression and uncontrolled or serious comorbid illness.
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- 2017
49. Effect of APOE genotype on amyloid deposition, brain volume, and memory in cognitively normal older individuals
- Author
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Lim, Y.Y., Williamson, R., Laws, S.M., Villemagne, V.L., Bourgeat, P., Fowler, C., Rainey-Smith, S., Salvado, O., Martins, R.N., Rowe, C.C., Masters, C.L., Maruff, P., Lim, Y.Y., Williamson, R., Laws, S.M., Villemagne, V.L., Bourgeat, P., Fowler, C., Rainey-Smith, S., Salvado, O., Martins, R.N., Rowe, C.C., Masters, C.L., and Maruff, P.
- Abstract
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 function, hippocampal volume and Aβ levels in cognitively normal individuals. 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 magnetic resonance imaging 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 Alzheimer’s disease in cognitively normal older adults, likely through a quantitative role in the disruption of Aβ clearance.
- Published
- 2017
50. Trajectories of depressive and anxiety symptoms in older adults: A 6-year prospective cohort study
- Author
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Holmes, S.E., Esterlis, I., Mazure, C.M., Lim, Y.Y., Ames, D., Rainey-Smith, S., Fowler, C., Ellis, K., Martins, R.N., Salvado, O., Doré, V., Villemagne, V.L., Rowe, C.C., Laws, S.M., Masters, C.L., Pietrzak, R.H., Maruff, P., Holmes, S.E., Esterlis, I., Mazure, C.M., Lim, Y.Y., Ames, D., Rainey-Smith, S., Fowler, C., Ellis, K., Martins, R.N., Salvado, O., Doré, V., Villemagne, V.L., Rowe, C.C., Laws, S.M., Masters, C.L., Pietrzak, R.H., and Maruff, P.
- Abstract
Objective: Depressive and anxiety symptoms are common in older adults, significantly affect quality of life, and are risk factors for Alzheimer's disease. We sought to identify the determinants of predominant trajectories of depressive and anxiety symptoms in cognitively normal older adults. Method: Four hundred twenty-three older adults recruited from the general community underwent Aβ positron emission tomography imaging, apolipoprotein and brain-derived neurotrophic factor genotyping, and cognitive testing at baseline and had follow-up assessments. All participants were cognitively normal and free of clinical depression at baseline. Latent growth mixture modeling was used to identify predominant trajectories of subthreshold depressive and anxiety symptoms over 6 years. Binary logistic regression analysis was used to identify baseline predictors of symptomatic depressive and anxiety trajectories. Results: Latent growth mixture modeling revealed two predominant trajectories of depressive and anxiety symptoms: a chronically elevated trajectory and a low, stable symptom trajectory, with almost one in five participants falling into the elevated trajectory groups. Male sex (relative risk ratio (RRR) = 3.23), lower attentional function (RRR = 1.90), and carriage of the brain-derived neurotrophic factor Val66Met allele in women (RRR = 2.70) were associated with increased risk for chronically elevated depressive symptom trajectory. Carriage of the apolipoprotein epsilon 4 allele (RRR = 1.92) and lower executive function in women (RRR = 1.74) were associated with chronically elevated anxiety symptom trajectory. Conclusion: Our results indicate distinct and sex-specific risk factors linked to depressive and anxiety trajectories, which may help inform risk stratification and management of these symptoms in older adults at risk for Alzheimer's disease.
- Published
- 2017
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