Anatomy and Neuroscience - Research Publications

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    Plasma A beta 42/40 ratio, p-tau181, GFAP, and NfL across the Alzheimer's disease continuum: A cross-sectional and longitudinal study in the AIBL cohort
    Chatterjee, P ; Pedrini, S ; Doecke, JD ; Thota, R ; Villemagne, VL ; Dore, V ; Singh, AK ; Wang, P ; Rainey-Smith, S ; Fowler, C ; Taddei, K ; Sohrabi, HR ; Molloy, MP ; Ames, D ; Maruff, P ; Rowe, CC ; Masters, CL ; Martins, RN (WILEY, 2022-07-21)
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    Identification of Leukocyte Surface P2X7 as a Biomarker Associated with Alzheimer's Disease
    Li, Y ; Huang, X ; Fowler, C ; Lim, YY ; Laws, SM ; Faux, N ; Doecke, JD ; Trounson, B ; Pertile, K ; Rumble, R ; Dore, V ; Villemagne, VL ; Rowe, CC ; Wiley, JS ; Maruff, P ; Masters, CL ; Gu, BJ (MDPI, 2022-07-01)
    Alzheimer's disease (AD) has shown altered immune responses in the periphery. We studied P2X7 (a proinflammatory receptor and a scavenger receptor) and two integrins, CD11b and CD11c, on the surface of circulating leukocytes and analysed their associations with Aβ-PET, brain atrophy, neuropsychological assessments, and cerebrospinal fluid (CSF) biomarkers. Total 287 age-matched, sex-balanced participants were recruited in a discovery cohort and two validation cohorts through the AIBL study and studied using tri-colour flow cytometry. Our results demonstrated reduced expressions of P2X7, CD11b, and CD11c on leukocytes, particularly monocytes, in Aβ +ve cases compared with Aβ -ve controls. P2X7 and integrin downregulation was observed at pre-clinical stage of AD and stayed low throughout disease course. We further constructed a polygenic risk score (PRS) model based on 12 P2RX7 risk alleles to assess the genetic impact on P2X7 function in AIBL and ADNI cohorts. No significant association was identified between the P2RX7 gene and AD, indicating that P2X7 downregulation in AD is likely caused by environmental changes rather than genetic factors. In conclusion, the downregulation of P2X7 and integrins at pre-clinical stage of AD indicates altered pro-inflammatory responses, phagocytic functions, and migrating capabilities of circulating monocytes in early AD pathogenesis. Our study not only improves our understanding of peripheral immune involvement in early stage of AD but also provides more insights into novel biomarker development, diagnosis, and prognosis of AD.
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    No Influence of Age-Related Hearing Loss on Brain Amyloid-beta
    Sarant, JZ ; Harris, DC ; Busby, PA ; Fowler, C ; Fripp, J ; Masters, CL ; Maruff, P ; Bendlin, B (IOS PRESS, 2022-01-01)
    BACKGROUND: Hearing loss is independently associated with a faster rate of cognitive decline in older adults and has been identified as a modifiable risk factor for dementia. The mechanism for this association is unknown, and there has been limited exploration of potential casual pathology. OBJECTIVE: Our objective was to investigate whether there was an association between degree of audiometrically measured hearing loss (HL) and brain amyloid-β (Aβ) in a pre-clinical sample. METHODS: Participants of the Australian Imaging and Biomarker Longitudinal Study (AIBL; n = 143) underwent positron emission tomography (PET) imaging and objective measurement of hearing thresholds within 5 years of imaging, as well as cognitive assessment within 2 years of imaging in this observational cohort study. RESULTS: With one exception, study participants who had cognitive assessments within 2 years of their PET imaging (n = 113) were classified as having normal cognition. There was no association between cognitive scores and degree of hearing loss, or between cognitive scores and Aβ load. No association between HL and Aβ load was found once age was controlled for. As previously reported, positive Apolipoprotein E4 (APOE4) carrier status increased the risk of being Aβ positive (p = 0.002). CONCLUSION: Degree of HL was not associated with positive Aβ status.
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    A deep learning framework identifies dimensional representations of Alzheimer's Disease from brain structure
    Yang, Z ; Nasrallah, IM ; Shou, H ; Wen, J ; Doshi, J ; Habes, M ; Erus, G ; Abdulkadir, A ; Resnick, SM ; Albert, MS ; Maruff, P ; Fripp, J ; Morris, JC ; Wolk, DA ; Davatzikos, C (NATURE PORTFOLIO, 2021-12-03)
    Heterogeneity of brain diseases is a challenge for precision diagnosis/prognosis. We describe and validate Smile-GAN (SeMI-supervised cLustEring-Generative Adversarial Network), a semi-supervised deep-clustering method, which examines neuroanatomical heterogeneity contrasted against normal brain structure, to identify disease subtypes through neuroimaging signatures. When applied to regional volumes derived from T1-weighted MRI (two studies; 2,832 participants; 8,146 scans) including cognitively normal individuals and those with cognitive impairment and dementia, Smile-GAN identified four patterns or axes of neurodegeneration. Applying this framework to longitudinal data revealed two distinct progression pathways. Measures of expression of these patterns predicted the pathway and rate of future neurodegeneration. Pattern expression offered complementary performance to amyloid/tau in predicting clinical progression. These deep-learning derived biomarkers offer potential for precision diagnostics and targeted clinical trial recruitment.
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    Higher Coffee Consumption Is Associated With Slower Cognitive Decline and Less Cerebral A beta-Amyloid Accumulation Over 126 Months: Data From the Australian Imaging, Biomarkers, and Lifestyle Study
    Gardener, SL ; Rainey-Smith, SR ; Villemagne, VL ; Fripp, J ; Dore, V ; Bourgeat, P ; Taddei, K ; Fowler, C ; Masters, CL ; Maruff, P ; Rowe, CC ; Ames, D ; Martins, RN ; AIBL, I (FRONTIERS MEDIA SA, 2021-11-19)
    Background: Worldwide, coffee is one of the most popular beverages consumed. Several studies have suggested a protective role of coffee, including reduced risk of Alzheimer's disease (AD). However, there is limited longitudinal data from cohorts of older adults reporting associations of coffee intake with cognitive decline, in distinct domains, and investigating the neuropathological mechanisms underpinning any such associations. Methods: The aim of the current study was to investigate the relationship between self-reported habitual coffee intake, and cognitive decline assessed using a comprehensive neuropsychological battery in 227 cognitively normal older adults from the Australian Imaging, Biomarkers, and Lifestyle (AIBL) study, over 126 months. In a subset of individuals, we also investigated the relationship between habitual coffee intake and cerebral Aβ-amyloid accumulation (n = 60) and brain volumes (n = 51) over 126 months. Results: Higher baseline coffee consumption was associated with slower cognitive decline in executive function, attention, and the AIBL Preclinical AD Cognitive Composite (PACC; shown reliably to measure the first signs of cognitive decline in at-risk cognitively normal populations), and lower likelihood of transitioning to mild cognitive impairment or AD status, over 126 months. Higher baseline coffee consumption was also associated with slower Aβ-amyloid accumulation over 126 months, and lower risk of progressing to "moderate," "high," or "very high" Aβ-amyloid burden status over the same time-period. There were no associations between coffee intake and atrophy in total gray matter, white matter, or hippocampal volume. Discussion: Our results further support the hypothesis that coffee intake may be a protective factor against AD, with increased coffee consumption potentially reducing cognitive decline by slowing cerebral Aβ-amyloid accumulation, and thus attenuating the associated neurotoxicity from Aβ-amyloid-mediated oxidative stress and inflammatory processes. Further investigation is required to evaluate whether coffee intake could be incorporated as a modifiable lifestyle factor aimed at delaying AD onset.
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    Using imputation to provide harmonized longitudinal measures of cognition across AIBL and ADNI
    Shishegar, R ; Cox, T ; Rolls, D ; Bourgeat, P ; Dore, V ; Lamb, F ; Robertson, J ; Laws, SM ; Porter, T ; Fripp, J ; Tosun, D ; Maruff, P ; Savage, G ; Rowe, CC ; Masters, CL ; Weiner, MW ; Villemagne, VL ; Burnham, SC (NATURE PORTFOLIO, 2021-12-10)
    To improve understanding of Alzheimer's disease, large observational studies are needed to increase power for more nuanced analyses. Combining data across existing observational studies represents one solution. However, the disparity of such datasets makes this a non-trivial task. Here, a machine learning approach was applied to impute longitudinal neuropsychological test scores across two observational studies, namely the Australian Imaging, Biomarkers and Lifestyle Study (AIBL) and the Alzheimer's Disease Neuroimaging Initiative (ADNI) providing an overall harmonised dataset. MissForest, a machine learning algorithm, capitalises on the underlying structure and relationships of data to impute test scores not measured in one study aligning it to the other study. Results demonstrated that simulated missing values from one dataset could be accurately imputed, and that imputation of actual missing data in one dataset showed comparable discrimination (p < 0.001) for clinical classification to measured data in the other dataset. Further, the increased power of the overall harmonised dataset was demonstrated by observing a significant association between CVLT-II test scores (imputed for ADNI) with PET Amyloid-β in MCI APOE-ε4 homozygotes in the imputed data (N = 65) but not for the original AIBL dataset (N = 11). These results suggest that MissForest can provide a practical solution for data harmonization using imputation across studies to improve power for more nuanced analyses.
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    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
    Fowler, C ; Rainey-Smith, SR ; Bird, S ; Bomke, J ; Bourgeat, P ; Brown, BM ; Burnham, SC ; Bush, A ; Chadunow, C ; Collins, S ; Doecke, J ; Dore, V ; Ellis, KA ; Evered, L ; Fazlollahi, A ; Fripp, J ; Gardener, SL ; Gibson, S ; Grenfell, R ; Harrison, E ; Head, R ; Jin, L ; Kamer, A ; Lamb, F ; Lautenschlager, NT ; Laws, SM ; Li, Q-X ; Lim, L ; Lim, YY ; Louey, A ; Macaulay, SL ; Mackintosh, L ; Martins, RN ; Maruff, P ; Masters, CL ; McBride, S ; Milicic, L ; Peretti, M ; Pertile, K ; Porter, T ; Radler, M ; Rembach, A ; Robertson, J ; Rodrigues, M ; Rowe, CC ; Rumble, R ; Salvado, O ; Savage, G ; Silbert, B ; Soh, M ; Sohrabi, HR ; Taddei, K ; Taddei, T ; Thai, C ; Trounson, B ; Tyrrell, R ; Vacher, M ; Varghese, S ; Villemagne, VL ; Weinborn, M ; Woodward, M ; Xia, Y ; Ames, D (IOS PRESS, 2021-01-01)
    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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    Longitudinal Trajectories in Cortical Thickness and Volume Atrophy: Superior Cognitive Performance Does Not Protect Against Brain Atrophy in Older Adults
    Gardener, SL ; Weinborn, M ; Sohrabi, HR ; Doecke, JD ; Bourgeat, P ; Rainey-Smith, SR ; Shen, K-K ; Fripp, J ; Taddei, K ; Maruff, P ; Salvado, O ; Savage, G ; Ames, D ; Masters, CL ; Rowe, CC ; Martins, RN ; O’Bryant, S (IOS PRESS, 2021-01-01)
    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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    SPON1 Is Associated with Amyloid-beta and APOE epsilon 4-Related Cognitive Decline in Cognitively Normal Adults
    Fernandez, S ; Burnham, SC ; Milicic, L ; Savage, G ; Maruff, P ; Peretti, M ; Sohrabi, HR ; Lim, YY ; Weinborn, M ; Ames, D ; Masters, CL ; Martins, RN ; Rainey-Smith, S ; Rowe, CC ; Salvado, O ; Groth, D ; Verdile, G ; Villemagne, VL ; Porter, T ; Laws, SM (IOS PRESS, 2021-01-01)
    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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    Learning deficit in cognitively normal APOE epsilon 4 carriers with LOW beta-amyloid
    Lim, YY ; Baker, JE ; Mills, A ; Bruns, L ; Fowler, C ; Fripp, J ; Rainey-Smith, SR ; Ames, D ; Masters, CL ; Maruff, P (WILEY, 2021-01-01)
    INTRODUCTION: In cognitively normal (CN) adults, increased rates of amyloid beta (Aβ) accumulation can be detected in low Aβ (Aβ-) apolipoprotein E (APOE) ε4 carriers. We aimed to determine the effect of ε4 on the ability to benefit from experience (ie, learn) in Aβ- CNs. METHODS: Aβ- CNs (n = 333) underwent episodic memory assessments every 18 months for 108 months. A subset (n = 48) completed the Online Repeatable Cognitive Assessment-Language Learning Test (ORCA-LLT) over 6 days. RESULTS: Aβ- ε4 carriers showed significantly lower rates of improvement on episodic memory over 108 months compared to non-carriers (d = 0.3). Rates of learning on the ORCA-LLT were significantly slower in Aβ- ε4 carriers compared to non-carriers (d = 1.2). DISCUSSION: In Aβ- CNs, ε4 is associated with a reduced ability to benefit from experience. This manifested as reduced practice effects (small to moderate in magnitude) over 108 months on the episodic memory composite, and a learning deficit (large in magnitude) over 6 days on the ORCA-LLT. Alzheimer's disease (AD)-related cognitive abnormalities can manifest before preclinical AD thresholds.