Medicine (Austin & Northern Health) - Research Publications

Permanent URI for this collection

Search Results

Now showing 1 - 10 of 80
  • Item
    No Preview Available
    Plasma glial fibrillary acidic protein is associated with reactive astrogliosis assessed via 18F-SMBT-1 PET
    Chatterjee, P ; Dore, V ; Pedrini, S ; Krishnadas, N ; Thota, RN ; Bourgeat, P ; Rainey‐Smith, S ; Burnham, SC ; Fowler, C ; Taddei, K ; Mulligan, RS ; Ames, D ; Masters, CL ; Fripp, J ; Rowe, C ; Martins, RN ; Villemagne, VL (Wiley, 2022-12)
    Background Reactive astrogliosis is an early event along the Alzheimer’s disease (AD) continuum. We have shown that plasma glial fibrillary acidic protein (GFAP), reflecting reactive astrogliosis, is elevated in cognitively unimpaired individuals with preclinical AD (Chatterjee et al., 2021). We reported similar findings using 18F‐SMBT‐1, a PET tracer for monoamine oxidase B (MAO‐B) (Villemagne et al., 2022). To provide further evidence of their relationship with reactive astrogliosis we investigated the association between GFAP and 18F‐SMBT‐1 in the same participants. Method Plasma GFAP, Aβ42 and Aβ40 levels were measured using the Single Molecule Array platform in 71 participants comprising 54 healthy controls (12 Aβ+ and 42 Aβ‐), 11 MCI(3 Aβ+ and 8 Aβ‐) and 6 probable AD(5 Aβ+ and 1 Aβ‐) patients from the Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing cohort. These participants also underwent 18F‐SMBT‐1 and Aβ PET imaging. Aβ imaging results were expressed in Centiloids (CL; ≥20 CL classified as Aβ+). 18F‐SMBT‐1 Standard Uptake Value Ratio (SUVR) were generated using the subcortical white matter as reference region. Linear regression analyses were carried out using plasma GFAP levels as the dependent variable and regional 18F‐SMBT‐1 SUVR as the independent variable, before and after adjusting for age, sex, soluble Aβ (plasma Aβ1‐42/Aβ1‐40 ratio) and insoluble Aβ (Aβ PET). Result Plasma GFAP was significantly associated with 18F‐SMBT‐1 SUVR in brain regions of early Aβ deposition, such as the supramarginal gyrus (SG, β=.361, p=.002), posterior cingulate (PC, β=.308, p=.009), lateral temporal (LT, β=.299, p=.011), lateral occipital (LO, β=.313, p=.008) before adjusting for any covariates. After adjusting for covariates age, sex and soluble Aβ, GFAP was significantly associated with 18F‐SMBT‐1 PET signal in the SG (β=.333, p<.001), PC (β=.278, p=.005), LT (β=.256, p=.009), LO (β=.296, p=.004) and superior parietal (SP, β=.243, p=.016). On adjusting for age, sex and insoluble Aβ, GFAP was significantly associated with SMBT‐1 PET in the SG (β=.211, p=.037) however only a trend towards significance was observed in the PC (β=.186, p=.052) and LT (β=.171, p=.067) (Figure 1). Conclusion There is an association between plasma GFAP and regional SMBT‐1 PET that is primarily driven by brain Aβ load.
  • Item
    No Preview Available
    Alzheimer’s disease specific MRI brain regions are differentially associated with accelerated decline as defined using sigmoidal cognitive turning point methodology in amyloid‐positive AIBL participants
    Gillis, C ; Cespedes, MI ; Maserejian, NN ; Dore, V ; Maruff, P ; Fowler, C ; Rainey‐Smith, S ; Villemagne, VL ; Rowe, C ; Martins, RN ; Vacher, M ; Masters, CL ; Doecke, JD (Wiley, 2022-12)
    Background Variability in cognitive decline among adults with Alzheimer’s disease (AD) is seen across studies. While such variability is often modelled using linear models, in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study, application of a sigmoidal methodology has shown excellent precision in modelling cognitive and biomarker changes. Here we expand these findings by examining associations of brain volumes in AD specific Regions of Interest (ROIs) with accelerated cognitive decline among amyloid‐beta positive (Ab+) AIBL participants. Method Longitudinal cognitive scores for the AIBL PACC, Language, Visuospatial functioning and CDR‐SB were mapped to sigmoidal trajectories, with a threshold defining the inflection point of accelerated cognitive decline. Participants to the left of the threshold were classified as having non‐accelerated decline (non‐accelerators), and participants beyond the threshold were classed as accelerators (Figure 1B). Using these classifications, we investigated differences in 16 ICV corrected ROI (left and right hemispheres pooled) for reductions in brain volume via generalised linear models adjusted for age, gender, and APOE‐e4 status. Three participant subgroups were tested: 1) Ab+/Tau unknown, 2) Ab+/Tau‐ and 3) Ab+/Tau+. Significant t‐values for the summed ROI volumes were mapped on a standard brain mesh for visualisation. Result Of regions tested, two stood out consistently amongst top markers in each of the participant subgroups and cognitive outcomes: 1) supramarginal volume and 2) middle temporal volume (Figure 1C). Largest volume differences between accelerators and non‐accelerators were seen in the Ab+/Tau+ group; whilst smallest p‐values were in the Ab+/Tau unknown group due to a larger sample size (Table 1). Brain mesh visualization showed most of the AD signature ROIs altered in accelerator groups as compared with non‐accelerator groups. Figure 1D shows the AD signature for each cognitive outcome amongst the Ab+/Tau participant group. Top ranked ROI for the left being middle temporal volume (T=7.10, PACC) and supramarginal volume (T=7.10, CDR‐SB). Conclusion Sigmoid analyses of MRI using binary cognitive scores show decreased ROI volumes in AIBL Ab+ participants with accelerated cognitive decline. This effect was mediated by known information on Tauopathy. Whilst effect sizes were high, smaller sample sizes in some groups affected p‐values and should therefore be replicated in larger samples.
  • Item
    No Preview Available
    Comparing the longitudinal progression of CSF biomarkers with PET Amyloid biomarkers for Alzheimer’s disease
    Cox, T ; Bourgeat, P ; Dore, V ; Doecke, JD ; Fripp, J ; Chatterjee, P ; Schindler, EE ; Benzinger, TLS ; Rowe, C ; Villemagne, VL ; Weiner, MW ; Morris, JC ; Masters, CL (Wiley, 2022-12)
    Background Cerebrospinal fluid (CSF) soluble biomarkers are useful at detecting pre‐clinical levels of Alzheimer’s disease (AD) biomarkers of b‐amyloid (Ab) and tau. Disease progression times for participants in longitudinal studies can be estimated for different biomarkers. Utilizing a new technique, this work compared the disease progression times between CSF and PET biomarkers. Methods Four hundred and ten participants from the Alzheimer’s Dementia Onset and Progression in International Cohorts (ADOPIC) including participants form ACS/OASIS, ADNI and AIBL with three or more data points of longitudinal CSF Ab42 and pTau181 (pTau) and Ab PET were selected. PET results were expressed in Centiloid (CL), (299 cognitively unimpaired, 107 mild cognitively impaired, 4 AD dementia; aged 69±9; 216 females (NAIBL=30, NADNI=252, NOASIS=128). Disease trajectory curves for individual biomarkers and the pTau/Ab42 ratio were created by: 1) Fitting a function to the rates of change of the variable of interest versus its mean value), 2) integrating the fit to obtain longitudinal trajectory curves as a function of disease progression time for each of the variables. The participants’ disease progression time along each curve were estimated. Threshold values for Ab PET and pTau/Ab42 ratios were calculated using a gaussian mixture model. Estimates of age of onset were calculated using the progression times. The participants’ disease progression times for each of the different variables were compared using rank correlations. Results Rank correlations for the progression times were: r(Ab42, Ab PET) = 0.75, r(pTau, Ab PET)=0.62, and r(pTau/Ab42, Ab PET)=0.83. The estimated ages at which participants’ reach Ab PET and the pTau/Ab42 ratio thresholds are compared in Fig 1, the average age at which were estimated to reach the threshold values were 55 yr for pTau/Ab42 (threshold of 0.021) and 61 yr for Ab PET (threshold of 22 CL). Conclusions The high correlation between pTau/Ab42 and Ab PET, indicates that pTau/Ab42 captures the progression of AD pathology better than the individual CSF biomarkers. On average participants’ reach abnormal levels of pTau/Ab42 earlier than Ab PET. Further work is required to understand individual variations in progression times.
  • Item
    No Preview Available
    Altered levels of plasma kallikrein‐7 in prodromal Alzheimer’s disease
    Roberts, BR ; Roberts, AM ; Cortes, L ; Fowler, C ; Villemagne, VL ; Masters, CL ; Ryan, TM (Wiley, 2022-12)
    Background The accumulation of Aβ is thought to be dependent on imbalances in production or clearance of the peptide. At the core of the production and the breakdown of Aβ are changes in the activity of proteases. Several studies have suggested that the level and activity of brain proteases involved in the clearance pathway are perturbed in the disease. Given that AD is essentially a protease disease, we sought to determine if key proteases were altered in the blood plasma fraction, reflecting changes that are occur in the brain. Method We used a fast commercial tool to investigate the level of 34 proteases in plasma between healthy controls and AD patients. Next we used an ELISA and western blot assays to validate results from the discovery assay. Result We discovered that the protease kallikrein‐7 (KLK7) was significantly elevated in AD plasma. We then asked how early in the disease time course is KLK7 elevated. We used plasma from cognitively normal cases (n=120) with either high or low levels of brain amyloid based on PET imaging and found that KLK7 leaves are decreased. Conclusion These results suggest that the plasma level of Kallikrein‐7 may be an important tool in detecting elevated levels of brain amyloid before symptoms of AD become apparent.
  • Item
    No Preview Available
    Relationship between amyloid and tau levels and its impact on tau spreading
    Dore, V ; Krishnadas, N ; Bourgeat, P ; Huang, K ; Li, S ; Burnham, SC ; Masters, CL ; Fripp, J ; Villemagne, VL ; Rowe, CC (Wiley, 2021-12)
    Background Previous studies have shown that Aß‐amyloid (Aß) likely promotes tau to spread beyond the medial temporal lobe. However, the Aß levels necessary for tau to spread in the neocortex is still unclear. Method 466 participants underwent tau imaging with [18F]MK6420 and Aß imaging with [18F]NAV4694 (Fig. 1). Aß scans were quantified on the Centiloid (CL) scale with a cut‐off of 25CL for abnormal levels of Aß (A+). Tau scans were quantified in three regions of interest (ROI) (mesial temporal (Me); temporoparietal neocortex (Te); and rest of neocortex (R)) and four mesial temporal region (entorhinal cortex, amygdala, hippocampus and parahippocampus) using the cerebellar cortex as reference region. Regional tau thresholds were established as the 95%ile of the cognitively unimpaired A‐ subjects. The prevalence of abnormal tau levels (T+) along the Centiloid continuum was determined. Result The plots of prevalence of T+ (Fig. 2) show earlier and greater increase along the Centiloid continuum in the medial temporal area compared to neocortex. Prevalence of T+ was low but associated with Aß level between 10‐40 CL reaching 23% in Me, 15% in Te and 11% in R. Between 40‐70 CL, the prevalence of T+ subjects per CL increased four‐fold faster and at 70 CL was 64% in Me, 51% in Te and 37% in R. In cognitively unimpaired (Fig. 3), there were no T+ in R below 50 CL. The highest prevalence of T+ was found in the entorhinal cortex, reaching 40% at 40 CL and 80% at 60 CL. Conclusion Outside the entorhinal cortex, abnormal levels of cortical tau on PET are rarely found with Aß levels below 40 CL. Above 40 CL prevalence of T+ accelerates in all areas. Moderate Aß levels are required before neocortical tau becomes detectable.
  • Item
    No Preview Available
    Investigating the impact of scatter correction on Centiloid
    Li, S ; O'Keefe, G ; Gillman, A ; Burnham, SC ; Masters, CL ; Williams, R ; Rowe, CC ; Fripp, J ; Bourgeat, P ; Villemagne, VL ; Dore, V (Wiley, 2021-12)
    Abstract Background Centiloid (CL) is a semiquantitative measure of amyloid‐β burden based on the ratio between neo‐cortical target region and the whole cerebellum. Photon scatter is one of the major sources of noise in PET data. Scatter correction methods are very different across PET cameras. In this study, we investigate how scatter correction affects the CL for inter/intra‐cameras by comparing PET images with/without scatter correction. Method 203 subjects (Siemens mCT Biography (N=109), Philips Gemini TF 64 (N=94)) from the AIBL study were scanned with 18F‐NAV6240. All PET images were reconstructed off‐line with scatter correction enabled and then disabled. All images were processed by CapAIBL to generate CL values. The ΔCL, which was calculated as the difference between the scatter corrected CL and non‐scatter corrected CL, was investigated to quantify the impact of scatter correction. For the intra‐camera comparison, all subjects were categorised in three groups based on the head tilt along anteroposterior axis compared to the MNI‐152 template. For inter‐camera comparison, the head tilt angle was included as covariate into an ANOVA. Hierarchical linear regressions that included head tilt and camera models were used as covariates to investigate their effect on CL. Result Figure 1 shows that scatter correction has a larger impact on the cerebellum cortex than in neocortex. Figure 2 shows that scatter correction depends on the head position, and it has more impact on subjects with higher CL for both cameras. Figure 3 presents that scatter corrections from two different cameras have different impact on CL values. Both head tilt and camera model had an impact on the scatter correction with (F=19.5, p=1.67e‐5) and (F=109.4, p=1.1e‐20), respectively. The b coefficients were 0.38CL/degree for head tilt and 8.2CL for the camera model, where more scatter is corrected on the Siemens CT than on the Philips Gemini TF. Conclusion Our results show that difference in scatter correction from different cameras have a significant impact on CL, it is yet to be known whether it is caused by hardware difference or software difference. Additional investigations using test‐retest data is needed to further characterize the real impact of scatter correction on Centiloid.
  • Item
    No Preview Available
    Higher coffee consumption is associated with slower cognitive decline and Aβ‐amyloid accumulation over 126 months: Data from the AIBL study
    Gardener, SL ; Rainey‐Smith, SR ; Villemagne, VLL ; Fripp, J ; Dore, V ; Bourgeat, P ; Taddei, K ; Masters, CL ; Maruff, PT ; Rowe, CC ; Ames, D ; Martins, RN (Wiley, 2021-12)
    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 available in cohorts of older adults reporting associations of coffee intake with cognitive decline, in distinct domains, and investigating the neuropathological mechanisms underpinning these associations. Method The aim of the current study was to investigate the relationship between self‐reported baseline coffee intake (mean = 280 ± 323 g/day) and cognitive decline assessed using a comprehensive neuropsychological battery, over 126 months, in 227 cognitively normal individuals from the Australian Imaging, Biomarkers, and Lifestyle (AIBL) study. We also sought to investigate the relationship between coffee intake and cerebral Aβ‐amyloid accumulation and brain volumes in a subset of individuals (n=60; and n=51, respectively) over 126 months. Result Higher baseline coffee consumption was associated with slower cognitive decline in executive function, attention, and the AIBL Preclinical AD Cognitive Composite (PACC; shown to reliably measure the first signs of cognitive decline in at‐risk cognitively normal populations) over 126 months. Higher baseline coffee consumption was also associated with slower Aβ‐amyloid accumulation over 126 months, and lower risk of transitioning from ‘negative’ Aβ‐amyloid status to ‘moderate’, and ‘very high’ Aβ‐amyloid burden over the same time period. There were no associations between coffee intake and atrophy in total grey matter, white matter, or hippocampal volume. Conclusion Our results further support the hypothesis that coffee intake may be a protective factor against AD, with increased coffee consumption reducing cognitive decline potentially 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 how coffee intake could be incorporated as one modifiable lifestyle factor aimed at delaying AD onset.
  • Item
    No Preview Available
    How lifestyle shapes the brain: Associations between physical activity, sleep, beta‐amyloid and cognitive function in older adults
    Sewell, KR ; Rainey‐Smith, SR ; Villemagne, VLL ; Peiffer, JJ ; Sohrabi, HR ; Taddei, K ; Ames, D ; Maruff, PT ; Laws, SM ; Masters, CL ; Rowe, CC ; Martins, RN ; Erickson, KI ; Brown, BM (Wiley, 2021-12)
    Abstract Background Lifestyle factors such as sleep and physical activity influence risk of cognitive decline and dementia. Higher habitual physical activity and optimal sleep are associated with better cognitive function and lower levels of Alzheimer’s disease biomarkers, including beta‐amyloid (Aß). There is currently a poor understanding of how physical activity may influence the relationship between sleep and cognition, and whether exercise and sleep interact to influence cognition and Aß. Developing this understanding is crucial for creating effective lifestyle interventions for dementia prevention. Method Data from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study were utilised to determine whether self‐reported physical activity moderates the cross‐sectional relationship between self‐reported sleep parameters (duration, efficiency, latency, disturbance, quality), cognitive function (episodic memory, attention and processing speed, executive function), and brain Aß (quantified by amyloid positron emission tomography, using the Centiloid scale). Analyses were adjusted for age, sex, APOE ε4 carriage, mood, premorbid intelligence, and collection point. Participants were 404 community‐dwelling cognitively normal older adults aged 60 and above (75.3 5.7 years). Data from a subset of participants (n = 220, aged 75.2 5.6 years) were used for analyses with AB as the outcome. Result Physical activity moderated the relationship between sleep duration and episodic memory (ß = ‐.09, SE = .03, p = .005), and sleep efficiency and episodic memory (ß = ‐.08, SE = .03, p = .016). Physical activity moderated the relationship between sleep duration and A® (ß = ‐.12, SE = .06, p = .036), and sleep quality and Aß (ß = .12, SE = .06, p = .029). Conclusion Physical activity may play an important role in the relationship between sleep and cognitive function, and sleep and brain Aß. Future longitudinal and intervention studies in this area are crucial for informing interventions for dementia prevention.
  • Item
    No Preview Available
    Empirically derived composite cognitive test scores to predict preclinical and clinical stages of Alzheimer’s disease
    Shishegar, R ; Chai, TY ; Cox, T ; Lamb, F ; Robertson, JS ; Laws, SM ; Porter, T ; Fripp, J ; Doecke, JD ; Tosun‐Turgut, D ; Maruff, PT ; Savage, G ; Rowe, CC ; Masters, CL ; Weiner, MW ; Villemagne, VLL ; Burnham, SC (Wiley, 2021-12)
    Abstract Background Alzheimer’s disease (AD) clinical trials require cognitive test scores that assess change in cognitive function accurately. Here, we propose new composite cognitive test scores to detect earlier stages of AD accurately by using the full neuropsychological testing battery (in ADNI) and a manifold learning dimension reduction technique namely UMAP. Method Data for this study included N=1585 ADNI participants ([492 cognitively normal (CN), 804 mild cognitively impaired (MCI), 289 AD; aged 73.8±7.1; 708 females]; Table 1). Subjects with 3 or more follow‐up sessions were included. Cognitive test scores with more than 60% missing data were excluded. Missing data within included test scores were imputed using the MissForest algorithm. A linear mixed model using all follow‐up data was applied to calculate the random slope (rate of change) and random intercept for each cognitive score and for each subject. The scores and demographic measurements: age, gender, years of education and APOE‐ɛ4 status were used to inform the UMAP. Levels for the output variable were defined as: 1) stable CN, 2) CN who progressed to MCI or probable dementia due to AD, 3) stable MCI, 4) MCI who progressed to dementia AD and 5) dementia due to AD. The model calculated two composite scores. These cognitive stages were predicted using Support Vector Machine (SVM) analysis of both the new composite scores and the traditional clinical rating measures of Clinical Dementia Rating (CDR) and Mini‐Mental State Examination (MMSE). Result Predicting cognitive stages using the proposed composite scores show a highly significant improvement with a 0.981 accuracy and 0.976 reliability (evaluated by Cohen's kappa coefficient), compared to using the combination of CDR and MMSE scores covaried for demographics, which had 0.660 accuracy and 0.567 reliability. Individuals’ clinical and preclinical stages with regards to UMAP two‐dimensional embedding and the clinical rating measures, CDR and MMSE, are presented in Figure 1. Table 2 reports the importance of the test measures on the UMAP components used in AD staging predictions. Conclusion The results here suggest that the proposed empirically derived composite cognitive test scores provides a practical solution to differentiate cognitive stages with a high accuracy and reliability.
  • Item
    No Preview Available
    Plasma p217+tau concordance with 18F-NAV4694 beta-amyloid and 18F-MK6240 tau PET in mild Alzheimer’s disease and cognitively unimpaired participants in the AIBL/ADNeT cohort
    Rowe, CC ; Doecke, JD ; Saad, ZS ; Triana‐Baltzer, G ; Slemmon, JR ; Krishnadas, N ; Fowler, CJ ; Rainey‐Smith, SR ; Ward, L ; Robertson, J ; Martins, RN ; Fripp, J ; Masters, CL ; Villemagne, VL ; Kolb, HC ; Dore, V (Wiley, 2021-12)
    Abstract Background Beta‐amyloid (Aß) PET assists diagnosis of Alzheimer’s disease (AD) and has an important role in selection for trials. Aß PET is costly. Reports suggest that plasma measures of phospho‐tau have high concordance with both Aß and tau PET. We compared a new assay, plasma p217+tau to Aß and tau PET. Method 181 MCI/mild AD and 222 cognitively unimpaired (CU) participants in AIBL and the Australian Dementia Network (ADNeT) trial screening program were studied. Aß PET threshold was set at 25 centiloids (CL) as the standard for defining a positive scan and also at 50 CL which best correlates with NIA/AA AD neuropathologic change criteria. In CU we also evaluated a 20 CL PET threshold as this may be used in preclinical trial selection. Tau PET threshold was set at the SUVR (normalised to cerebellar cortex) for a meta‐temporal ROI (entorhinal cortex, amygdala, parahippocampus, and fusiform, inferior and middle temporal gyri) at the 95th percentile of Aß PET negative CU. Plasma p217+tau was measured with SIMOA using a Janssen in‐house assay. ROC area under the curve (AUC) was generated with Youden Index defined sensitivity (sens) and specificity (spec). Result Rank‐order correlation between p217+tau and Aß CL was significant in MCI/AD: ρ=0.65, p<10‐22 and CU: ρ=0.45, p<10‐12 and with tau SUVR for MCI/AD:ρ=0.68, p<10‐25 and CU:ρ=0.32, p<10‐7. In MCI/AD the AUC for p217+tau to predict Aß >25CL was 0.91 (sens 83%, spec 85%) and at >50CL was 0.90 (sens 73%, spec 93%). For tau+ PET the AUC was 0.86 (sens 73%, spec 90%). In the CU, the AUC vs Aß >25CL was 0.84 (sens 81%, spec 81%) dropping to 0.79 (sens 72%, spec 82%) for the 20CL PET threshold. The AUC vs tau+ PET in CU was 0.87 (sens 90%, spec 76%). Conclusion Plasma p217+tau showed good concordance with PET defined Aß and tau positivity in both MCI/AD and CU indicating potential to support the diagnosis of AD and to screen for preclinical AD trials. Early triage with p217+tau may reduce the number of screening Aß PET needed to identify Aß+ PET CU for preclinical trials by 50%.