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Authors: Watt, Andrew D. | Villemagne, Victor L. | Barnham, Kevin J.

Article Type: Review Article

Abstract: Over the past 100 years, there has been an exponential increase in our understanding of the underlying pathology of Alzheimer's disease (AD). This growth in knowledge has largely stemmed from the intensification of research into AD which has occurred over the past three decades and the incorporation of the amyloid cascade hypothesis as the generally accepted dogma of AD pathogenesis. While at times contentious, the notion that AD arises from aberrations in amyloid-β (Aβ) production and degradation has led to a number of significant breakthroughs in the way in which AD is currently diagnosed and in the attempts at disease …modifying therapies, from investigations into the underlying factors mediating the aggregation of Aβ to the development of therapeutic strategies and measures of neuroimaging allowing Aβ burden to be monitored within the AD-affected brain. This review focuses on some of the recent work we have conducted toward elucidating the role of Aβ in AD. Show more

Keywords: Biomarker, blood, copper, mass spectrometry, metal chaperone, NMDA, toxicity, zinc

DOI: 10.3233/JAD-2012-129017

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S283-S293, 2013

Authors: Watt, Andrew D. | Jenkins, Nicole L. | McColl, Gawain | Collins, Steven | Desmond, Patricia M.

Article Type: Research Article

Abstract: Rosen et al. thoughtfully extend the ethical discussion surrounding disease-modifying therapies in late-stage Alzheimer’s disease (AD) to correctly emphasize that the perceived quality of life (QoL) of the individual living with the disease is a critical component to decisions regarding their clinical care. The primary purpose of our original article regarding the use of disease-modifying therapeutics in late-stage AD was to ensure that those affected by AD and their primary care team are empowered to make informed care decisions in the best interest of the individual living with AD. Consequently, it appears axiomatic that major therapeutic decisions need to incorporate …consideration of the current and future QoL of individuals living with dementia; however, in the absence of effective restorative therapies, it is important to acknowledge the context within which extant QoL measures were developed and question whether such measures are adequate to inform treatment decisions that may hold the potential to significantly or perhaps indefinitely prolong severe disability. Show more

Keywords: Alzheimer’s disease, ethics, late-stage, restoration, quality of life, therapeutics

DOI: 10.3233/JAD-190033

Citation: Journal of Alzheimer's Disease, vol. 68, no. 4, pp. 1321-1323, 2019

Authors: Watt, Andrew D. | Jenkins, Nicole L. | McColl, Gawain | Collins, Steven | Desmond, Patricia M.

Article Type: Review Article

Abstract: There is hope that the continuing efforts of researchers will yield a disease-modifying drug for Alzheimer’s disease. Such a drug is likely to be capable of halting, or significantly slowing, the underlying pathological processes driving cognitive decline; however, it is unlikely to be capable of restoring brain function already lost through the pathological process. A therapy capable of halting Alzheimer’s disease, while not providing restoration of function, may prompt serious ethical questions. For example, is there a stage in the disease process when it becomes too late for therapeutic intervention to commence? And who bears the responsibility of making such …a decision? Conversations regarding the ethics of treating neurodegenerative conditions with non-restorative drugs have been largely absent within both clinical and research communities. Such discussions are urgently required to ensure that patients’ rights and well-being are protected when such therapeutic options become available. Show more

Keywords: Alzheimer’s disease, ethics, late-stage, restoration, palliative care, therapeutics

DOI: 10.3233/JAD-180865

Citation: Journal of Alzheimer's Disease, vol. 68, no. 4, pp. 1311-1316, 2019

Authors: Watt, Andrew D. | Perez, Keyla A. | Rembach, Alan R. | Masters, Colin L. | Villemagne, Victor L. | Barnham, Kevin J.

Article Type: Research Article

Abstract: Effective therapeutic interventions for Alzheimer's disease (AD) will require treatment regimes to move toward the earliest stages of the disease. For this to occur the field has to identify biomarkers that are able to accurately identify individuals at risk for progression toward AD in the presymptomatic stage. One very significant implication is that some form of population-based screening will need to be undertaken in order to identify those at risk. To date, efforts in neuroimaging brain amyloid-β (Aβ) and changes in cerebrospinal fluid Aβ and tau levels shows promise, however, it is questionable as to whether these methods are applicable …for screening the general population. The Aβ peptide is also found in blood which is the most economical and efficient biological fluid to analyze. Unfortunately, investigations into blood-based diagnostic markers have produced mixed results. This variability is likely to be the result of differences in the preanalytical processing of samples and as such is delaying progress in the field. Reported preanalytical processing techniques from 87 recent articles focusing on the measurement of Aβ in blood were compared, to investigate whether basic sample-handling techniques were comparable between studies. This comparison revealed that not only is it likely that some of the variability in blood-based results is attributable to discrepancies in preanalytical methodologies but also that the field is failing to adequately report sample processing techniques. This review highlights the current shortcomings in methodological reporting and recommends a standardized blood collection methodology based on the limited consensus of the reviewed articles. Show more

Keywords: Alzheimer's disease, amyloid-β, biomarkers, blood, plasma, protocol, standardized

DOI: 10.3233/JAD-2012-120058

Citation: Journal of Alzheimer's Disease, vol. 30, no. 2, pp. 323-336, 2012

Authors: Watt, Andrew D. | Perez, Keyla A. | Faux, Noel G. | Pike, Kerryn E. | Rowe, Christopher C. | Bourgeat, Pierrick | Salvado, Olivier | Masters, Colin L. | Villemagne, Victor L. | Barnham, Kevin J.

Article Type: Research Article

Abstract: Diagnostic measures for Alzheimer's disease (AD) commonly rely on evaluating the levels of amyloid-β (Aβ) peptides within the cerebrospinal fluid (CSF) of affected individuals. These levels are often combined with levels of an additional non-Aβ marker to increase predictive accuracy. Recent efforts to overcome the invasive nature of CSF collection led to the observation of Aβ species within the blood cellular fraction, however, little is known of what additional biomarkers may be found in this membranous fraction. The current study aimed to undertake a discovery-based proteomic investigation of the blood cellular fraction from AD patients (n = 18) and healthy …controls (HC; n = 15) using copper immobilized metal affinity capture and Surface Enhanced Laser Desorption/Ionisation Time-Of-Flight Mass Spectrometry. Three candidate biomarkers were observed which could differentiate AD patients from HC (ROC AUC > 0.8). Bivariate pairwise comparisons revealed significant correlations between these markers and measures of AD severity including; MMSE, composite memory, brain amyloid burden, and hippocampal volume. A partial least squares regression model was generated using the three candidate markers along with blood levels of Aβ. This model was able to distinguish AD from HC with high specificity (90%) and sensitivity (77%) and was able to separate individuals with mild cognitive impairment (MCI) who converted to AD from MCI non-converters. While requiring further characterization, these candidate biomarkers reaffirm the potential efficacy of blood-based investigations into neurodegenerative conditions. Furthermore, the findings indicate that the incorporation of non-amyloid markers into predictive models, function to increase the accuracy of the diagnostic potential of Aβ. Show more

Keywords: Amyloid-β, biomarkers, blood, copper, diagnostics, SELDI-TOF-MS

DOI: 10.3233/JAD-2010-101722

Citation: Journal of Alzheimer's Disease, vol. 24, no. 1, pp. 47-59, 2011

Authors: Watt, Andrew D. | Perez, Keyla A. | Ang, Ching-Seng | O'Donnell, Paul | Rembach, Alan | Pertile, Kelly K. | Rumble, Rebecca L. | Trounson, Brett O. | Fowler, Christopher J. | Faux, Noel G. | Masters, Colin L. | Villemagne, Victor L. | Barnham, Kevin J.

Article Type: Research Article

Abstract: Biomarkers enabling the preclinical identification of Alzheimer's disease (AD) remain one of the major unmet challenges in the field. The blood cellular fractions offer a viable alternative to current cerebrospinal fluid and neuroimaging modalities. The current study aimed to replicate our earlier reports of altered binding within the AD-affected blood cellular fraction to copper-loaded immobilized metal affinity capture (IMAC) arrays. IMAC and anti-amyloid-β (Aβ) antibody arrays coupled with mass spectrometry were used to analyze blood samples collected from 218 participants from within the AIBL Study of Aging. Peripheral Aβ was fragile and prone to degradation in the AIBL samples, even …when stored at −80°C. IMAC analysis of the AIBL samples lead to the isolation and identification of alpha-defensins 1 and 2 at elevated levels in the AD periphery, validating earlier findings. Alpha-defensins 1 and 2 were elevated in AD patients indicating that an inflammatory phenotype is present in the AD periphery; however, peripheral Aβ levels are required to supplement their prognostic power. Show more

Keywords: α-defensins, Alzheimer's disease, amyloid-β, biomarkers, blood, inflammation, mass spectrometry

DOI: 10.3233/JAD-142286

Citation: Journal of Alzheimer's Disease, vol. 44, no. 4, pp. 1131-1143, 2015

Authors: Rembach, Alan | Watt, Andrew D. | Wilson, William J. | Villemagne, Victor L. | Burnham, Samantha C. | Ellis, Kathryn A. | Maruff, Paul | Ames, David | Rowe, Christopher C. | Macaulay, S. Lance | Bush, Ashley I. | Martins, Ralph N. | Masters, Colin L. | Doecke, James D. | the AIBL Research Group

Article Type: Research Article

Abstract: Background: We evaluated the utility of longitudinal measures of plasma amyloid-β (Aβ) as a means to identify pre-symptomatic cognitive decline in Alzheimer’s disease (AD) when coupled to neuroimaging and neuropsychological parameters. Methods: Participants from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study were grouped based upon cognitive change and changes in measurable levels of neocortical amyloid over 36 months. Participants were classified as those who transitioned for cognitive decline and change in neocortical amyloid, those healthy controls that did not transition, and stable AD participants over 36 months. Results: Comparisons of plasma Aβ levels between the transition and non-transitional groups …showed Aβ1-42 and the Aβ1-42 /Aβ1-40 ratio were significantly decreased at baseline (p = 0.008 and p = 0.002, respectively) and at 18 months (p = 0.003 and p = 0.004, respectively). Both measures of neocortical amyloid and two previously published composite scores validated the creation of the novel transitional grouping (p < 0.0001). In addition Aβn-42 performed well as a longitudinal prognostic indicator of transition toward cognitive decline, with a significant decrease in the transition group at the 18 month time point (p = 0.01). Conclusion: We demonstrated that baseline plasma Aβ1-42 and the Aβ1-42 /Aβ1-40 ratio were putative biomarkers indicative of cognitive decline and validated this result using 18 month data. We created a novel transitional grouping and validated this measure using published measures of neocortical amyloid and composite memory scores. These findings suggest that longitudinal plasma Aβ could contribute to a pre-symptomatic biomarker panel for AD. Show more

Keywords: Alzheimer's disease, biomarkers, diagnosis, neocortical amyloid burden, Pittsburgh compound B, plasma amyloid-β, positron emission topography

DOI: 10.3233/JAD-131802

Citation: Journal of Alzheimer's Disease, vol. 40, no. 1, pp. 95-104, 2014

Authors: Rembach, Alan | Doecke, James D. | Roberts, Blaine R. | Watt, Andrew D. | Faux, Noel G. | Volitakis, Irene | Pertile, Kelly K. | Rumble, Rebecca L. | Trounson, Brett O. | Fowler, Christopher J. | Wilson, William | Ellis, Kathryn A. | Martins, Ralph N. | Rowe, Christopher C. | Villemagne, Victor L. | Ames, David | Masters, Colin L | AIBL research group | Bush, Ashley I.

Article Type: Research Article

Abstract: Background: Several studies have reported that peripheral levels of copper and ceruloplasmin (CP) can differentiate patients with Alzheimer’s disease (AD) from non-AD cases. The aim of this study was to determine the diagnostic value of serum copper, CP, and non-CP copper levels in a large cohort of AD subjects. Methods: Serum copper and CP concentrations were measured at baseline and at 18-months in participants from the Australian Imaging Biomarkers and Lifestyle Study of Ageing. Cross-sectional and longitudinal analyses were conducted using both univariate and multivariate testing adjusting for age, gender, total protein, and ApoE ε4 genotype status. Results: There was …no significant difference in levels of serum copper or CP between the AD and healthy control groups, however, we identified a near-significant decrease in non-CP copper in the mild cognitive impairment and AD groups at baseline (p = 0.02) that was significant at 18-months (p = 0.003). Conclusion: Our results suggest that there may be decreased non-CP copper levels in mild cognitive impairment and AD, which is consistent with diminished copper-dependent biochemical activities described in AD. Show more

Keywords: Alzheimer's disease, biomarkers, ceruloplasmin, copper, serum

DOI: 10.3233/JAD-121474

Citation: Journal of Alzheimer's Disease, vol. 34, no. 1, pp. 171-182, 2013