Melbourne Medical School Collected Works - Research Publications
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ItemEfficacy of probucol on cognitive function in Alzheimer's disease: study protocol for a double-blind, placebo-controlled, randomised phase II trial (PIA study)(BMJ PUBLISHING GROUP, 2022-02)INTRODUCTION: Preclinical, clinical and epidemiological studies support the hypothesis that aberrant systemic metabolism of amyloid beta (Aβ) in the peripheral circulation is causally related to the development of Alzheimer's disease (AD). Specifically, recent studies suggest that increased plasma concentrations of lipoprotein-Aβ compromise the brain microvasculature, resulting in extravasation and retention of the lipoprotein-Aβ moiety. The latter results in an inflammatory response and neurodegeneration ensues. Probucol, a historic cholesterol-lowering drug, has been shown in murine models to suppress lipoprotein-Aβ secretion, concomitant with maintaining blood-brain-barrier function, suppressing neurovascular inflammation and supporting cognitive function. This protocol details the probucol in Alzheimer's study, a drug intervention trial investigating if probucol has potential to attenuate cognitive decline, delay brain atrophy and reduce cerebral amyloid burden in patients with mild-to-moderate AD. METHODS AND ANALYSIS: The study is a phase II, randomised, placebo-controlled, double-blind single-site clinical trial held in Perth, Australia. The target sample is 314 participants with mild-to-moderate AD. Participants will be recruited and randomised (1:1) to a 104-week intervention consisting of placebo induction for 2 weeks followed by 102 weeks of probucol (Lorelco) or placebo. The primary outcome is changed in cognitive performance determined via the Alzheimer's Disease Assessment Scales-Cognitive Subscale test between baseline and 104 weeks. Secondary outcomes measures will be the change in brain structure and function, cerebral amyloid load, quality of life, and the safety and tolerability of Lorelco, after a 104week intervention. ETHICS AND DISSEMINATION: The study has been approved by the Bellberry Limited Human Research Ethics Committee (approval number: HREC2019-11-1063; Version 4, 6 October 2021). Informed consent will be obtained from participants prior to any study procedures being performed. The investigator group will disseminate study findings through peer-reviewed publications, key conferences and local stakeholder events. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (ACTRN12621000726853).
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ItemDietary Patterns Are Associated with Cognition among Older People with Mild Cognitive Impairment(MDPI, 2012-11)There has been increasing interest in the influence of diet on cognition in the elderly. This study examined the cross-sectional association between dietary patterns and cognition in a sample of 249 people aged 65-90 years with mild cognitive impairment (MCI). Two dietary patterns; whole and processed food; were identified using factor analysis from a 107-item; self-completed Food Frequency Questionnaire. Logistic regression analyses showed that participants in the highest tertile of the processed food pattern score were more likely to have poorer cognitive functioning; in the lowest tertile of executive function (OR 2.55; 95% CI: 1.08-6.03); as assessed by the Cambridge Cognitive Examination. In a group of older people with MCI; a diet high in processed foods was associated with some level of cognitive impairment.
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ItemA Cluster-Randomised Trial of Staff Education to Improve the Quality of Life of People with Dementia Living in Residential Care: The DIRECT Study(PUBLIC LIBRARY SCIENCE, 2011-11-30)BACKGROUND: The Dementia In Residential care: EduCation intervention Trial (DIRECT) was conducted to determine if delivery of education designed to meet the perceived need of GPs and care staff improves the quality of life of participants with dementia living in residential care. METHODOLOGY/PRINCIPAL FINDINGS: This cluster-randomised controlled trial was conducted in 39 residential aged care facilities in the metropolitan area of Perth, Western Australia. 351 care facility residents aged 65 years and older with Mini-Mental State Examination ≤ 24, their GPs and facility staff participated. Flexible education designed to meet the perceived needs of learners was delivered to GPs and care facility staff in intervention groups. The primary outcome of the study was self-rated quality of life of participants with dementia, measured using the QOL-Alzheimer's Disease Scale (QOL-AD) at 4 weeks and 6 months after the conclusion of the intervention. Analysis accounted for the effect of clustering by using multi-level regression analysis. Education of GPs or care facility staff did not affect the primary outcome at either 4 weeks or 6 months. In a post hoc analysis excluding facilities in which fewer than 50% of staff attended an education session, self-rated QOL-AD scores were 6.14 points (adjusted 95%CI 1.14, 11.15) higher at four-week follow-up among residents in facilities randomly assigned to the education intervention. CONCLUSION: The education intervention directed at care facilities or GPs did not improve the quality of life ratings of participants with dementia as a group. This may be explained by the poor adherence to the intervention programme, as participants with dementia living in facilities where staff participated at least minimally seemed to benefit. TRIAL REGISTRATION: ANZCTR.org.au ACTRN12607000417482.
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ItemHomocysteine, Grey Matter and Cognitive Function in Adults with Cardiovascular Disease(PUBLIC LIBRARY SCIENCE, 2012-03-07)BACKGROUND: Elevated total plasma homocysteine (tHcy) has been associated with cognitive impairment, vascular disease and brain atrophy. METHODS: We investigated 150 volunteers to determine if the association between high tHcy and cerebral grey matter volume and cognitive function is independent of cardiovascular disease. RESULTS: Participants with high tHcy (≥15 µmol/L) showed a widespread relative loss of grey matter compared with people with normal tHcy, although differences between the groups were minimal once the analyses were adjusted for age, gender, diabetes, hypertension, smoking and prevalent cardiovascular disease. Individuals with high tHcy had worse cognitive scores across a range of domains and less total grey matter volume, although these differences were not significant in the adjusted models. CONCLUSIONS: Our results suggest that the association between high tHcy and loss of cerebral grey matter volume and decline in cognitive function is largely explained by increasing age and cardiovascular diseases and indicate that the relationship is not causal.
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ItemFactors Associated with Self and Informant Ratings of the Quality of Life of People with Dementia Living in Care Facilities: A Cross Sectional Study(PUBLIC LIBRARY SCIENCE, 2010-12-13)BACKGROUND: There is no consensus regarding the optimal approach to assessment of the quality of life of people with dementia. We undertook the present study to describe and determine the factors associated with ratings of the quality of life of a cohort of people with dementia living in a residential care facility. METHODOLOGY/PRINCIPAL FINDINGS: 351 people with dementia living in residential care facilities, and their staff and family informants participated in this cross sectional observational study. Quality of life was measured using self (Quality of Life in Alzheimer's Disease [QoL-AD] scale), and informant (QoL-AD and Alzheimer's Disease Related QoL Scale) reports. 226 people (64%) with dementia (median MMSE 17; 12-21) were able to self rate the QoL-AD scale and these subjects' ratings were compared to ratings by staff and family. Both staff and family informant ratings of the QoL-AD underestimated self ratings (mean difference -7.8, 95% CI -8.8, -6.7 for staff rated QoL-AD; and mean difference -7.2, 95% CI -8.5, -6.0 for family rated QoL-AD). Self ratings of QoL were lower among people who were restrained, had fallen or had pain. Informant ratings of the QoL of the participants with dementia were consistently and significantly lower for people with severe cognitive impairment, who had fallen, had presence of neuropsychiatric symptoms, or where care giver distress was present. Documented restraint, reported pain and neuropsychiatric symptoms were independently associated with lower self rating of the QoL-AD in multivariate models. Cognitive impairment, case conferencing, hospitalizations and neuropsychiatric symptoms were found to be independently associated with staff rated ADRQL. CONCLUSIONS: The majority of people with dementia living in residential care facilities can rate their own QoL. Informant ratings underestimate self ratings of QoL of people with dementia, and appear to be associated with factors which are not associated with self ratings.
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ItemDementia in residential care: education intervention trial (DIRECT); protocol for a randomised controlled trial(BMC, 2010-05-26)BACKGROUND: There is scope to improve the quality of life (QOL) of people with dementia living in residential care facilities (RCF). The DIRECT study will determine if delivery of education to General Practitioners (GPs) and care staff improves the quality of life of residential care recipients with cognitive impairment. METHODS/DESIGN: A prospective randomised controlled trial conducted in residential aged care facilities in the metropolitan area of Perth, Western Australia. Participants are care facility residents, aged 65 years and older and with mini-mental state examination scores less than 25. GPs and care facility staff have been independently randomised to intervention or control groups. An education programme, designed to meet the perceived needs of learners, will be delivered to GPs and care staff in the intervention groups. The primary outcome of the study will be quality of life of the people with dementia, measured using the QOL-Alzheimer's Disease Scale (QOL-AD) and Alzheimer Disease Related QOL Scale (ADRQL), 4 weeks and 6 months after the conclusion of the education intervention. RESULTS: Recruitment of 351 people with dementia, cared for by staff in 39 residential facilities and 55 GPs, was undertaken between May 2007 and July 2008. Collection of baseline data is complete. Education has been delivered to GPs and Care staff between September 2008 and July 2009. Follow-up data collection is underway. DISCUSSION: The study results will have tangible implications for proprietors, managers and staff from the residential care sector and policy makers. The results have potential to directly benefit the quality of life of both patients and carers. TRIAL REGISTRATION: These trial methods have been prospectively registered (ACTRN12607000417482).
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ItemThe PACE Study: A randomised clinical trial of cognitive activity (CA) for older adults with mild cognitive impairment (MCI)(BMC, 2009-12-14)BACKGROUND: Research evidence from observational studies suggests that cognitive activity reduces the risk of cognitive impairment in later life as well as the rate of cognitive decline of people with dementia. The Promoting Healthy Ageing with Cognitive Exercise (PACE) study has been designed to determine whether a cognitive activity intervention decreases the rate of cognitive decline amongst older adults with mild cognitive impairment (MCI). METHODS/DESIGN: The study will recruit 160 community-dwelling men and women aged 65 years of age or over with mild cognitive impairment (MCI). Participants will be randomly allocated to two treatment groups: non-specific education and cognitive activity. The intervention will consist of ten 90-minute sessions delivered twice per week over a period of five weeks. The primary outcome measure of the study is the change from baseline in the total score on the Cambridge Cognitive Score (CAMCOG). Secondary outcomes of interest include changes in memory, attention, executive functions, mood and quality of life. Primary endpoints will be collected 12, 52 and 104 weeks after the baseline assessment. DISCUSSION: The proposed project will produce the best available evidence on the merits of increased cognitive activity as a strategy to prevent cognitive decline among older adults with MCI. We anticipate that the results of this study will have implications for the development of evidence-based preventive strategies to reduce the rate of cognitive decline amongst older people at risk of dementia. TRIAL REGISTRATION: ACTRN12608000556347.
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ItemFalls, Depression and Antidepressants in Later Life: A Large Primary Care Appraisal(PUBLIC LIBRARY SCIENCE, 2008-06-18)BACKGROUND: Depression and falls are common and co-exist for older people. Safe management of each of these conditions is important to quality of life. METHODS: A cross-sectional survey was used to examine medication use associated with injurious and non-injurious falls in 21,900 community-dwelling adults, aged 60 years or over from 383 Australian general practices recruited for the DEPS-GP Project. Falls and injury from falls, medication use, depressive symptoms (Primary Health Questionnaire (PHQ-9)), clinical morbidity, suicidal ideation and intent, health status (SF-12 Health Survey), demographic and lifestyle information was reported in a standardised survey. FINDINGS: Respondents were 71.8 years (sd 7.7) of age and 58.4% were women. 24% 11% and 8% reported falls, fall related injury, and sought medical attention respectively. Antidepressant use (odds ratio, OR: 1.46; 95% confidence interval, 95%CI: 1.25, 1.70), questionable depression (5-14 on PHQ OR: 1.32, 95%CI: 1.13, 1.53) and clinically significant symptoms of depression (15 or more on PHQ OR: 1.70, 95%CI: 1.14, 1.50) were independently associated with multiple falls. SSRI use was associated with the highest risk of multiple falls (OR: 1.66, 95%CI: 1.36, 2.02) amongst all psychotropic medications. Similar associations were observed for injurious falls. Over 60% of those with four accumulated risk factors had multiple falls in the previous year (OR: 3.40, 95%CI: 1.79, 6.45); adjusted for other demographic and health factors. INTERPRETATION: Antidepressant use (particularly SSRIs) was strongly associated with falls regardless of presence of depressive symptoms. Strategies to prevent falls should become a routine part of the management of older people with depression.
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ItemNo Preview AvailableThe KICA Carer: informant information to enhance the Kimberley Indigenous Cognitive Assessment(CAMBRIDGE UNIV PRESS, 2016-01)BACKGROUND: A quality dementia-screening tool is required for older remote Aboriginal Australians who have high rates of dementia and limited access to appropriate medical equipment and clinicians. The Kimberley Indigenous Cognitive Assessment (KICA Cog) is a valid cognitive test for dementia in Aboriginal and Torres Strait Islander peoples. The KICA cognitive informant questionnaire (KICA Carer) had yet to be analyzed to determine validity alone or in combination with the KICA Cog. METHODS: The KICA Carer was completed by nominated informants of 349 remote-living Aboriginal Australians in the Kimberley region, Western Australia. Validity was assessed by comparing KICA Carer with Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) and International Classification of Diseases (ICD-10) consensus diagnoses based on a blinded specialist review. KICA Carer and KICA Cog were then compared to determine joint validity. RESULTS: A KICA Carer score of ≥3/16 gave optimum sensitivity (76.2%) and specificity (81.4%), area under curve (AUC) 0.89 (95% CI = 0.85, 0.94) with positive predictive value (PPV) of 35.8%, and negative predictive value (NPV) of 96.2%. A KICA Cog score of ≤33/39 gave a sensitivity of 92.9% and specificity of 89.9%, AUC 0.96 (95% CI = 0.94, 0.98), with PPV of 55.6% and NPV of 98.9%. Cut-off scores of KICA Cog ≤ 33/39 and KICA Carer ≥ 2/16 in series indicate possible dementia, with sensitivity of 90.5% and specificity of 93.5%. In this setting, PPV was 66.5% and NPV was 98.6%. CONCLUSIONS: The KICA Carer is an important tool to accurately screen dementia in remote Aboriginal Australians when the KICA Cog is unable to be used for a patient. It is readily accepted by caregivers. KEY POINTS: • For the best practice in the cognitive assessment of an Aboriginal Australian aged over 45 years, KICA Cog should be utilized. • In cases where Aboriginal patients are not assessed directly, KICA Carer should be conducted with an informant. A cut-off score of ≥3/16 should be used (these tools can be downloaded from www.wacha.org.au/kica.html).
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ItemA Randomized Trial to Reduce the Prevalence of Depression and Self-Harm Behavior in Older Primary Care Patients(ANNALS FAMILY MEDICINE, 2012)PURPOSE: We wanted to determine whether an educational intervention targeting general practitioners reduces the 2-year prevalence of depression and self-harm behavior among their older patients. METHODS: Our study was a cluster randomized controlled trial conducted between July 2005 and June 2008. We recruited 373 Australian general practitioners and 21,762 of their patients aged 60 years or older. The intervention consisted of a practice audit with personalized automated audit feedback, printed educational material, and 6 monthly educational newsletters delivered over a period of 2 years. Control physicians completed a practice audit but did not receive individualized feedback. They also received 6 monthly newsletters describing the progress of the study, but they were not offered access to the educational material about screening, diagnosis and management of depression, and suicide behavior in later life. The primary outcome was a composite measure of clinically significant depression (Patient Health Questionnaire score ≥10) or self-harm behavior (suicide thoughts or attempt during the previous 12 months). Information about the outcomes of interest was collected at the baseline assessment and again after 12 and 24 months. We used logistic regression models to estimate the effect of the intervention in a complete case analysis and intention-to-treat analysis by imputed chain equations (primary analysis). RESULTS: Older adults treated by general practitioners assigned to the intervention experienced a 10% (95% CI, 3%-17%) reduction in the odds of depression or self-harm behavior during follow-up compared with older adults treated by control physicians. Post hoc analyses showed that the relative effect of the intervention on depression was not significant (OR = 0.93; 95% CI, 0.83-1.03), but its impact on self-harm behavior over 24 months was (OR = 0.80; 95% CI, 0.68-0.94). The beneficial effect of the intervention was primarily due to the relative reduction of self-harm behavior among older adults who did not report symptoms at baseline. The intervention had no obvious effect in reducing the 24-month prevalence of depression or self-harm behavior in older adults who had symptoms at baseline. CONCLUSIONS: Practice audit and targeted education of general practitioners reduced the 2-year prevalence of depression and self-harm behavior by 10% compared with control physicians. The intervention had no effect on recovery from depression or self-harm behavior, but it prevented the onset of new cases of self-harm behavior during follow-up. Replication of these results is required before we can confidently recommend the roll-out of such a program into normal clinical practice.