Florey Department of Neuroscience and Mental Health - Research Publications
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ItemProgressive impairments in executive function in the APP/PS1 model of Alzheimer’s disease as measured by translatable touchscreen testing( 2019-08-21)Executive function deficits in Alzheimer’s disease (AD) occur early in disease progression and may be predictive of cognitive decline. However, no preclinical studies have identified deficits in rewarded executive function in the commonly used APP/PS1 mouse model. To address this, we assessed 12-26 month old APP/PS1 mice on rewarded reversal and/or extinction tasks. 16-month-old, but not 13- or 26-month-old, APP/PS1 mice showed an attenuated rate of extinction. Reversal deficits were seen in 22-month-old, but not 13-month-old APP/PS1 animals. We then confirmed that impairments in reversal were unrelated to previously reported visual impairments in both AD mouse models and humans. Age, but not genotype, had a significant effect on markers of retinal health, indicating the deficits seen in APP/PS1 mice were directly related to cognition. This is the first characterisation of rewarded executive function in APP/PS1 mice, and has great potential to facilitate translation from preclinical models to the clinic.
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ItemParadoxical effects of exercise on hippocampal plasticity and cognition in mice with a heterozygous null mutation in the serotonin transporter gene(WILEY, 2019-09)BACKGROUND AND PURPOSE: Exercise is known to improve cognitive function, but the exact synaptic and cellular mechanisms remain unclear. We investigated the potential role of the serotonin (5-HT) transporter (SERT) in mediating these effects. EXPERIMENTAL APPROACH: Hippocampal long-term potentiation (LTP) and neurogenesis were measured in standard-housed and exercising (wheel running) wild-type (WT) and SERT heterozygous (HET) mice. We also assessed hippocampal-dependent cognition using the Morris water maze (MWM) and a spatial pattern separation touchscreen task. KEY RESULTS: SERT HET mice had impaired hippocampal LTP regardless of the housing conditions. Exercise increased hippocampal neurogenesis in WT mice. However, this was not observed in SERT HET animals, even though both genotypes used the running wheels to a similar extent. We also found that standard-housed SERT HET mice displayed altered cognitive flexibility than WT littermate controls in the MWM reversal learning task. However, SERT HET mice no longer exhibited this phenotype after exercise. Cognitive changes, specific to SERT HET mice in the exercise condition, were also revealed on the touchscreen spatial pattern separation task, especially when the cognitive pattern separation load was at its highest. CONCLUSIONS AND IMPLICATIONS: Our study is the first evidence of reduced hippocampal LTP in SERT HET mice. We also show that functional SERT is required for exercise-induced increase in adult neurogenesis. Paradoxically, exercise had a negative impact on hippocampal-dependent cognitive tasks, especially in SERT HET mice. Taken together, our results suggest unique complex interactions between exercise and altered 5-HT homeostasis.
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ItemProtocol for evaluation of enhanced models of primary care in the management of stroke and other chronic disease (PRECISE): A data linkage healthcare evaluation study.(Swansea University, 2019-08-05)INTRODUCTION: The growing burden of chronic diseases means some governments have been providing financial incentives for multidisciplinary care and self-management support delivered within primary care. Currently, population-based evaluations of the effectiveness of these policies are lacking. AIM: To outline the methodological approach for our study that is designed to evaluate the effectiveness (including cost) of primary care policies for chronic diseases in Australia using stroke as a case study. METHODS: Person-level linkages will be undertaken between registrants from the Australian Stroke Clinical Registry (AuSCR) and (i) Government-held Medicare Australia claims data, to identify receipt or not of chronic disease management and care coordination primary care items; (ii) state government-held hospital data, to define outcomes; and (iii) government-held pharmaceutical and aged care claims data, to define covariates. N=1500 randomly selected AuSCR registrants will be sent surveys to obtain patient experience information. In Australia, unique identifiers are unavailable. Therefore, personal-identifiers will be submitted to government data linkage units. Researchers will merge the de-identified datasets for analysis using a project identifier. An economic evaluation will also be undertaken. ANALYSIS: The index event will be the first stroke recorded in the AuSCR. Multivariable competing risks Poisson regression for multiple events, adjusted by a propensity score, will be used to test for differences in the rates of hospital presentations and medication adherence for different care (policy) types. Our estimated sample size of 25,000 patients will provide 80% estimated power (ɑ>0.05) to detect a 6-8% difference in rates. The incremental costs per Quality-adjusted life years gained of community-based care following the acute event will be estimated from a health sector perspective. CONCLUSION: Completion of this study will provide a novel and comprehensive evaluation of the effectiveness and cost-effectiveness of Australian primary care policies. Its success will enable us to highlight the value of data-linkage for this type of research.
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ItemChanges in Activity Levels in the First Month after Stroke(SOC PHYSICAL THERAPY SCIENCE, 2013-05)[Purpose] To quantify the activity levels of individuals in an acute stroke ward, and to determine if their activity levels change within the first month after stroke. [Methods] In this pilot study, participant activity was monitored prospectively over a single day from 8 a.m. to 5 p.m. on two separate occasions. Individuals with confirmed stroke > 18 years of age and less than 15 days post-stroke at the time of recruitment were eligible for inclusion in this study. Activity was recorded using an electronic device. The first day was scheduled within 15 days and the second at four weeks post-stroke. We looked at the following activity categories: number of transitions, and the times spent lying, sitting and in dynamic activity. [Results] Sixteen individuals were included in this study with a median age of 79.5 years (interquartile range 62.5 to 85). Fifty-six % of the participants had mild, 31% had moderate and 13% had severe stroke, according to the NIHSS score. There were no significant changes in number of transitions, or times spent in dynamic activity and lying and sitting. [Conclusion] Activity levels were low at an acute stroke ward and did not significantly change within the first month.
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ItemEvolution of ischemic damage and behavioural deficit over 6 months after MCAo in the rat: Selecting the optimal outcomes and statistical power for multi-centre preclinical trials(PUBLIC LIBRARY SCIENCE, 2017-02-09)Key disparities between the timing and methods of assessment in animal stroke studies and clinical trial may be part of the reason for the failure to translate promising findings. This study investigates the development of ischemic damage after thread occlusion MCAo in the rat, using histological and behavioural outcomes. Using the adhesive removal test we investigate the longevity of behavioural deficit after ischemic stroke in rats, and examine the practicality of using such measures as the primary outcome for future studies. Ischemic stroke was induced in 132 Spontaneously Hypertensive Rats which were assessed for behavioural and histological deficits at 1, 3, 7, 14, 21, 28 days, 12 and 24 weeks (n>11 per timepoint). The basic behavioural score confirmed induction of stroke, with deficits specific to stroke animals. Within 7 days, these deficits resolved in 50% of animals. The adhesive removal test revealed contralateral neglect for up to 6 months following stroke. Sample size calculations to facilitate the use of this test as the primary experimental outcome resulted in cohort sizes much larger than are the norm for experimental studies. Histological damage progressed from a necrotic infarct to a hypercellular area that cleared to leave a fluid filled cavity. Whilst absolute volume of damage changed over time, when corrected for changes in hemispheric volume, an equivalent area of damage was lost at all timepoints. Using behavioural measures at chronic timepoints presents significant challenges to the basic science community in terms of the large number of animals required and the practicalities associated with this. Multicentre preclinical randomised controlled trials as advocated by the MultiPART consortium may be the only practical way to deal with this issue.
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ItemRelationship Between Glycated Hemoglobin and Stroke Risk: A Systematic Review and Meta-Analysis(WILEY, 2018-06-05)BACKGROUND: Diabetes mellitus is a major risk factor for ischemic stroke. Rising hemoglobin A1c (HbA1c) levels are associated with microvascular diabetes mellitus complication development; however, this relationship has not been established for stroke risk, a macrovascular complication. METHODS AND RESULTS: We conducted a systematic review and meta-analysis of observational cohort and nested case-control cohort studies assessing the association between rising HbA1c levels and stroke risk in adults (≥18 years old) with and without type 1 or type 2 diabetes mellitus. Random-effects model meta-analyses were used to calculate pooled adjusted hazard ratios (HRs) and their precision. The systematic review yielded 36 articles, of which 29 articles (comprising n=532 779 participants) were included in our meta-analysis. Compared to non-diabetes mellitus range HbA1c (<5.7%), diabetes mellitus range HbA1c (≥6.5%) was associated with an increased risk of first-ever stroke with average HR (95% confidence interval) of 2.15 (1.76, 2.63), whereas pre-diabetes mellitus range HbA1c (5.7-6.5%) was not (average HR [95% confidence interval], 1.19 [0.87, 1.62]). For every 1% HbA1c increment (or equivalent), the average HR (95% confidence interval) for first-ever stroke was 1.12 (0.91, 1.39) in non-diabetes mellitus cohorts and 1.17 (1.09, 1.25) in diabetes mellitus cohorts. For every 1% HbA1c increment, both non-diabetes mellitus and diabetes mellitus cohorts had a higher associated risk of first-ever ischemic stroke with average HR (95% confidence interval) of 1.49 (1.32, 1.69) and 1.24 (1.11, 1.39), respectively. CONCLUSIONS: A rising HbA1c level is associated with increased first-ever stroke risk in cohorts with a diabetes mellitus diagnosis and increased risk of first-ever ischemic stroke in non-diabetes mellitus cohorts. These findings suggest that more intensive HbA1c glycemic control targets may be required for optimal ischemic stroke prevention.
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ItemKCTD12 modulation of GABA(B) receptor function(JOHN WILEY & SONS LTD, 2017-08)The molecular composition and functional diversity of native GABAB receptors (GABABR) are still poorly understood, thus hindering development of selective GABABR ligands. Potassium channel tetramerization domain-containing protein (KCTD) 12 is a GABABR auxiliary subunit and mouse KCTD12 can alter GABABR function. In this study, we sought to characterize the effects of human KCTD12 on GABABR kinetics and pharmacology, using an automated electrophysiological assay. Seizure susceptibility and ethanol consumption were also investigated in a KCTD12 knockout mouse model. Human KCTD12 co-expression altered the kinetics of GABABR-mediated GIRK channels, speeding rates of both activation and desensitization. Analysis of concentration-response curves showed that KCTD12 coexpression did not alter effects of the agonists GABA or baclofen on GABABR. KCTD12 coexpression enhanced the potentiating effects of the positive allosteric modulator CGP7930, and its effects on GABABR activation and desensitization. The function of KCTD12 in vivo was examined, using the KCTD12 knockout mouse model. The knockout mice were more resistant to a pentylenetetrazole proconvulsant challenge suggesting reduced seizure susceptibility. In the two bottle preference test, KCTD12 knockout mice demonstrated a reduced consumption at high ethanol concentrations. In summary, human KCTD12 accelerated the kinetics of GABABR in vitro, in a manner possibly sensitive to allosteric pharmacological modulation. This study also provides novel in vivo evidence that the interaction between KCTD12 and GABABR is of physiological significance, and may be a mechanism to more selectively modulate GABABR.
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ItemNew-Onset Atrial Fibrillation After Coronary Artery Bypass Graft and Long-Term Risk of Stroke: A Meta-Analysis(WILEY, 2017-12)BACKGROUND: New-onset atrial fibrillation (NOAF) after coronary artery bypass graft is related to an increased short-term risk of stroke and mortality. We investigated whether the long-term risk of stroke is increased. METHODS AND RESULTS: We performed a systematic review and meta-analysis of studies that included patients who had coronary artery bypass graft and who afterwards developed NOAF during their index admission; these patients did not have previous atrial fibrillation. The primary outcome was risk of stroke at 6 months or more in patients who developed NOAF compared with those who did not. Odds ratios, relative risk, and hazard ratios were considered equivalent; outcomes were pooled on the log-ratio scale using a random-effects model and reported as exponentiated effect-sizes. We included 16 studies, comprising 108 711 participants with a median follow-up period of 2.05 years. Average participant age was 66.8 years, with studies including an average of 74.8% males. There was an increased long-term risk of stroke in the presence of NOAF (unadjusted studies effect-sizes=1.36, 95% confidence interval, 1.12-1.65, P=0.001, adjusted studies effect-sizes=1.25, 95% confidence interval, 1.09-1.42, P=0.001). There was evidence of moderate effect variation because of heterogeneity in studies reporting unadjusted (P=0.021, I2=49.8%) and adjusted data (P=0.081, I2=49.1%), and publication bias in the latter group (Egger's test, P=0.031). Sensitivity analysis on unadjusted data by study quality, design, and surgery did not alter the effect direction. CONCLUSIONS: Presence of NOAF in patients post-coronary artery bypass graft is associated with increased long-term risk of stroke compared with patients without NOAF. Further studies may show whether the increased risk is mediated by atrial fibrillation and whether anticoagulation reduces risk.
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ItemPatient and service factors associated with referral and admission to inpatient rehabilitation after the acute phase of stroke in Australia and Norway(BMC, 2019-11-21)BACKGROUND: Unequal access to inpatient rehabilitation after stroke has been reported. We sought to identify and compare patient and service factors associated with referral and admission to an inpatient rehabilitation facility (IRF) after acute hospital care for stroke in two countries with publicly-funded healthcare. METHODS: We compared two cohorts of stroke patients admitted consecutively to eight acute public hospitals in Australia in 2013-2014 (n = 553), and to one large university hospital in Norway in 2012-2013 (n = 723). Outcomes were: referral to an IRF; admission to an IRF if referred. Logistic regression models were used to identify and compare factors associated with each outcome. RESULTS: Participants were similar in both cohorts: mean age 73 years, 40-44% female, 12-13% intracerebral haemorrhage, ~ 77% mild stroke (National Institutes of Health Stroke Scale < 8). Services received during the acute admission differed (Australia vs. Norway): stroke unit treatment 82% vs. 97%, physiotherapy 93% vs. 79%, occupational therapy 83% vs. 77%, speech therapy 78% vs. 13%. Proportions referred to an IRF were: 48% (Australia) and 37% (Norway); proportions admitted: 35% (Australia) and 28% (Norway). Factors associated with referral in both countries were: moderately severe stroke, receiving stroke unit treatment or allied health assessments during the acute admission, living in the community, and independent pre-stroke mobility. Directions of associations were mostly congruent; however younger patients were more likely to be referred and admitted in Norway only. Models for admission among patients referred identified few associated factors suggesting that additional factors were important for this stage of the process. CONCLUSIONS: Similar factors were associated with referral to inpatient rehabilitation after acute stroke in both countries, despite differing service provision and access rates. Assuming it is not feasible to provide inpatient rehabilitation to all patients following stroke, the criteria for the selection of candidates need to be understood to address unwanted biases.
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ItemDose Articulation in Preclinical and Clinical Stroke Recovery: Refining a Discovery Research Pipeline and Presenting a Scoping Review Protocol(FRONTIERS MEDIA SA, 2019-11-06)Introduction: Despite an increase in the quality of clinical trials in stroke recovery, interventions have failed to markedly impact the trajectory of recovery after stroke. Failure may be due to the lack of consideration for the complexity of dose and its articulation within research trials. Prior to commencing the scoping review, we identified two research gaps to be addressed. Firstly, transparent application of a multidimensional definition of dose to clinical trial phases and secondly, the development of a quality tool to critique the articulation of dose across the pipeline. Building on this, we present the protocol for a scoping review that aims to synthesis what is known about dose articulation in stroke recovery in preclinical and clinical populations, and characterize research designs and statistical approaches used in dose articulation trials, and the associated advantages and disadvantages. Methods: The scoping review will apply Arksey and O'Malley's methodological framework. Two systematic searches that target preclinical and clinical literature will be run in Medline and Embase, which will be complimented by consultation with field experts and hand searching of included trials and relevant reviews. Search results will be imported into Covidence for transparent management. One reviewer will screen all abstracts and titles. Two reviewers will screen full text and a third reviewer included to resolve discrepancies. A standardized data charting form will be used to extract information and appraise the intervention description, risk of bias, and quality of both preclinical and clinical studies. Results will be summarized in tabular and narrative format to inform the development of recommendations for future research. Ethics approval is not required as data used will be secondary and de-identified. Conclusion: Development of a new quality tool to appraise the quality of both preclinical and clinical dose studies may serve to strengthen collaborative efforts between the fields. The findings from this review will advance the use of a discovery pipeline in stroke recovery research to ultimately inform clinical practice.
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