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Objective To determine whether alteplase alters the development of ischemic lesions on brain imaging after stroke. Methods The Third International Stroke Trial (IST-3) was a randomized controlled trial of IV alteplase for ischemic stroke. We assessed CT or brain MRI at baseline (pretreatment) and 24 to 48 hours posttreatment for acute lesion visibility, extent, and swelling, masked to all other data. We analyzed associations between treatment allocation, change in brain tissue appearances between baseline and follow-up imaging, and 6-month functional outcome in IST-3. We performed a meta-analysis of randomized trials of alteplase vs control with pre- and postrandomization imaging. Results Of 3,035 patients recruited in IST-3, 2,916 had baseline and follow-up brain imaging. Progression in either lesion extent or swelling independently predicted poorer 6-month outcome (adjusted odds ratio [OR] = 0.92, 95% confidence interval [CI] 0.88–0.96, p < 0.001; OR = 0.73, 95% CI 0.66–0.79, p < 0.001, respectively). Patients allocated alteplase were less likely than controls to develop increased lesion visibility at follow-up (OR = 0.77, 95% CI 0.67–0.89, p < 0.001), but there was no evidence that alteplase reduced progression of lesion extent or swelling. In meta-analysis of 6 trials including IST-3 (n = 4,757), allocation to alteplase was associated with a reduction in ischemic lesion extent on follow-up imaging (OR = 0.85, 95% CI 0.76–0.95, p = 0.004). Conclusion Alteplase was associated with reduced short-term progression in lesion visibility. In meta-analysis, alteplase reduced lesion extent. These findings may indicate that alteplase improves functional outcome by reducing tissue damage. Classification of evidence This study provides Class II evidence that IV alteplase impedes the progression of ischemic brain lesions on imaging after stroke.

Elevated serum and cerebrospinal fluid concentrations of S100β, a protein predominantly found in glia, are associated with intracranial injury and neurodegeneration, although concentrations are also influenced by several other factors. The longitudinal association between serum S100β concentrations and brain health in nonpathological aging is unknown. In a large group (baseline N = 593; longitudinal N = 414) of community-dwelling older adults at ages 73 and 76 years, we examined cross-sectional and parallel longitudinal changes between serum S100β and brain MRI parameters: white matter hyperintensities, perivascular space visibility, white matter fractional anisotropy and mean diffusivity (MD), global atrophy, and gray matter volume. Using bivariate change score structural equation models, correcting for age, sex, diabetes, and hypertension, higher S100β was cross-sectionally associated with poorer general fractional anisotropy (r = -0.150, p = 0.001), which was strongest in the anterior thalamic (r = -0.155, p < 0.001) and cingulum bundles (r = -0.111, p = 0.005), and survived false discovery rate correction. Longitudinally, there were no significant associations between changes in brain imaging parameters and S100β after false discovery rate correction. These data provide some weak evidence that S100β may be an informative biomarker of brain white matter aging.

Elevated serum and cerebrospinal fluid concentrations of S100β, a protein predominantly found in glia, are associated with intracranial injury and neurodegeneration, though concentrations are also influenced by several other factors. The longitudinal association between serum S100β concentrations and brain health in non-pathological ageing is unknown. In a large group (baseline N = 593; longitudinal N = 414) of community-dwelling older adults at ages 73 and 76 years, we examined cross-sectional and parallel longitudinal changes between serum S100β and brain MRI parameters: white matter hyperintensities (WMH), perivascular space visibility, white matter fractional anisotropy (FA) and mean diffusivity (MD), global atrophy and grey matter volume. Using bivariate change score structural equation models, correcting for age, sex, diabetes and hypertension, higher S100β was cross-sectionally associated with poorer general FA (r = -0.150, p = 0.001), which was strongest in the anterior thalamic (r = -0.155, p < 0.001) and cingulum bundles (r = -0.111, p = 0.005), and survived false discovery rate (FDR) correction. Longitudinally, there were no significant associations between changes in brain imaging parameters and S100β following FDR correction. These data provide some weak evidence that S100β may be an informative biomarker of brain white matter ageing.

Gait and balance impairment is highly prevalent in older people. We aimed to assess whether and how single markers of small vessel disease (SVD) or a combination thereof explain gait and balance function in the elderly. We analysed 678 community-dwelling healthy subjects from the Lothian Birth Cohort 1936 at the age of 71–74 years who had undergone comprehensive risk factor assessment, gait and balance assessment as well as brain MRI. We investigated the impact of individual SVD markers (white matter hyperintensity – WMH, microbleeds, lacunes, enlarged perivascular spaces, brain atrophy) as seen on structural brain MRI and of a global SVD score on the patients’ performance. A regression model revealed that age, sex, and hypertension significantly explained gait speed. Among SVD markers white matter hyperintensity (WMH) score or volume were additional significant and independent predictors of gait speed in the regression model. A similar association was seen with the global SVD score. Our study confirms a negative impact of SVD-related morphologic brain changes on gait speed in addition to age, sex and hypertension independent from brain atrophy. The presence of WMH seems to be the major driving force for SVD on gait impairment in healthy elderly subjects.

Copy of poster presented at at the Society for Teaching Psychology's preconference at SPSP in January 2017.This research was conducted by Zoe Morris, Nick Gamble and myself at Monash University. The poster was designed collaboratively. The research project commenced in 2016, and this poster describes the result of an attempt to integrate teaching, research and clinical education in a postgraduate psychology training program.Recommended citation:Costello, S., Morris, Z. A., and Gamble, N. (2017). Working smarter, not harder: Integrating teaching, research, and clinical experience in a careers assessment service. Poster presented at the Society for Teaching Psychology preconference, Society for Personality and Social Psychology annual convention, San Antonio, TX. doi:10.6084/m9.figshare.4564174

Slides from a paper presented at the New Zealand Psychological Society's annual conference in Christchurch, 2017.

Objective: To investigate whether the location and extent of the CT hyperdense artery sign (HAS) at presentation affects response to IV alteplase in the randomized controlled Third International Stroke Trial (IST-3). Methods: All prerandomization and follow-up (24–48 hours) CT brain scans in IST-3 were assessed for HAS presence, location, and extent by masked raters. We assessed whether HAS grew, persisted, shrank, or disappeared at follow-up, the association with 6-month functional outcome, and effect of alteplase. IST-3 is registered (ISRCTN25765518). Results: HAS presence (vs absence) independently predicted poor 6-month outcome (increased Oxford Handicap Scale [OHS]) on adjusted ordinal regression analysis (odds ratio [OR] 0.66, p < 0.001). Outcome was worse in patients with more (vs less) extensive HAS (OR 0.61, p = 0.027) but not in proximal (vs distal) HAS (p = 0.420). Increasing age was associated with more HAS growth at follow-up (OR 1.01, p = 0.013). Treatment with alteplase increased HAS shrinkage/disappearance at follow-up (OR 0.77, p = 0.006). There was no significant difference in HAS shrinkage with alteplase in proximal (vs distal) or more (vs less) extensive HAS (p = 0.516 and p = 0.580, respectively). There was no interaction between presence vs absence of HAS and benefit of alteplase on 6-month OHS (p = 0.167). Conclusions: IV alteplase promotes measurable reduction in HAS regardless of HAS location or extent. Alteplase increased independence at 6 months in patients with and without HAS. Classification of evidence: This study provides Class I evidence that for patients within 6 hours of ischemic stroke with a CT hyperdense artery sign, IV alteplase reduced intra-arterial hyperdense thrombus.

Stable carbon–, nitrogen–, and oxygen–isotope analyses of animal bones and teeth from 28 archaeological sites are used to reconstruct human subsistence behaviour, i.e., increased maize horticulturalism, during the Late Woodland period (A.D. 1000–1650) in southwestern Ontario. The isotopic data provided dietary, seasonal, and geographic information, which was analysed within archaeological, symbolic, and ecological contexts and used to reconstruct the diets, hunting patterns, and animal processing practices of two neighbouring groups, the Ontario Iroquoian and Western Basin peoples. Paleodietary and seasonality analyses focused on the following species: canids (domestic dogs, foxes, and wolves), wild turkeys and white-tailed deer, though additional fauna (including black bears, raccoons, and squirrels) were also analysed. Bone (n=324) and dentine (n=11) collagen provided dietary information, specifically concerning access to maize and trophic position. The carbon– and nitrogen–isotope composition of modern plants (n= 8) and animals (n=87) was used to expand the local food web and understand abilities of modern animals to access crops. Structural carbonate isotopic analyses for archaeological (n=126) and modern (n=28) individuals provided additional information about trophic position, post–mortem alteration, and geographic affiliation. Serially sampled enamel was analysed for several deer and a dog, and was successfully paired with x–radiographs to create an enamel formation sequence, which enables reconstruction of short term (seasonal) diets. The domestic dog isotopic data expanded our understanding of human dietary change over the Late Woodland period for both Ontario Iroquoian and Western Basin peoples, including different emphases on protein sources (i.e., fish). Wild fauna, particularly foxes, wild turkeys, raccoons and squirrels, were able to access maize. The turkey isotopic data suggest a unique hunting strategy at some Ontario Iroquoian sites, i.e., the purposeful discard of maize to create a predictable field hunting zone. An unexpected relationship between the δ13Ccol and δ13Csc values of deer appears to reflect a post–mortem processing (i.e., boiling) practice. This thesis has expanded our understanding of Late Woodland diets, horticultural and hunting practices. It has also demonstrated that fauna may be used to reconstruct human behaviour and ideology in lieu of the destructive analysis of human remains.

OBJECTIVE: To determine the magnitude of potentially causal relationships among vascular risk factors (VRFs), large-artery atheromatous disease (LAD), and cerebral white matter hyperintensities (WMH) in 2 prospective cohorts.METHODS: We assessed VRFs (history and measured variables), LAD (in carotid, coronary, and leg arteries), and WMH (on structural MRI, visual scores and volume) in: (a) community-dwelling older subjects of the Lothian Birth Cohort 1936, and (b) patients with recent nondisabling stroke. We analyzed correlations, developed structural equation models, and performed mediation analysis to test interrelationships among VRFs, LAD, and WMH.RESULTS: In subjects of the Lothian Birth Cohort 1936 (n = 881, mean age 72.5 years [SD ±0.7 years], 49% with hypertension, 33% with moderate/severe WMH), VRFs explained 70% of the LAD variance but only 1.4% to 2% of WMH variance, of which hypertension explained the most. In stroke patients (n = 257, mean age 74 years [SD ±11.6 years], 61% hypertensive, 43% moderate/severe WMH), VRFs explained only 0.1% of WMH variance. There was no direct association between LAD and WMH in either sample. The results were the same for all WMH measures used.CONCLUSIONS: The small effect of VRFs and LAD on WMH suggests that WMH have a large "nonvascular," nonatheromatous etiology. VRF modification, although important, may be limited in preventing WMH and their stroke and dementia consequences. Investigation of, and interventions against, other suspected small-vessel disease mechanisms should be addressed.