ARDC Research Link Australia

ORCID Profile
Orcid icon. 0000-0002-3589-2964

Current Organisations
University College London , University of Manchester , University of New Haven , Imperial College London , National University of Ireland Galway , Galway University Hospitals

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Publications

Publication

Highly degradable porous melt-derived bioactive glass foam scaffolds for bone regeneration

Publisher: Elsevier BV

Date: 07-2017

DOI: 10.1016/J.ACTBIO.2017.04.030

Abstract: A challenge in using bioactive melt-derived glass in bone regeneration is to produce scaffolds with interconnected pores while maintaining the amorphous nature of the glass and its associated bioactivity. Here we introduce a method for creating porous melt-derived bioactive glass foam scaffolds with low silica content and report in vitro and preliminary in vivo data. The gel-cast foaming process was adapted, employing temperature controlled gelation of gelatin, rather than the in situ acrylic polymerisation used previously. To form a 3D construct from melt derived glasses, particles must be fused via thermal processing, termed sintering. The original Bioglass® 45S5 composition crystallises upon sintering, altering its bioactivity, due to the temperature difference between the glass transition temperature and the crystallisation onset being small. Here, we optimised and compared scaffolds from three glass compositions, ICIE16, PSrBG and 13-93, which were selected due to their widened sintering windows. Amorphous scaffolds with modal pore interconnect diameters between 100-150µm and porosities of 75% had compressive strengths of 3.4±0.3MPa, 8.4±0.8MPa and 15.3±1.8MPa, for ICIE16, PSrBG and 13-93 respectively. These porosities and compressive strength values are within the range of cancellous bone, and greater than previously reported foamed scaffolds. Dental pulp stem cells attached to the scaffold surfaces during in vitro culture and were viable. In vivo, the scaffolds were found to regenerate bone in a rabbit model according to X-ray micro tomography imaging. This manuscript describes a new method for making scaffolds from bioactive glasses using highly bioactive glass compositions. The glass compositions have lower silica content that those that have been previously made into amorphous scaffolds and they have been designed to have similar network connectivity to that of the original (and commercially used) 45S5 Bioglass. The aim was to match Bioglass' bioactivity. The scaffolds retain the amorphous nature of bioactive glass while having an open pore structure and compressive strength similar to porous bone (the original 45S5 Bioglass crystallises during sintering, which can cause reduced bioactivity or instability). The new scaffolds showed unexpectedly rapid bone regeneration in a rabbit model.

Publication

Systemic inflammation as a moderator between sleep and incident dementia

Publisher: Oxford University Press (OUP)

Date: 29-08-2020

DOI: 10.1093/SLEEP/ZSAA164

Abstract: To determine whether C-reactive protein (CRP), a marker of systemic inflammation, moderates the association between sleep and incident dementia. We studied Framingham Heart Study participants who completed at baseline a serum CRP assessment and in-home polysomnography to measure sleep duration, sleep efficiency, sleep latency, wake after sleep onset (WASO), number of awakenings, arousal index, and apnea–hypopnea index. Participants were ided into groups according to their CRP level: low (& mg/L), average (1–3 mg/L), and high inflammation (& mg/L). Surveillance for outcomes (incident all-cause and Alzheimer’s disease [AD] dementia) commenced at baseline and continued up to 22.5 years. In 291 participants (mean age 67.5 ± 4.9 years, 51.6% men) followed for 13.4 ± 5.4 years, we observed 43 cases of all-cause dementia, 33 of which were clinically consistent with AD. Whereas no direct association between CRP or sleep exposures was observed with incident dementia, CRP levels interacted with nighttime wakefulness when predicting both incident all-cause and AD dementia. In the high CRP group, longer WASO (hazard ratio [HR], 2.89 95% CI, 1.31–6.34) and more nighttime awakenings (HR, 4.55 95% CI, 1.19–17.38) were associated with higher risk of incident dementia. In the low CRP group, fewer nighttime awakenings were associated with a higher risk of incident dementia (HR, 0.07 95% CI, 0.01–0.68). Our findings suggest that inflammation moderates the association between sleep, particularly nighttime wakefulness, and dementia risk. The presence of inflammation may be an important determinant in evaluating how sleep disturbances relate to neurodegeneration.

Publication

Association of CD14 with incident dementia and markers of brain aging and injury

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 09-12-2019

DOI: 10.1212/WNL.0000000000008682

Abstract: To test the hypothesis that the inflammatory marker plasma soluble CD14 (sCD14) associates with incident dementia and related endophenotypes in 2 community-based cohorts. Our s les included the prospective community-based Framingham Heart Study (FHS) and Cardiovascular Health Study (CHS) cohorts. Plasma sCD14 was measured at baseline and related to the incidence of dementia, domains of cognitive function, and MRI-defined brain volumes. Follow-up for dementia occurred over a mean of 10 years (SD 4) in the FHS and a mean of 6 years (SD 3) in the CHS. We studied 1,588 participants from the FHS (mean age 69 ± 6 years, 47% male, 131 incident events) and 3,129 participants from the CHS (mean age 72 ± 5 years, 41% male, 724 incident events) for the risk of incident dementia. Meta-analysis across the 2 cohorts showed that each SD unit increase in sCD14 was associated with a 12% increase in the risk of incident dementia (95% confidence interval 1.03–1.23 p = 0.01) following adjustments for age, sex, APOE ε4 status, and vascular risk factors. Higher levels of sCD14 were associated with various cognitive and MRI markers of accelerated brain aging in both cohorts and with a greater progression of brain atrophy and a decline in executive function in the FHS. sCD14 is an inflammatory marker related to brain atrophy, cognitive decline, and incident dementia.

Publication

The association between blood pressure variability (BPV) with dementia and cognitive function: a systematic review and meta-analysis protocol.

Publisher: Springer Science and Business Media LLC

Date: 15-10-2018

DOI: 10.1186/S13643-018-0811-9

Publication

Growth Differentiation Factor 15 and NT‐proBNP as Blood‐Based Markers of Vascular Brain Injury and Dementia

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 06-10-2020

DOI: 10.1161/JAHA.119.014659

Abstract: GDF15 (growth differentiation factor 15) and NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide) may offer promise as biomarkers for cognitive outcomes, including dementia. We determined the association of these biomarkers with cognitive outcomes in a community‐based cohort. Plasma GDF15 (n=1603) and NT‐proBNP levels (n=1590) (53% women mean age, 68.7 years) were measured in dementia‐free Framingham Offspring cohort participants at examination 7 (1998–2001). Participants were followed up for incident dementia. Secondary outcomes included Alzheimer disease dementia, magnetic resonance imaging structural brain measures, and neurocognitive performance. During a median 11.8‐year follow‐up, 131 participants developed dementia. On multivariable Cox proportional‐hazards analysis, higher circulating GDF15 was associated with an increased risk of incident all‐cause and Alzheimer disease dementia (hazard ratio [HR] per SD increment in natural log‐transformed biomarker value, 1.54 [95% CI, 1.22–1.95] and 1.37 [95% CI, 1.03–1.81], respectively), whereas higher plasma NT‐proBNP was also associated with an increased risk of all‐cause dementia (HR, 1.32 95% CI, 1.05–1.65). Elevated GDF15 was associated with lower total brain and hippoc al volumes, greater white matter hyperintensity volume, and poorer cognitive performance. Elevated NT‐proBNP was associated with greater white matter hyperintensity volume and poorer cognitive performance. Addition of both biomarkers to a conventional risk factor model improved dementia risk classification (net reclassification improvement index, 0.25 95% CI, 0.05–0.45). Elevated plasma GDF15 and NT‐proBNP were associated with vascular brain injury on magnetic resonance imaging, poorer neurocognitive performance, and increased risk of incident dementia in in iduals aged years. Both biomarkers improved dementia risk classification beyond that of traditional clinical risk factors, indicating their potential value in predicting incident dementia.

Publication

Association Between Blood Pressure Variability and Cerebral Small‐Vessel Disease: A Systematic Review and Meta‐Analysis

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 07-01-2016

DOI: 10.1161/JAHA.119.013841

Abstract: Research links blood pressure variability ( BPV ) with stroke however, the association with cerebral small‐vessel disease ( CSVD ) remains unclear. As BPV and mean blood pressure are interrelated, it remains uncertain whether BPV adds additional information to understanding cerebrovascular morphological characteristics. A systematic review was performed from inception until March 3, 2019. Eligibility criteria included population, adults without stroke ( weeks) exposure, BPV quantified by any metric over any duration comparison, (1) low versus high or mean BPV and (2) people with versus without CSVD and outcomes, (1) CSVD as subcortical infarct, lacunae, white matter hyperintensities, cerebral microbleeds, or enlarged perivascular spaces and (2) standardized mean difference in BPV . A total of 27 articles were meta‐analyzed, comprising 12 309 unique brain scans. A total of 31 odds ratios ( OR s) were pooled, indicating that higher systolic BPV was associated with higher odds for CSVD ( OR, 1.27 95% CI, 1.14–1.42 I 2 =85%) independent of mean systolic pressure. Likewise, higher diastolic BPV was associated with higher odds for CSVD ( OR, 1.30 95% CI, 1.14–1.48 I 2 =53%) independent of mean diastolic pressure. There was no evidence of a pairwise interaction between systolic/diastolic and BPV /mean OR s ( P =0.47), nor a difference between BPV versus mean pressure OR s ( P =0.58). Fifty‐four standardized mean differences were pooled and provided similar results for pairwise interaction ( P =0.38) and difference between standardized mean differences ( P =0.70). On the basis of the available studies, BPV was associated with CSVD independent of mean blood pressure. However, more high‐quality longitudinal data are required to elucidate whether BPV contributes unique variance to CSVD morphological characteristics.

Publication