Wave intensity analysis: A novel non-invasive method for determining arterial wave transmission

Wave intensity analysis is a novel technique for assessing wavelet transmission in the cardiovascular system. Using this tool, we have developed non-invasive techniques to study wave transmission in both central & peripheral arteries in man. The aim of this study was to determine the reproducibility of various haemodynamic measures in the carotid, brachial and radial arteries. 12 treated hypertensive men underwent applanation tonometry and pulsed Doppler ultrasound studies of the carotid, brachial and radial arteries on 2 occasions. Coefficients of variation for the local wave speed, cardiac compression wave intensity and main reflected wave intensity ranged between 3.7-6.6%, 8.2-11.4% and 12.5-19.6% respectively. We conclude that non-invasive methods used for wave intensity analysis are reproducible & provide additional information regarding the complex phenomenon of arterial wave transmission in man

Regional thalamic neuropathology in patients with hippocampal sclerosis and epilepsy: A postmortem study

Purpose Clinical, experimental, and neuroimaging data all indicate that the thalamus is involved in the network of changes associated with temporal lobe epilepsy (TLE), particularly in association with hippocampal sclerosis (HS), with potential roles in seizure initiation and propagation. Pathologic changes in the thalamus may be a result of an initial insult, ongoing seizures, or retrograde degeneration through reciprocal connections between thalamic and limbic regions. Our aim was to carry out a neuropathologic analysis of the thalamus in a postmortem (PM) epilepsy series, to assess the distribution, severity, and nature of pathologic changes and its association with HS. Methods Twenty-four epilepsy PM cases (age range 25-87 years) and eight controls (age range 38-85 years) were studied. HS was classified as unilateral (UHS, 11 cases), bilateral (BHS, 4 cases) or absent (No-HS, 9 cases). Samples from the left and right sides of the thalamus were stained with cresyl violet (CV), and for glial firbillary acidic protein (GFAP) and synaptophysin. Using image analysis, neuronal densities (NDs) or field fraction staining values (GFAP, synaptophysin) were measured in four thalamic nuclei: anteroventral nucleus (AV), lateral dorsal nucleus (LD), mediodorsal nucleus (MD), and ventrolateral nucleus (VL). The results were compared within and between cases. Key Findings The severity, nature, and distribution of thalamic pathology varied between cases. A pattern that emerged was a preferential involvement of the MD in UHS cases with a reduction in mean ND ipsilateral to the side of HS (p = 0.05). In UHS cases, greater field fraction values for GFAP and lower values for synaptophysin and ND were seen in the majority of cases in the MD ipsilateral to the side of sclerosis compared to other thalamic nuclei. In addition, differences in the mean ND between classical HS, atypical HS, and No-HS cases were noted in the ipsilateral MD (p < 0.05), with lower values observed in HS. Significance Our study demonstrates that stereotypical pathologic changes, as seen in HS, are not clearly defined in the thalamus. This may be partly explained by the heterogeneity of our PM study group. With quantitation, there is some evidence for preferential involvement of the MD, suggesting a potential role in TLE, which requires further investigation. © Wiley Periodicals, Inc. © 2013 The Authors. Epilepsia published by Wiley Periodicals, Inc. on behalf of the International League Against Epilepsy

Spatiotemporal dynamics of PDGFRβ expression in pericytes and glial scar formation in penetrating brain injuries in adults

AIMS: Understanding the spatiotemporal dynamics of reactive cell types following brain injury is important for future therapeutic interventions. We have previously used penetrating cortical injuries following intracranial recordings as a brain repair model to study scar-forming nestin-expressing cells. We now explore the relationship between nestin-expressing cells, PDGFRβ+ pericytes and Olig2+ glia, including their proliferation and functional maturation. METHODS: In 32 cases, ranging from 3 to 461 days post injury (dpi), immunohistochemistry for PDGFRβ, nestin, GFAP, Olig2, MCM2, Aquaporin 4 (Aq4), Glutamine Synthetase (GS), and Connexin 43 (Cx43) were quantified for cell densities, labelling index (LI) and cellular co-expression at the injury site compared to control regions. RESULTS: PDGFRβ labelling highlighted both pericytes and multipolar parenchymal cells. PDGFRβ LI and PDGFRβ+ /MCM2+ cells significantly increased in injury zones at 10-13 dpi with migration of pericytes away from vessels with increased co-localisation of PDGRFβ with nestin compared to control regions (p < 0.005). Olig2+ /MCM2+ cell populations peaked at 13 dpi with significantly higher cell densities at injury sites than in control regions (p < 0.01) and decreasing with dpi (p < 0.05). Cx43 LI was reduced in acute injuries but increased with dpi (p < 0.05) showing significant cellular co-localisation with nestin and GFAP (p<0.005 and p<0.0001) but not PDGFRβ. CONCLUSIONS: These findings indicate that PDGFRβ+ and Olig2+ cells contribute to the proliferative fraction following penetrating brain injuries, with evidence of pericyte migration. Dynamic changes in Cx43 in glial cell types with dpi suggests functional alterations during temporal stages of brain repair. This article is protected by copyright. All rights reserved

Granule Cell Dispersion in Human Temporal Lobe Epilepsy: Proteomics Investigation of Neurodevelopmental Migratory Pathways

Granule cell dispersion (GCD) is a common pathological feature observed in the hippocampus of patients with Mesial Temporal Lobe Epilepsy (MTLE). Pathomechanisms underlying GCD remain to be elucidated, but one hypothesis proposes aberrant reactivation of neurodevelopmental migratory pathways, possibly triggered by febrile seizures. This study aims to compare the proteomes of basal and dispersed granule cells in the hippocampus of eight MTLE patients with GCD to identify proteins that may mediate GCD in MTLE. Quantitative proteomics identified 1,882 proteins, of which 29% were found in basal granule cells only, 17% in dispersed only and 54% in both samples. Bioinformatics analyses revealed upregulated proteins in dispersed samples were involved in developmental cellular migratory processes, including cytoskeletal remodeling, axon guidance and signaling by Ras homologous (Rho) family of GTPases (P < 0.01). The expression of two Rho GTPases, RhoA and Rac1, was subsequently explored in immunohistochemical and in situ hybridization studies involving eighteen MTLE cases with or without GCD, and three normal post mortem cases. In cases with GCD, most dispersed granule cells in the outer-granular and molecular layers have an elongated soma and bipolar processes, with intense RhoA immunolabeling at opposite poles of the cell soma, while most granule cells in the basal granule cell layer were devoid of RhoA. A higher percentage of cells expressing RhoA was observed in cases with GCD than without GCD (P < 0.004). In GCD cases, the percentage of cells expressing RhoA was significantly higher in the inner molecular layer than the granule cell layer (P < 0.026), supporting proteomic findings. In situ hybridization studies using probes against RHOA and RAC1 mRNAs revealed fine peri- and nuclear puncta in granule cells of all cases. The density of cells expressing RHOA mRNAs was significantly higher in the inner molecular layer of cases with GCD than without GCD (P = 0.05). In summary, our study has found limited evidence for ongoing adult neurogenesis in the hippocampus of patients with MTLE, but evidence of differential dysmaturation between dispersed and basal granule cells has been demonstrated, and elevated expression of Rho GTPases in dispersed granule cells may contribute to the pathomechanisms underpinning GCD in MTLE

The AgeWell study of behavior change to promote health and wellbeing in later life: study protocol for a randomized controlled trial.

This is the final version of the article. Available from Biomed Central via the DOI in this record.BACKGROUND: Lifestyle factors playing a role in the development of late-life disability may be modifiable. There is a need for robust evidence about the potential for prevention of disability through behavior change interventions. METHODS/DESIGN: This feasibility study involves the development, implementation and initial testing of a behavior change intervention in a naturalistic setting. A small-scale randomized controlled trial (RCT) will investigate the implementation of a goal-setting intervention aimed at promoting behavior change in the domains of physical and cognitive activity in the context of a community resource center for over-50s. Healthy older participants attending the center (n = 75) will be randomized to one of three conditions: control (an interview involving a general discussion about the center); goal-setting (an interview involving identification of up to five personal goals in the domains of physical activity, cognitive activity, diet and health, and social engagement); or goal-setting with mentoring (the goal-setting interview followed by bi-monthly telephone mentoring). All participants will be reassessed after 12 months. Primary outcomes are levels of physical and cognitive activity. Secondary outcomes address psychosocial (self-efficacy, mood, quality of life), cognitive (memory and executive function), and physical fitness (functional and metabolic) domains. Cost-effectiveness will also be examined. DISCUSSION: This study will provide information about the feasibility of a community-based lifestyle intervention model for over-50s and of the implementation of a goal-setting intervention for behavior change, together with initial evidence about the short-term effects of goal-setting on behavior. TRIAL REGISTRATION: Current Controlled Trials ISRCTN30080637 (http://www.controlled-trials.com).This study is funded by the Medical Research Council (UK) through the Lifelong Health and Well-being programme. The funder plays no role in the design of the study, in the collection, analysis and interpretation of data, or in the decision to submit the manuscript for publication. Professors Carol Brayne, Martin Knapp, Mike Martin, and Robin Morris advised on and critically reviewed the study proposal. John Clifford Jones, Maldwyn Roberts, and Stephen Williams of Age Cymru Gwynedd a Môn are responsible for setting up and managing the Nefyn AgeWell Centre. Julie Nixon is conducting the interviews and Jennifer Cooney is contributing to data collection. Anne Krayer will collect and analyze qualitative data for the biographical narrative analysis. Blood samples are analyzed by NHS laboratory staff at Ysbyty Gwynedd, Bangor. Sources of funding for each author are as follows: LC: Higher Education Funding Council for Wales; JVH: National Health Service/ Welsh Assembly Government; IRJ: Higher Education Funding Council for Wales; SMN: Medical Research Council grant; JT: Higher Education Funding Council for Wales; CJW: Welsh Assembly Government

Characterisation of medullary astrocytic populations in respiratory nuclei and alterations in sudden unexpected death in epilepsy

Central failure of respiration during a seizure is one possible mechanism for sudden unexpected death in epilepsy (SUDEP). Neuroimaging studies indicate volume loss in the medulla in SUDEP and a post mortem study has shown reduction in neuromodulatory neuropeptidergic and monoaminergic neurones in medullary respiratory nuclear groups. Specialised glial cells identified in the medulla are considered essential for normal respiratory regulation including astrocytes with pacemaker properties in the pre-Botzinger complex and populations of subpial and perivascular astrocytes, sensitive to increased pCO2, that excite respiratory neurones. Our aim was to explore niches of medullary astrocytes in SUDEP cases compared to controls. In 48 brainstems from three groups, SUDEP (20), epilepsy controls (10) and non-epilepsy controls (18), sections through the medulla were labelled for GFAP, vimentin and functional markers, astrocytic gap junction protein connexin43 (Cx43) and adenosine A1 receptor (A1R). Regions including the ventro-lateral medulla (VLM; for the pre-Bötzinger complex), Median Raphe (MR) and lateral medullary subpial layer (MSPL) were quantified using image analysis for glial cell populations and compared between groups. Findings included morphologically and regionally distinct vimentin/Cx34-positive glial cells in the VLM and MR in close proximity to neurones. We noted a reduction of vimentin-positive glia in the VLM and MSPL and Cx43 glia in the MR in SUDEP cases compared to control groups (p < 0.05-0.005). In addition, we identified vimentin, Cx43 and A1R positive glial cells in the MSPL region which likely correspond to chemosensory glia identified experimentally. In conclusion, altered medullary glial cell populations could contribute to impaired respiratory regulatory capacity and vulnerability to SUDEP and warrant further investigation

Neuropeptide depletion in the amygdala in sudden unexpected death in epilepsy: A postmortem study

OBJECTIVE: Sudden unexpected death in epilepsy (SUDEP) is typically unwitnessed but can be preceded by seizures in the period prior to death. Peri-ictal respiratory dysfunction is a likely mechanism for some SUDEP, and central apnea has been shown following amygdala stimulation. The amygdala is enriched in neuropeptides that modulate neuronal activity and can be transiently depleted following seizures. In a postmortem SUDEP series, we sought to investigate alterations of neuropeptidergic networks in the amygdala, including cases with recent poor seizure control. METHODS: In 15 SUDEP cases, 12 epilepsy controls, and 10 nonepilepsy controls, we quantified the labeling index (LI) for galanin, neuropeptide Y (NPY), and somatostatin (SST) in the lateral, basal, and accessory basal nuclei and periamygdala cortex with whole slide scanning image analysis. Within the SUDEP group, seven had recent generalized seizures with recovery 24 hours prior to death (SUDEP-R). RESULTS: Galanin, NPY, and SST LIs were significantly lower in all amygdala regions in SUDEP cases compared to epilepsy controls (P < .05 to P < .0005), and galanin LI was lower in the lateral nucleus compared to nonepilepsy controls (P < .05). There was no difference in the LI in the SUDEP-R group compared to other SUDEP. Higher LI was noted in epilepsy controls than nonepilepsy controls; this was significant for NPY in lateral and basal nuclei (P < .005 and P < .05). SIGNIFICANCE: A reduction in galanin in the lateral nucleus in SUDEP could represent acute depletion, relevant to postictal amygdala dysfunction. In addition, increased amygdala neuropeptides in epilepsy controls support their seizure-induced modulation, which is relatively deficient in SUDEP; this could represent a vulnerability factor for amygdala dysfunction in the postictal period

Cost-Effectiveness Findings from the Agewell Pilot Study of Behaviour Change to Promote Health and Wellbeing in Later Life.

Background: Participation in cognitive and physical activities may help to maintain health and wellbeing in older people. The Agewell study explored the feasibility of increasing cognitive and physical activity in older people through a goal-setting approach. This paper describes the findings of the cost-effectiveness analysis. Method: Individuals over the age of 50 and attending an Agewell centre in North Wales were randomised to one of three conditions: control (IC), goal-setting (GS), or goal-setting with mentoring (GM). We undertook a cost-effectiveness analysis comparing GS vs. IC, GM vs. IC and GM vs. GS. The primary outcome measure for this analysis was the QALY, calculated using the EQ-5D. Participants’ health and social care contacts were recorded and costed using national unit costs. Results: Seventy participants were followed-up at 12 months. Intervention set up and delivery costs were £252 per participant in the GS arm and £269 per participant in the GM arm. Mean health and social care costs over 12 months were £1,240 (s.d. £3,496) per participant in the IC arm, £1,259 (s.d. £3,826) per participant in the GS arm and £1,164 (s.d. £2,312) per participant in the GM arm. At a willingness to pay threshold of £20,000 per QALY there was a 65% probability that GS was cost-effective compared to IC (ICER of £1,070). However, there was only a 41% probability that GM was cost-effective compared to IC (ICER of £2,830) at a threshold of £20,000 per QALY. Conclusion: Setting up and running the community based intervention was feasible. Due to the small sample size it is not possible to draw a firm conclusion about cost-effectiveness; however, our preliminary results suggest that goal- setting is likely to be cost-effective compared to the control condition of no goal-setting, the addition of mentoring was effective but not cost-effective.Lifelong Health and Well-being Programme through the Medical Research Counci

A spatiotemporal study of gliosis in relation to depth electrode tracks in drug-resistant epilepsy.

Key questions remain regarding the processes governing gliogenesis following central nervous system injury that are critical to understanding both beneficial brain repair mechanisms and any long-term detrimental effects, including increased risk of seizures. We have used cortical injury produced by intracranial electrodes (ICEs) to study the time-course and localization of gliosis and gliogenesis in surgically resected human brain tissue. Seventeen cases with ICE injuries of 4-301 days age were selected. Double-labelled immunolabelling using a proliferative cell marker (MCM2), markers of fate-specific transcriptional factors (PAX6, SOX2), a microglial marker (IBA1) and glial markers (nestin, GFAP) was quantified in three regions: zone 1 (immediate vicinity: 0-350 μm), zone 2 (350-700 μm) and zone 3 (remote ≥2000 μm) in relation to the ICE injury site. Microglial/macrophage cell densities peaked at 28-30 days post-injury (dpi) with a significant decline in proliferating microglia with dpi in all zones. Nestin-expressing cells (NECs) were concentrated in zones 1 and 2, showed the highest regenerative capacity (MCM2 and PAX6 co-expression) and were intimately associated with capillaries within the organizing injury cavity. There was a significant decline in nestin/MCM2 co-expressing cells with dpi in zones 1 and 2. Nestin-positive fibres remained in the chronic scar, and NECs with neuronal morphology were noted in older injuries. GFAP-expressing glia were more evenly distributed between zones, with no significant decline in density or proliferative capacity with dpi. Colocalization between nestin and GFAP in zone 1 glial cells decreased with increasing dpi. In conclusion, NECs at acute injury sites are a proliferative, transient cell population with capacity for maturation into astrocytes with possible neuronal differentiation observed in older injuries

The Agewell trial: a pilot randomised controlled trial of a behaviour change intervention to promote healthy ageing and reduce risk of dementia in later life.

This is the final version of the article. Available from BioMed Central via the DOI in this record.BACKGROUND: Lifestyle factors represent prime targets for behaviour change interventions to promote healthy ageing and reduce dementia risk. We evaluated a goal-setting intervention aimed at promoting increased cognitive and physical activity and improving mental and physical fitness, diet and health. METHODS: This was a pilot randomised controlled trial designed to guide planning for a larger-scale investigation, provide preliminary evidence regarding efficacy, and explore feasibility and acceptability. Primary outcomes were engagement in physical and cognitive activity. Participants aged over 50 living independently in the community were recruited through a community Agewell Centre. Following baseline assessment participants were randomly allocated to one of three conditions: control (IC) had an interview in which information about activities and health was discussed; goal-setting (GS n = 24) had an interview in which they set behaviour change goals relating to physical, cognitive and social activity, health and nutrition; and goal-setting with mentoring (GM, n = 24) had the goal-setting interview followed by bi-monthly telephone mentoring. Participants and researchers were blinded to group assignment. Participants were reassessed after 12 months. RESULTS: Seventy-five participants were randomised (IC n = 27, GS n = 24, GM n = 24). At 12-month follow-up, the two goal-setting groups, taken together (GS n = 21, GM n = 22), increased their level of physical (effect size 0.37) and cognitive (effect size 0.15) activity relative to controls (IC n = 27). In secondary outcomes, the two goal-setting groups taken together achieved additional benefits compared to control (effect sizes ≥ 0.2) in memory, executive function, cholesterol level, aerobic capacity, flexibility, balance, grip strength, and agility. Adding follow-up mentoring produced further benefits compared to goal-setting alone (effect sizes ≥ 0.2) in physical activity, body composition, global cognition and memory, but not in other domains. Implementation of the recruitment procedure, assessment and intervention was found to be feasible and the approach taken was acceptable to participants, with no adverse effects. CONCLUSIONS: A brief, low-cost goal-setting intervention is feasible and acceptable, and has the potential to achieve increased activity engagement. TRIAL REGISTRATION: Current Controlled Trials ISRCTN30080637.This trial was funded by Medical Research Council grant G1001888/1 to LC, JVH, IRJ, JT and CJW. The funding body played no role in the design of the study, in collection, analysis and interpretation of data, in the writing of the manuscript, or in the decision to submit the manuscript for publication. We acknowledge the support of Age Cymru Gwynedd a Môn including John Clifford Jones, Maldwyn Roberts, Stephen Williams and Mici Plwm. We would like to thank Sharman Harris and Catrin Searell, Department of Clinical Chemistry, Ysbyty Gwynedd, Bangor, the volunteers at the Nefyn Agewell Centre, and all the members of the Nefyn Agewell Centre, and especially all those who took part in the research project. We are grateful to Professor Carol Brayne, Cambridge University, Professor Martin Knapp, London School of Economics, Professor Mike Martin, Zürich University, and Professor Robin Morris, King’s College London Institute of Psychiatry, who acted as external advisors to the project. Special thanks go to Andrew Brand for statistical advice