How long has NICE taken to produce Technology Appraisal guidance? A retrospective study to estimate predictors of time to guidance.

OBJECTIVES: To assess how long the UK's National Institute for Health and Clinical Excellence's (NICE) Technology Appraisal Programme has taken to produce guidance and to determine independent predictors of time to guidance. DESIGN: Retrospective time to event (survival) analysis. SETTING: Technology Appraisal guidance produced by NICE. DATASOURCE: All appraisals referred to NICE by February 2010 were included, except those referred prior to 2001 and a number that were suspended. OUTCOME MEASURE: Duration from the start of an appraisal (when the scope document was released) until publication of guidance. RESULTS: Single Technology Appraisals (STAs) were published significantly faster than Multiple Technology Appraisals (MTAs) with median durations of 48.0 (IQR; 44.3-75.4) and 74.0 (IQR; 60.9-114.0) weeks, respectively (p <0.0001). Median time to publication exceeded published process timelines, even after adjusting for appeals. Results from the modelling suggest that STAs published guidance significantly faster than MTAs after adjusting for other covariates (by 36.2 weeks (95% CI -46.05 to -26.42 weeks)) and that appeals against provisional guidance significantly increased the time to publication (by 42.83 weeks (95% CI 35.50 to 50.17 weeks)). There was no evidence that STAs of cancer-related technologies took longer to complete compared with STAs of other technologies after adjusting for potentially confounding variables and only weak evidence suggesting that the time to produce guidance is increasing each year (by 1.40 weeks (95% CI -0.35 to 2.94 weeks)). CONCLUSIONS: The results from this study suggest that the STA process has resulted in significantly faster guidance compared with the MTA process irrespective of the topic, but that these gains are lost if appeals are made against provisional guidance. While NICE processes continue to evolve over time, a trade-off might be that decisions take longer but at present there is no evidence of a significant increase in duration

Cerebrovascular disease in ageing and Alzheimer's disease

Cerebrovascular disease (CVD) and Alzheimer’s disease (AD) have more in common than their association with ageing. They share risk factors and overlap neuropathologically. Most patients with AD have Aβ amyloid angiopathy and degenerative changes affecting capillaries, and many have ischaemic parenchymal abnormalities. Structural vascular disease contributes to the ischaemic abnormalities in some patients with AD. However, the stereotyped progression of hypoperfusion in this disease, affecting first the precuneus and cingulate gyrus, then the frontal and temporal cortex and lastly the occipital cortex, suggests that other factors are more important, particularly in early disease. Whilst demand for oxygen and glucose falls in late disease, functional MRI, near infrared spectroscopy to measure the saturation of haemoglobin by oxygen, and biochemical analysis of myelin proteins with differential susceptibility to reduced oxygenation have all shown that the reduction in blood flow in AD is primarily a problem of inadequate blood supply, not reduced metabolic demand. Increasing evidence points to non-structural vascular dysfunction rather than structural abnormalities of vessel walls as the main cause of cerebral hypoperfusion in AD. Several mediators are probably responsible. One that is emerging as a major contributor is the vasoconstrictor endothelin-1 (EDN1). Whilst there is clearly an additive component to the clinical and pathological effects of hypoperfusion and AD, experimental and clinical observations suggest that the disease processes also interact mechanistically at a cellular level in a manner that exacerbates both. The elucidation of some of the mechanisms responsible for hypoperfusion in AD and for the interactions between CVD and AD has led to the identification of several novel therapeutic approaches that have the potential to ameliorate ischaemic damage and slow the progression of neurodegenerative disease

Cost-effectiveness of HCV case-finding for people who inject drugs via dried blood spot testing in specialist addiction services and prisons

ObjectivesPeople who inject drugs (PWID) are at high risk for acquiring hepatitis C virus (HCV), but many are unaware of their infection. HCV dried blood spot (DBS) testing increases case-finding in addiction services and prisons. We determine the cost-effectiveness of increasing HCV case-finding among PWID by offering DBS testing in specialist addiction services or prisons as compared to using venepuncture.DesignCost-utility analysis using a dynamic HCV transmission model among PWID, including: disease progression, diagnosis, treatment, injecting status, incarceration and addition services contact.Setting uk interventionDBS testing in specialist addiction services or prisons. Intervention impact was determined by a meta-analysis of primary data.Primary and secondary outcome measuresCosts (in UK £, £1=US$1.60) and utilities (quality-adjusted life years, QALYs) were attached to each state and the incremental cost effectiveness ratio (ICER) determined. Multivariate uncertainty and one-way sensitivity analyses were performed.ResultsFor a £20 000 per QALY gained willingness-to-pay threshold, DBS testing in addiction services is cost-effective (ICER of £14 600 per QALY gained). Under the base-case assumption of no continuity of treatment/care when exiting/entering prison, DBS testing in prisons is not cost-effective (ICER of £59 400 per QALY gained). Results are robust to changes in HCV prevalence; increasing PWID treatment rates to those for ex-PWID considerably reduces ICER (£4500 and £30 000 per QALY gained for addiction services and prison, respectively). If continuity of care is &gt;40%, the prison DBS ICER falls below £20 000 per QALY gained.ConclusionsDespite low PWID treatment rates, increasing case-finding can be cost-effective in specialist addiction services, and in prisons if continuity of treatment/care is ensured

Pericyte Contractile Responses to Endothelin-1 and Aβ Peptides:Assessment by Electrical Impedance Assay

Pericytes are vascular mural cells that contract and relax in response to vasoactive stimuli to regulate neurovascular coupling and cerebral blood flow. Pericytes are damaged and degenerate in Alzheimer’s disease (AD). We previously showed that the level of the regulatory vasoconstrictor, endothelin-1 (EDN1), is elevated in AD cerebral cortex and upregulated by amyloid-beta (Aβ). We have used electrical impedance analysis to monitor the contractile and proliferative response of cultured human fetal and adult brain-derived pericytes to EDN1 in real-time. EDN1 caused transient, dose-dependent contraction of fetal and adult brain pericytes that was mediated by EDN1 type A receptors and increased the subsequent proliferation of fetal but not adult cells. The contractile responses to EDN1 were weaker in the adult pericytes. The EDN1-mediated contractile response of fetal pericytes was unchanged after exposure to Aβ1–40 or Aβ1–42 (0.1–10 μM) for 1 h but both contraction and subsequent relaxation were significantly impaired upon exposure to Aβ for 24 h. These data suggest that chronic exposure to Aβ interferes with EDN1-mediated pericyte contractility, potentially contributing to neurovascular uncoupling and reduced cerebral blood flow in AD

Differing associations between Aβ accumulation, hypoperfusion, blood–brain barrier dysfunction and loss of PDGFRB pericyte marker in the precuneus and parietal white matter in Alzheimer's disease

Recent studies implicate loss of pericytes in hypoperfusion and blood–brain barrier (BBB) leakage in Alzheimer's disease (AD). In this study, we have measured levels of the pericyte marker, platelet-derived growth factor receptor-β (PDGFRB), and fibrinogen (to assess blood–brain barrier leakage), and analyzed their relationship to indicators of microvessel density (von Willebrand factor level), ante-mortem oxygenation (myelin-associated glycoprotein:proteolipid protein-1 ratio and vascular endothelial growth factor level), Aβ level and plaque load, in precuneus and underlying white matter from 49 AD to 37 control brains. There was reduction in PDGFRB and increased fibrinogen in the precuneus in AD. These changes correlated with reduction in oxygenation and with plaque load. In the underlying white matter, increased fibrinogen correlated with reduced oxygenation, but PDGFRB level was unchanged. The level of platelet-derived growth factor-ββ (PDGF-BB), important for pericyte maintenance, was increased in AD but mainly in the insoluble tissue fraction, correlating with insoluble Aβ level. Loss of the PDGFRB within the precuneus in AD is associated with fibrinogen leakage and reduced oxygenation, and related to fibrillar Aβ accumulation. In contrast, fibrinogen leakage and reduced oxygenation of underlying white matter occur independently of loss of PDGFRB, perhaps secondary to reduced transcortical perfusion. </jats:p

Pathophysiology of hypoperfusion of the precuneus in early Alzheimer’s disease

The earliest decline in cerebral perfusion in Alzheimer's disease (AD) is in the medial parietal cortex (precuneus). We have analyzed precuneus in post‐mortem tissue from 70 AD and 37 control brains to explore the pathophysiology of the hypoperfusion: the contribution of arteriolosclerotic small vessel disease (SVD) and cerebral amyloid angiopathy (CAA), and of the vasoconstrictors endothelin‐1 (EDN1) and angiotensin II (Ang II), and the association with Aβ. The myelin‐associated glycoprotein:proteolipid protein‐1 ratio (MAG:PLP1) was used as an indicator of oxygenation of the precuneus prior to death. MAG:PLP1 was reduced ∼50% in early AD (Braak stage III–IV). Although MAG:PLP1 remained low in advanced AD (stage V–VI), the reduction was less pronounced, possibly reflecting falling oxygen demand. Reduction in cortical MAG:PLP1 correlated with elevation in vascular endothelial growth factor (VEGF), another marker of hypoperfusion. Cortical MAG:PLP1 declined nonsignificantly with increasing SVD and CAA, but significantly with the concentration of EDN1, which was elevated approximately 75% in AD. In contrast, with reduction in cortical MAG:PLP1, Ang II level and angiotensin‐converting enzyme (ACE) activity declined, showing a normal physiological response to hypoperfusion. MAG:PLP1 was reduced in the parietal white matter (WM) in AD but here the decline correlated positively (ie, physiologically) with WM EDN1. However, the decline of MAG:PLP1 in the WM was associated with increasing cortical EDN1 and perhaps reflected vasoconstriction of perforating arterioles, which traverse the cortex to perfuse the WM. EDN1 in the cortex correlated highly significantly with both soluble and insoluble Aβ42, shown previously to upregulate neuronal endothelin‐converting enzyme‐2 (ECE2), but not with Aβ40. Our findings demonstrate reduced oxygenation of the precuneus in early AD and suggest that elevated EDN1, resulting from Aβ42‐mediated upregulation of ECE2, is a contributor

Pathological changes within the cerebral vasculature in Alzheimer's disease:New perspectives

Cerebrovascular disease underpins vascular dementia (VaD), but structural and functional changes to the cerebral vasculature contribute to disease pathology and cognitive decline in Alzheimer's disease (AD). In this review, we discuss the contribution of cerebral amyloid angiopathy and non‐amyloid small vessel disease in AD, and the accompanying changes to the density, maintenance and remodelling of vessels (including alterations to the composition and function of the cerebrovascular basement membrane). We consider how abnormalities of the constituent cells of the neurovascular unit – particularly of endothelial cells and pericytes – and impairment of the blood‐brain barrier (BBB) impact on the pathogenesis of AD. We also discuss how changes to the cerebral vasculature are likely to impair Aβ clearance – both intra‐periarteriolar drainage (IPAD) and transport of Aβ peptides across the BBB, and how impaired neurovascular coupling and reduced blood flow in relation to metabolic demand increase amyloidogenic processing of APP and the production of Aβ. We review the vasoactive properties of Aβ peptides themselves, and the probable bi‐directional relationship between vascular dysfunction and Aβ accumulation in AD. Lastly, we discuss recent methodological advances in transcriptomics and imaging that have provided novel insights into vascular changes in AD, and recent advances in assessment of the retina that allow in vivo detection of vascular changes in the early stages of AD

Dysregulation of ACE-1 in Normal Aging and the Early Stages of Alzheimer's Disease

An imbalance in the renin–angiotensin system (RAS) is associated with cognitive decline and disease pathology in Alzheimer’s disease (AD). In this study, we have investigated changes in the brain angiotensin-converting enzyme-1 (ACE-1) and angiotensin-II (Ang-II), and the counter-regulatory angiotensin-converting enzyme-2 (ACE-2), in the frontal and temporal cortex during normal aging and in the early stages of AD. We studied a cohort of normal aging (n = 121; 19–95 years age-at-death) from the Sudden Death Brain Bank, University of Edinburgh, United Kingdom, and AD and age-matched controls (n = 60) from the South West Dementia Brain Bank, University of Bristol, United Kingdom, stratified according to Braak tangle stage (BS): 0–II, III–IV (intermediate disease), and V–VI (end-stage disease). ACE-1 and ACE-2 enzyme activity were measured using fluorogenic peptide activity assays. ACE-1, ACE-2, and Ang-II protein level were measured by enzyme-linked immunosorbent assay (ELISA). In both regions, ACE-1 protein and Ang-II levels correlated positively with age whereas ACE-1 enzyme activity was inversely related to age. ACE-1 protein correlated positively with Ang-II, whilst ACE-1 activity correlated inversely with Ang-II in normal aging. ACE-1 enzyme activity was elevated at an early/intermediate stage, BS III–IV compared to BS 0–II in the temporal cortex in AD. ACE-2 protein and enzyme activity were unchanged with aging and in AD. In conclusion, ACE-1 activity is induced in the early stages of AD independently from normal physiological age-related changes in ACE-1 protein