Effect of high-flow nasal oxygen on hypoxaemia during procedural sedation: a systematic review and meta-analysis.

We conducted a systematic review to evaluate the effect of high-flow nasal oxygen and conventional oxygen therapy during procedural sedation amongst adults and children. We searched MEDLINE, EMBASE and CINAHL for randomised controlled trials that reported the effects of high-flow nasal oxygen during procedural sedation. The primary outcome measure was hypoxaemia and the secondary outcomes were minimum oxygen saturation; hypercarbia; requirement for airway manoeuvres; and procedure interruptions. The quality of evidence was assessed using the revised Cochrane risk-of bias tool and grading of recommendations, assessment, development and evaluation (GRADE). Nineteen randomised controlled trials (4121 patients) including three in children were included. Administration of high-flow nasal oxygen reduced hypoxaemia, risk ratio (95%CI) 0.37 (0.24-0.56), p < 0.001; minor airway manoeuvre requirements, risk ratio (95%CI) 0.26 (0.11-0.59), p < 0.001; procedural interruptions, risk ratio (95%CI) 0.17 (0.05-0.53), p = 0.002; and increased minimum oxygen saturation, mean difference (95%CI) 4.1 (2.70-5.50), p < 0.001; as compared with the control group. High-flow nasal oxygen had no impact on hypercarbia, risk ratio (95%CI) 1.24 (0.97-1.58), p = 0.09, I2 = 0%. High-flow nasal oxygen reduced the incidence of hypoxaemia regardless of the procedure involved, degree of fractional inspired oxygen, risk-profile of patients and mode of propofol administration. The evidence was ascertained as moderate for all outcomes except for procedure interruptions. In summary, high-flow nasal oxygen compared with conventional oxygenation techniques reduced the risk of hypoxaemia, increased minimum oxygen saturation and reduced the requirement for airway manoeuvres. High-flow nasal oxygen should be considered in patients at risk of hypoxaemia during procedural sedation.

Effect of high-flow vs. low-flow nasal plus mouthguard oxygen therapy on hypoxaemia during sedation: a multicentre randomised controlled trial.

Whether high-flow vs. low-flow nasal oxygen reduces hypoxaemia for sedation during endoscopic retrograde cholangiopancreatography is currently unknown. In this multicentre trial, 132 patients ASA physical status 3 or higher, BMI > 30 kg.m-2 or with known or suspected obstructive sleep apnoea were randomly allocated to high-flow nasal oxygen up to 60 l.min-1 at 100% FI O2 or low-flow nasal oxygen at 4 l.min-1 . The low-flow nasal oxygen group also received oxygen at 4 l.min-1 through an oxygenating mouthguard, totalling 8 l.min-1 . Primary outcome was hypoxaemia, defined as Sp O2 < 90% regardless of duration. Hypoxaemia occurred in 7.7% (5/65) of patients with high-flow and 9.1% (6/66) with low-flow nasal oxygen (percentage point difference -1.4%, 95%CI -10.9 to 8.0; p = 0.77). Between the groups, there were no significant differences in frequency of hypoxaemic episodes; lowest Sp O2 ; peak transcutaneous carbon dioxide; hypercarbia (transcutaneous carbon dioxide > 2.66 kPa from baseline); requirement of chin lift/jaw thrust; nasopharyngeal airway insertion; bag-mask ventilation; or tracheal intubation. Following adjustment for duration of the procedure, the primary outcome remained non-significant. In high-risk patients undergoing endoscopic retrograde cholangiopancreatography, oxygen therapy with high-flow nasal oxygen did not reduce the rate of hypoxaemia, hypercarbia or the need for airway interventions, compared with combined oral and nasal low-flow oxygen.

Life expectancy inequalities in Wales before COVID-19: an exploration of current contributions by age and cause of death and changes between 2002 and 2018.

OBJECTIVES: The COVID-19 pandemic in Wales and the UK has highlighted significant and historic inequalities in health between social groups. To better understand the composition of these inequalities and inform planning after the pandemic, we undertook a decomposition of life expectancy inequalities between the most and least deprived quintiles for men and women by age and cause of death and explored trends between 2002 and 2018. STUDY DESIGN: Statistical decomposition of life expectancy inequalities by age and cause of death using routine population mortality datasets. METHODS: We used routine statistics from the Office for National Statistics for the period 2002-2018 on population and deaths in Wales stratified by age, gender, Welsh Index of Multiple Deprivation (WIMD) 2019 quintile and cause of death, categorised by International Classification of Disease, version 10, code into 15 categories of public health relevance. We aggregated data to 3-year rolling figures to account for low numbers of events in some groups annually. Next, we estimated life expectancy at birth by quintile, gender and period using life table methods. Lastly, we performed a decomposition analysis using the Arriaga method to identify the specific disease categories and ages at which excess deaths occur in more disadvantaged areas to highlight potential areas for action. RESULTS: Life expectancy inequalities between the most and least WIMD quintiles rose for both genders between 2002 and 2018: from 4.69 to 6.02 years for women (an increase of 1.33 years) and from 6.34 to 7.42 years for men (an increase of 1.08 years). Exploratory analysis of these trends suggested that the following were most influential for women: respiratory disease (1.50 years), cancers (1.36 years), circulatory disease (1.35 years) and digestive disease (0.51 years). For men, the gap was driven by circulatory disease (2.01 years), cancers (1.39 years), respiratory disease (1.25 years), digestive disease (0.79 years), drug- and alcohol-related conditions (0.54 years) and external causes (0.54 years). Contributions for women from respiratory disease, cancers, dementia and drug- and alcohol-related conditions appeared to be increasing, while among men, there were rising contributions from respiratory, digestive and circulatory disease. CONCLUSIONS: Life expectancy inequalities in Wales remain wide and have been increasing, particularly among women, with indications of worsening trends since 2010 following the introduction of fiscal austerity. As agencies recover from the pandemic, these findings should be considered alongside any resumption of services in Wales or future health and public policy.

Low back pain and disc degeneration are decreased following chronic toll-like receptor 4 inhibition in a mouse model.

OBJECTIVE: Intervertebral disc degeneration is a leading cause of chronic low back pain (LBP) but current treatment is limited. Toll-like receptors (TLRs) on disc cells are activated by endogenous extracellular matrix (ECM) fragments and modulate degeneration in vitro. This study investigated whether inhibiting TLR4 slows disc degeneration and reduces behavioral signs of LBP in vivo. DESIGN: 7-9-month old wild-type and secreted protein acidic and rich in cysteine (SPARC)-null (a model of disc degeneration and LBP) male mice were treated with TAK-242 (TLR4 inhibitor) once, and following a 10-day washout, mice were treated 3 times/week for 8 weeks. Behavioral signs of axial discomfort and radiating leg pain were assessed weekly with the grip force assay and acetone test, respectively. Following treatment, pain-related spinal cord changes were evaluated and lumbar discs were excised and cultured. Cytokine secretion from discs was evaluated with protein arrays. RESULTS: SPARC-null mice displayed elevated signs of axial and radiating pain at baseline compared to wild-type. Chronic, but not acute, TLR4 inhibition reduced behavioral signs of pain compared to vehicle. SPARC-null mice have increased calcitonin gene-related peptide (CGRP)- and glial fibrillary acidic protein (GFAP)-immunoreactivity (astrocyte marker) in the dorsal horn compared to wild-type, which is reduced by chronic TLR4 inhibition. Ex vivo degenerating discs from SPARC-null mice secrete increased levels of many pro-inflammatory cytokines, which chronic TLR4 inhibition reduced. CONCLUSION: Chronic TLR4 inhibition decreased behavioral signs of LBP, pain-related neuroplasticity and disc inflammation in SPARC-null mice. TAK-242 inhibits TLR4 activation within discs, as evidenced by decreases in cytokine release. Therefore, TLRs are potential therapeutic targets to slow disc degeneration and reduce pain.

Nerve Growth Factor Is Regulated by Toll-Like Receptor 2 in Human Intervertebral Discs.

Nerve growth factor (NGF) contributes to the development of chronic pain associated with degenerative connective tissue pathologies, such as intervertebral disc degeneration and osteoarthritis. However, surprisingly little is known about the regulation of NGF in these conditions. Toll-like receptors (TLR) are pattern recognition receptors classically associated with innate immunity but more recently were found to be activated by endogenous alarmins such as fragmented extracellular matrix proteins found in degenerating discs or cartilage. In this study we investigated if TLR activation regulates NGF and which signaling mechanisms control this response in intervertebral discs. TLR2 agonists, TLR4 agonists, or IL-1ß (control) treatment increased NGF, brain-derived neurotrophic factor (BDNF), and IL-1ß gene expression in human disc cells isolated from healthy, pain-free organ donors. However, only TLR2 activation or IL-1ß treatment increased NGF protein secretion. TLR2 activation increased p38, ERK1/2, and p65 activity and increased p65 translocation to the cell nucleus. JNK activity was not affected by TLR2 activation. Inhibition of NF-κB, and to a lesser extent p38, but not ERK1/2 activity, blocked TLR2-driven NGF up-regulation at both the transcript and protein levels. These results provide a novel mechanism of NGF regulation in the intervertebral disc and potentially other pathogenic connective tissues. TLR2 and NF-κB signaling are known to increase cytokines and proteases, which accelerate matrix degradation. Therefore, TLR2 or NF-κB inhibition may both attenuate chronic pain and slow the degenerative progress in vivo.

Next-to-Next-to Leading Order QCD Predictions for Single Jet Inclusive Production at the LHC.

We report the first calculation of fully differential jet production at leading color in all partonic channels at next-to-next-to leading order in perturbative QCD and compare to the available ATLAS 7 TeV data. We discuss the size and shape of the perturbative corrections along with their associated scale variation across a wide range in jet transverse momentum, p_{T}, and rapidity, y. We find significant effects, especially at low p_{T}, and discuss the possible implications for parton distribution function fits.

Precise Predictions for Dijet Production at the LHC.

We present the calculation of dijet production, doubly differential in dijet mass m_{jj} and rapidity difference |y^{*}|, at leading color in all partonic channels at next-to-next-to-leading order (NNLO) in perturbative QCD. We consider the long-standing problems associated with scale choice for dijet production at next-to-leading order (NLO) and investigate the impact of including the NNLO contribution. We find that the NNLO theory provides reliable predictions, even when using scale choices that display pathological behavior at NLO. We choose the dijet invariant mass as the theoretical scale on the grounds of perturbative convergence and residual scale variation and compare the predictions to the ATLAS 7 TeV 4.5 fb^{-1} data.

Urothelial cells may indicate underlying bacteriuria in pregnancy at term: a comparative study.

BACKGROUND: Urinary tract infection is common in pregnancy. Urine is sampled from by mid-stream collection (MSU). If epithelial cells are detected, contamination by vulvo-vagial skin and skin bacteria is assumed. Outside pregnancy, catheter specimen urine (CSU) is considered less susceptible to contamination. We compared MSU and CSU methods in term pregnancy to test these assumptions. METHODS: Healthy pregnant women at term gestation (n = 32, median gestation 38 + 6 weeks, IQR 37 + 6-39 + 2) undergoing elective caesarean section provided a MSU and CSU for paired comparison that were each analysed for bacterial growth and bladder distress by fresh microscopy, sediment culture and immunofluorescent staining. Participants completed a detailed questionnaire on lower urinary tract symptoms. Epithelial cells found in urine were tested for urothelial origin by immunofluorescent staining of Uroplakin III (UP3), a urothelial cell surface glycoprotein. Urothelial cells with closely associated bacteria, or "clue cells", were also counted. Wilcoxons signed rank test was used for paired analysis. RESULTS: Women reported multiple lower urinary tract symptoms (median 3, IQR 0-8). MSU had higher white blood cell counts (median 67 vs 46, z = 2.75, p = 0.005) and epithelial cell counts (median 41 vs 22, z = 2.57, p = 0.009) on fresh microscopy. The proportion of UP3+ cells was not different (0.920 vs 0.935, z = 0.08, p = 0.95), however MSU had a higher proportion of clue cells (0.978 vs 0.772, z = 3.17, p = 0.001). MSU had more bacterial growth on sediment culture compared to CSU specimens (median 8088 total cfu/ml vs 0, z = 4.86, p = 0.001). Despite this, routine laboratory cultures reported a negative screening culture for 40.6% of MSU specimens. CONCLUSION: Our findings have implications for the correct interpretation of MSU findings in term pregnancy. We observed that MSU samples had greater bacterial growth and variety when compared to CSU samples. The majority of epithelial cells in both MSU and CSU samples were urothelial in origin, implying no difference in contamination. MSU samples had a higher proportion of clue cells to UP3+ cells, indicating a greater sensitivity to bacterial invasion. Urinary epithelial cells should not be disregarded as contamination, instead alerting us to underlying bacterial activity.

Detecting objective and subjective cognitive effects of electroconvulsive therapy: intensity, duration and test utility in a large clinical sample.

BACKGROUND: Electroconvulsive therapy (ECT) is an effective treatment for depression but the extent and persistence of cognitive side-effects remain uncertain. It has been reported that there is little evidence that impairments last longer than up to 15 days post-ECT. However, relatively few studies have followed patients for even as long as 1 month post-ECT. Here we report results from a brief cognitive battery given prior to ECT and repeated five times up to 6 months post-ECT. METHOD: In a retrospective case-note study of routinely collected clinical data 126 patients treated with ECT completed two neuropsychological tests [Cambridge Neuropsychological Test Automated Battery (CANTAB) spatial recognition memory (SRM) and Mini Mental State Examination (MMSE)] and two subjective reports of memory function, prior to ECT. Patients were reassessed following ECT and at 1, 3 and 6 months post-ECT although not all patients completed all assessments. RESULTS: Performance relative to pre-ECT baseline was significantly poorer at each post-ECT assessment up to 3 months post-ECT using the CANTAB SRM, but was improved at 6 months. Conversely, MMSE score showed improvements relative to baseline from 1 month post-ECT. Mood and subjective memory scores improved following ECT and were correlated with one another, but not with either neuropsychological measure. CONCLUSIONS: The CANTAB SRM task revealed reversible cognitive deficiencies relative to a pre-ECT baseline for at least 3 months following ECT, while MMSE score and patients' subjective reports showed only improvement. Visuospatial memory scores eventually exceeded baseline 6 months post-ECT.

Emperor penguin body surfaces cool below air temperature.

Emperor penguins Aptenodytes forsteri are able to survive the harsh Antarctic climate because of specialized anatomical, physiological and behavioural adaptations for minimizing heat loss. Heat transfer theory predicts that metabolic heat loss in this species will mostly depend on radiative and convective cooling. To examine this, thermal imaging of emperor penguins was undertaken at the breeding colony of Pointe Géologie in Terre Adélie (66°40' S 140° 01' E), Antarctica in June 2008. During clear sky conditions, most outer surfaces of the body were colder than surrounding sub-zero air owing to radiative cooling. In these conditions, the feather surface will paradoxically gain heat by convection from surrounding air. However, owing to the low thermal conductivity of plumage any heat transfer to the skin surface will be negligible. Future thermal imaging studies are likely to yield further insights into the adaptations of this species to the Antarctic climate.

Relationship between measures of aerobic fitness, speed and repeated sprint ability in full and part time youth soccer players.

AIM: The aim of the study was to investigate the relationship between repeated sprint ability (RSA) involving changes in direction, short linear sprinting and aerobic capacity in young elite soccer players. A secondary aim was to assess any differences in performance of these assessments between players of different age groups. METHODS: Thirty-two male adolescent soccer players belonging to the same elite club academy were assessed for RSA comprising 6 x 40m efforts interspersed by 25s recovery, linear sprinting speed over 15m, and aerobic capacity via the YYIE2 assessment. RESULTS: There was a significant correlation between performance in the YYIE2 and RSA total time, RSA fastest sprint and RSA percentage decrement (r = -0.71, -0.53, and -0.52 respectively. P<0.05). Significant differences were observed between age groups for distance covered in the YYIE2, RSA total time and RSA fastest sprint (P<0.01). No significant differences were observed for short linear sprinting. CONCLUSION: Assessments of RSA over 40m and incorporating changes of direction appear to be significantly correlated with YYIE2 performance in young elite level soccer players. In addition older players performed significantly better in the YYIE2 assessment and RSA protocol but not in short linear sprinting. These results have implications for the design of assessment protocols for young elite soccer players of different ages.

An investigation of the international literature on nurse practitioner private practice models.

AIM: To investigate and synthesize the international literature surrounding nurse practitioner (NP) private practice models in order to provide an exposition of commonalities and differences. BACKGROUND: NP models of service delivery have been established internationally and most are based in the public healthcare system. In recent years, opportunities for the establishment of NP private practice models have evolved, facilitated by changes in legislation and driven by identification of potential patient need. To date, NP private practice models have received less attention in the literature and, to the authors' knowledge, this is the first international investigation of NP private practice models. DESIGN: Integrative literature review. METHOD: A literature search was undertaken in October 2012. Database sources utilized included Medical Literature Analyses and Retrieval (MEDLINE), the Cumulative Index of Nursing and Allied Health Literature (CINAHL), ProQuest, Scopus and the Cochrane Database of Systematic Reviews (CDSR). The grey literature was also searched. The following Medical Subject Headings (MeSH) and search terms used both individually and in combination included nurse practitioners; private practice; joint practice; collaboration; and insurance, health and reimbursement. Once literature had been identified, a thematic analysis was undertaken to extract themes. RESULTS: Thirty manuscripts and five publications from the grey literature were included in the final review. Private practice NP roles were identified in five countries, with the majority of the literature emanating from the USA. The thematic analysis resulted in the identification of five themes: reimbursement, collaborative arrangements, legislation, models of care and acceptability. CONCLUSION: Proportionally, there are very few NPs engaged in private practice internationally. The most common NP private practice models were community based, with NPs working in clinic settings, either alone or with other health professionals. Challenges in the context of legislation and financial reimbursement were identified in each country where private practice is being undertaken.

"It's the most important work we will ever do": Chiropractic students, servicelearning experiences at a day laborer center in California.

OBJECTIVE: From 2009 to 2019, staff, students, and faculty volunteers from a chiropractic college started Mission Trip America, later re-named Service Trip America (STA), providing monthly free chiropractic services at a hiring hall for day laborers in San Francisco until the 2020 COVID-19 hiatus. We report on volunteers' service-learning experiences. METHODS: Mixed-methods analysis comprising document review, descriptive report of site visit records, and thematic analysis of semi-structured interviews with 12 student and faculty volunteers. RESULTS: STA conducted 104 visits (8-11 per year) including 2272 patient encounters. Document review revealed an average of 22 patients per visit, with 60% to 85% return patients. On average, 3 student interns and 2 student assistants attended each visit, supervised by a doctor of chiropractic faculty member and the program director. Most commonly, interns treated 8 patients during the 4- to 5-hour visits. Patient concerns included musculoskeletal problems and other health conditions commonly seen at chiropractic offices and teaching clinics. Interns also regularly saw chronic health problems exacerbated by poor living conditions, violence, limited access to health care, low educational attainment, chronic stress, and the extreme biomechanical loading resulting from heavy labor. Interview results yielded 4 themes: learning, attitudes, challenges, and program strengths. Interviewees described opportunities to learn while working with a marginalized population and discussed long-term effects on their postgraduation practice as chiropractors. CONCLUSION: Patients' physical, mental health, and psychosocial issues illustrated unique circumstances and profound needs of the underserved population being cared for by STA volunteers. Our findings may provide guidance for other community-based chiropractic service-learning programs in marginalized and underserved communities.

Influence of glioma tumour microenvironment on the transport of ANG1005 via low-density lipoprotein receptor-related protein 1.

BACKGROUND: ANG1005 consists of three molecules of paclitaxel conjugated via ester bonds to the 19-amino-acid peptide Angiopep-2. The new chemical agent has been shown to cross the blood-brain barrier (BBB) by receptor-mediated transcytosis via low-density lipoprotein receptor-related protein 1 (LRP1). The experiments here examined the role of LRP1 in the subsequent endocytosis of drug into cancer cells. METHODS: Localisation of ANG1005 and Angiopep-2 was examined by immunohistochemistry and in-vivo near-infrared fluorescence imaging in mice carrying orthotopic glioma tumours. Transport of ANG1005 and Angiopep-2 was examined in U87 glioblastoma cell lines. RESULTS: Systemically administered ANG1005 and Cy5.5Angiopep-2 localised to orthotopic glioma tumours in mice. The glioma transplants correlated with high expression levels of LRP1. Decreasing LRP1 activity, by RNA silencing or LRP1 competitors, decreased uptake of ANG1005 and Angiopep-2 into U87 glioblastoma cells. Conversely, LRP1 expression and endocytosis rates for ANG1005 and Angiopep-2 increased in U87 cells under conditions that mimicked the microenvironment near aggressive tumours, that is, hypoxic and acidic conditions. CONCLUSION: ANG1005 might be a particularly effective chemotherapeutic agent for the wide array of known LRP1-expressing brain and non-brain cancers, in particular those with an aggressive phenotype.

Estimating metabolic heat loss in birds and mammals by combining infrared thermography with biophysical modelling.

Infrared thermography (IRT) is a technique that determines surface temperature based on physical laws of radiative transfer. Thermal imaging cameras have been used since the 1960s to determine the surface temperature patterns of a wide range of birds and mammals and how species regulate their surface temperature in response to different environmental conditions. As a large proportion of metabolic energy is transferred from the body to the environment as heat, biophysical models have been formulated to determine metabolic heat loss. These models are based on heat transfer equations for radiation, convection, conduction and evaporation and therefore surface temperature recorded by IRT can be used to calculate heat loss from different body regions. This approach has successfully demonstrated that in birds and mammals heat loss is regulated from poorly insulated regions of the body which are seen to be thermal windows for the dissipation of body heat. Rather than absolute measurement of metabolic heat loss, IRT and biophysical models have been most useful in estimating the relative heat loss from different body regions. Further calibration studies will improve the accuracy of models but the strength of this approach is that it is a non-invasive method of measuring the relative energy cost of an animal in response to different environments, behaviours and physiological states. It is likely that the increasing availability and portability of thermal imaging systems will lead to many new insights into the thermal physiology of endotherms.

Relationships between components of physical activity, cardiorespiratory fitness, cardiac autonomic health, and brain-derived neurotrophic factor.

The aim of this study was to examine the relationships between physical activity, cardiorespiratory fitness, cardiac autonomic health, and brain-derived neurotrophic factor concentrations in healthy men (n = 28) and women (n = 16). Cardiorespiratory fitness (VO2max, litres x min(-1)) was estimated from heart rate and work rate using a 6-min cycle ergometer test, cardiac autonomic health was assessed from supine measures of heart rate variability using standard telemetry techniques, physical activity was assessed by questionnaire, and brain-derived neurotrophic factor by enzyme-linked immunosorbant assay (ELISA). There was no significant difference in cardiorespiratory fitness between men (3.75 +/- 0.84 litres x min(-1)) and women (3.43 +/- 0.72 litres x min(-1)) (P = 0.206). Similarly, there was no significant difference in Baecke scores (work, sport, and leisure) between men and women. Cardiorespiratory fitness was significantly correlated with seated heart rate (r = -0.445, P = 0.002, n = 44), the heart rate variability measure SD12 (index of cardiac autonomic health) (r = 0.462, P = 0.035, n = 21), and Baecke sport score (r = 0.536, P = 0.000, n = 43). Cardio autonomic health (SD12) was negatively associated with brain-derived neurotrophic factor concentration although this correlation did not attain statistical significance (r = -0.324, P = 0.152, n = 21). The results show that cardiorespiratory fitness was significantly correlated with the Baecke sport (rather than work or leisure) score and cardiac autonomic function (SD12). However, SD12 was not significantly associated with resting concentrations of serum brain-derived neurotrophic factor, a key regulator of energy metabolism and neural plasticity.

Calculations for deep inelastic scattering using fast interpolation grid techniques at NNLO in QCD and the extraction of α s from HERA data.

The extension of interpolation-grid frameworks for perturbative QCD calculations at next-to-next-to-leading order (NNLO) is presented for deep inelastic scattering (DIS) processes. A fast and flexible evaluation of higher-order predictions for any a posteriori choice of parton distribution functions (PDFs) or value of the strong coupling constant is essential in iterative fitting procedures to extract PDFs and Standard Model parameters as well as for a detailed study of the scale dependence. The APPLfast project, described here, provides a generic interface between the parton-level Monte Carlo program NNLOjet and both the APPLgrid and fastNLO libraries for the production of interpolation grids at NNLO accuracy. Details of the interface for DIS processes are presented together with the required interpolation grids at NNLO, which are made available. They cover numerous inclusive jet measurements by the H1 and ZEUS experiments at HERA. An extraction of the strong coupling constant is performed as an application of the use of such grids and a best-fit value of α s ( M Z ) = 0.1170 ( 15 ) exp ( 25 ) th is obtained using the HERA inclusive jet cross section data.

Abeta deposits in older non-demented individuals with cognitive decline are indicative of preclinical Alzheimer's disease.

Approximately 30% of healthy persons aged over 75 years show Abeta deposition at autopsy. It is postulated that this represents preclinical Alzheimer's disease (AD). We evaluated the relationship between Abeta burden as assessed by PiB PET and cognitive decline in a well-characterized, non-demented, elderly cohort. PiB PET studies and cognitive tests were performed on 34 elderly participants (age 73+/-6) from the longitudinal Melbourne Healthy Aging Study (MHAS). Subjects were classified as being cognitively 'stable' or 'declining' by an independent behavioural neurologist based on clinical assessment and serial word-list recall scores from the preceding 6-10 years. Decline was calculated from the slope of the word-list recall scores. Abeta burden was quantified using Standardized Uptake Value normalized to cerebellar cortex. Ten subjects were clinically classified as declining. At the time of the PET scans, three of the declining subjects had mild cognitive impairment, one had AD, and six were declining but remained within the normal range for age on cognitive tests. Declining subjects were much more likely to show cortical PiB binding than stable subjects (70% vs. 17%, respectively). Neocortical Abeta burden correlated with word-list recall slopes (r=-0.78) and memory function (r=-0.85) in the declining group. No correlations were observed in the stable group. Abeta burden correlated with incident memory impairment and the rate of memory decline in the non-demented ageing population. These observations suggest that neither memory decline nor Abeta deposition are part of normal ageing and likely represent preclinical AD. Further longitudinal observations are required to confirm this hypothesis.