Immuno-epigenetic signature derived in saliva associates with the encephalopathy of prematurity and perinatal inflammatory disorders.

BACKGROUND: Preterm birth is closely associated with a phenotype that includes brain dysmaturation and neurocognitive impairment, commonly termed Encephalopathy of Prematurity (EoP), of which systemic inflammation is considered a key driver. DNA methylation (DNAm) signatures of inflammation from peripheral blood associate with poor brain imaging outcomes in adult cohorts. However, the robustness of DNAm inflammatory scores in infancy, their relation to comorbidities of preterm birth characterised by inflammation, neonatal neuroimaging metrics of EoP, and saliva cross-tissue applicability are unknown. METHODS: Using salivary DNAm from 258 neonates (n = 155 preterm, gestational age at birth 23.28 - 34.84 weeks, n = 103 term, gestational age at birth 37.00 - 42.14 weeks), we investigated the impact of a DNAm surrogate for C-reactive protein (DNAm CRP) on brain structure and other clinically defined inflammatory exposures. We assessed i) if DNAm CRP estimates varied between preterm infants at term equivalent age and term infants, ii) how DNAm CRP related to different types of inflammatory exposure (maternal, fetal and postnatal) and iii) whether elevated DNAm CRP associated with poorer measures of neonatal brain volume and white matter connectivity. RESULTS: Higher DNAm CRP was linked to preterm status (-0.0107 ± 0.0008, compared with -0.0118 ± 0.0006 among term infants; p < 0.001), as well as perinatal inflammatory diseases, including histologic chorioamnionitis, sepsis, bronchopulmonary dysplasia, and necrotising enterocolitis (OR range |2.00 | to |4.71|, p < 0.01). Preterm infants with higher DNAm CRP scores had lower brain volume in deep grey matter, white matter, and hippocampi and amygdalae (ß range |0.185| to |0.218|). No such associations were observed for term infants. Association magnitudes were largest for measures of white matter microstructure among preterms, where elevated epigenetic inflammation associated with poorer global measures of white matter integrity (ß range |0.206| to |0.371|), independent of other confounding exposures. CONCLUSIONS: Inflammatory-related DNAm captures the allostatic load of inflammatory burden in preterm infants. Such DNAm measures complement biological and clinical metrics when investigating the determinants of neurodevelopmental differences.

Predictors for infection severity for open tibial fractures: major trauma centre perspective.

INTRODUCTION: Open diaphyseal tibial fractures are the most common long-bone fractures and require a rapid approach to prevent devastating complications. Current literature reports the outcomes of open tibial fractures. However, there is no robust, up-to-date research on the predictive indicators of infection severity in a large open tibial fracture patient cohort. This study investigated the predictive factors of superficial infections and osteomyelitis in open tibial fractures. MATERIALS AND METHODS: A retrospective analysis of the tibial fracture database was carried out from 2014 to 2020. Criteria for inclusion was any tibial fracture including tibial plateau, shaft, pilon or ankle, with an open wound at the fracture site. Exclusion criteria included patients with a follow-up period of less than 12 months and who are deceased. A total of 235 patients were included in our study, of which 154 (65.6%), 42 (17.9%), and 39 (16.6%) developed no infection, superficial infection, or osteomyelitis, respectively. Patient demographics, injury characteristics, fracture characteristics, infection status and management details were collected for all patients. RESULTS: On multivariate modelling, patients with BMI > 30 (OR = 2.078, 95%CI [1.145-6.317], p = 0.025), Gustilo-Anderson (GA) type III (OR = 6.120, 95%CI [1.995-18.767], p = 0.001), longer time to soft tissue cover (p = 0.006) were more likely to develop a superficial infection, and patients with wound contamination (OR = 3.152, 95%CI [1.079-9.207], p = 0.036), GA-3 (OR = 3.387,95%CI [1.103-10.405], p = 0.026), longer to soft tissue cover (p = 0.007) were more likely to develop osteomyelitis. Univariate analysis also determined that risk factors for superficial infection were: BMI > 35 (OR = 6.107, 95%CI [2.283-16.332], p = 0.003) and wound contamination (OR = 2.249, 95%CI [1.015-5.135], p = 0.047); whilst currently smoking (OR = 2.298, 95%CI [1.087-4.856], p = 0.025), polytrauma (OR = 3.212, 95%CI [1.556-6.629], p = 0.001), longer time to definitive fixation (p = 0.023) were for osteomyelitis. However, none of these reached significance in multivariate analysis. CONCLUSION: Higher GA classification is a significant risk factor for developing superficial infection and osteomyelitis, with a stronger association with osteomyelitis, especially GA 3C fractures. Predictors for superficial infection included BMI and time to soft tissue closure. Time to definitive fixation, time to soft tissue closure, and wound contamination were associated with osteomyelitis.

A "bottom up" Health in All Policies program: Supporting local government wellbeing approaches.

ISSUE ADDRESSED: A wellbeing economy requires multiple inputs to enable the wholistic vision of a sustainable healthy population and planet. A Health in All Policies (HiAP) approach is a useful way to support policy makers and planners to implement the activities required to support a wellbeing economy. OUTLINE OF THE PROJECT: Aotearoa New Zealand's Government has explicitly set a path towards a wellbeing economy. Here, we report the utility of a HiAP approach in Greater Christchurch, the largest urban area in the South Island of New Zealand, to achieving the shared societal goals of a sustainable healthy population and environment. We use the World Health Organisation draft Four Pillars for HiAP implementation as a framework for discussion. SO WHAT?: The paper adds to the growing number of examples of city and regions supporting a wellbeing agenda, specifically focused on some of the successes and challenges for local HiAP practitioners working within a public health unit in influencing this work.

A comparison of blood and brain-derived ageing and inflammation-related DNA methylation signatures and their association with microglial burdens.

Inflammation and ageing-related DNA methylation patterns in the blood have been linked to a variety of morbidities, including cognitive decline and neurodegenerative disease. However, it is unclear how these blood-based patterns relate to patterns within the brain and how each associates with central cellular profiles. In this study, we profiled DNA methylation in both the blood and in five post mortem brain regions (BA17, BA20/21, BA24, BA46 and hippocampus) in 14 individuals from the Lothian Birth Cohort 1936. Microglial burdens were additionally quantified in the same brain regions. DNA methylation signatures of five epigenetic ageing biomarkers ('epigenetic clocks'), and two inflammatory biomarkers (methylation proxies for C-reactive protein and interleukin-6) were compared across tissues and regions. Divergent associations between the inflammation and ageing signatures in the blood and brain were identified, depending on region assessed. Four out of the five assessed epigenetic age acceleration measures were found to be highest in the hippocampus (ß range = 0.83-1.14, p ≤ 0.02). The inflammation-related DNA methylation signatures showed no clear variation across brain regions. Reactive microglial burdens were found to be highest in the hippocampus (ß = 1.32, p = 5 × 10-4 ); however, the only association identified between the blood- and brain-based methylation signatures and microglia was a significant positive association with acceleration of one epigenetic clock (termed DNAm PhenoAge) averaged over all five brain regions (ß = 0.40, p = 0.002). This work highlights a potential vulnerability of the hippocampus to epigenetic ageing and provides preliminary evidence of a relationship between DNA methylation signatures in the brain and differences in microglial burdens.

The UK Coronavirus Job Retention Scheme and diet, physical activity, and sleep during the COVID-19 pandemic: evidence from eight longitudinal population surveys.

BACKGROUND: In March 2020, the UK implemented the Coronavirus Job Retention Scheme (furlough) to minimise job losses. Our aim was to investigate associations between furlough and diet, physical activity, and sleep during the early stages of the COVID-19 pandemic. METHODS: We analysed data on 25,092 participants aged 16-66 years from eight UK longitudinal studies. Changes in employment, including being furloughed, were based on employment status before and during the first lockdown. Health behaviours included fruit and vegetable consumption, physical activity, and sleep. Study-specific estimates obtained using modified Poisson regression, adjusting for socio-demographic characteristics and pre-pandemic health and health behaviours, were statistically pooled using random effects meta-analysis. Associations were also stratified by sex, age, and education. RESULTS: Across studies, between 8 and 25% of participants were furloughed. Compared to those who remained working, furloughed workers were slightly less likely to be physically inactive (RR = 0.85; [95% CI 0.75-0.97]; I 2 = 59%) and did not differ overall with respect to low fruit and vegetable consumption or atypical sleep, although findings for sleep were heterogenous (I 2 = 85%). In stratified analyses, furlough was associated with lower fruit and vegetable consumption among males (RR = 1.11; [1.01-1.22]; I 2 = 0%) but not females (RR = 0.84; [0.68-1.04]; I 2 = 65%). Considering changes in quantity, furloughed workers were more likely than those who remained working to report increases in fruit and vegetable consumption, exercise, and hours of sleep. CONCLUSIONS: Those furloughed exhibited similar health behaviours to those who remained in employment during the initial stages of the pandemic. There was little evidence to suggest that adoption of such social protection policies in the post-pandemic recovery period and during future economic crises had adverse effects on population health behaviours.

The UK Coronavirus Job Retention Scheme and smoking, alcohol consumption and vaping during the COVID-19 pandemic: evidence from eight longitudinal population surveys.

BACKGROUND: Employment disruptions can impact smoking and alcohol consumption. During the COVID-19 pandemic, many countries implemented furlough schemes to prevent job loss. We examine how furlough was associated with smoking, vaping and alcohol consumption in the UK. METHODS: Data from 27,841 participants in eight UK adult longitudinal surveys were analysed. Participants self-reported employment status and current smoking, current vaping and alcohol consumption (>4 days/week or 5+ drinks per typical occasion) both before and during the early stages of the pandemic (April-July 2020). Risk ratios were estimated within each study using modified Poisson regression, adjusting for a range of potential confounders, including pre-pandemic behaviour. Findings were synthesised using random effects meta-analysis. RESULTS: Compared to stable employment and after adjustment for pre-pandemic characteristics, furlough was not associated with smoking (ARR = 1.05; 95% CI: 0.95-1.16; I2: 10%), vaping (ARR = 0.89; 95% CI: 0.74-1.08; I2: 0%) or drinking (ARR = 1.03; 95% CI: 0.94-1.13; I2: 48%). There were similar findings for no longer being employed, and stable unemployment, though this varied by sex: stable unemployment was associated with smoking for women (ARR = 1.35; 95% CI: 1.00-1.82; I2: 47%) but not men (0.84; 95% CI: 0.67-1.05; I2: 0%). No longer being employed was associated with vaping among women (ARR = 2.74; 95% CI: 1.59-4.72; I2: 0%) but not men (ARR = 1.25; 95% CI: 0.83-1.87; I2: 0%). CONCLUSIONS: We found no clear evidence of furlough or unemployment having adverse impacts on smoking, vaping or drinking behaviours during the early stages of the COVID-19 pandemic in the UK. Differences in risk compared to those who remained employed were largely explained by pre-pandemic characteristics.

Pre-pandemic mental health and disruptions to healthcare, economic and housing outcomes during the COVID-19 pandemic: evidence from 12 UK longitudinal studies.

BACKGROUND: The COVID-19 pandemic has disrupted lives and livelihoods, and people already experiencing mental ill health may have been especially vulnerable. AIMS: Quantify mental health inequalities in disruptions to healthcare, economic activity and housing. METHOD: We examined data from 59 482 participants in 12 UK longitudinal studies with data collected before and during the COVID-19 pandemic. Within each study, we estimated the association between psychological distress assessed pre-pandemic and disruptions since the start of the pandemic to healthcare (medication access, procedures or appointments), economic activity (employment, income or working hours) and housing (change of address or household composition). Estimates were pooled across studies. RESULTS: Across the analysed data-sets, 28% to 77% of participants experienced at least one disruption, with 2.3-33.2% experiencing disruptions in two or more domains. We found 1 s.d. higher pre-pandemic psychological distress was associated with (a) increased odds of any healthcare disruptions (odds ratio (OR) 1.30, 95% CI 1.20-1.40), with fully adjusted odds ratios ranging from 1.24 (95% CI 1.09-1.41) for disruption to procedures to 1.33 (95% CI 1.20-1.49) for disruptions to prescriptions or medication access; (b) loss of employment (odds ratio 1.13, 95% CI 1.06-1.21) and income (OR 1.12, 95% CI 1.06 -1.19), and reductions in working hours/furlough (odds ratio 1.05, 95% CI 1.00-1.09) and (c) increased likelihood of experiencing a disruption in at least two domains (OR 1.25, 95% CI 1.18-1.32) or in one domain (OR 1.11, 95% CI 1.07-1.16), relative to no disruption. There were no associations with housing disruptions (OR 1.00, 95% CI 0.97-1.03). CONCLUSIONS: People experiencing psychological distress pre-pandemic were more likely to experience healthcare and economic disruptions, and clusters of disruptions across multiple domains during the pandemic. Failing to address these disruptions risks further widening mental health inequalities.

An epigenetic predictor of death captures multi-modal measures of brain health.

Individuals of the same chronological age exhibit disparate rates of biological ageing. Consequently, a number of methodologies have been proposed to determine biological age and primarily exploit variation at the level of DNA methylation (DNAm). A novel epigenetic clock, termed 'DNAm GrimAge' has outperformed its predecessors in predicting the risk of mortality as well as many age-related morbidities. However, the association between DNAm GrimAge and cognitive or neuroimaging phenotypes remains unknown. We explore these associations in the Lothian Birth Cohort 1936 (n = 709, mean age 73 years). Higher DNAm GrimAge was strongly associated with all-cause mortality over the eighth decade (Hazard Ratio per standard deviation increase in GrimAge: 1.81, P < 2.0 × 10-16). Higher DNAm GrimAge was associated with lower age 11 IQ (ß = -0.11), lower age 73 general cognitive ability (ß = -0.18), decreased brain volume (ß = -0.25) and increased brain white matter hyperintensities (ß = 0.17). There was tentative evidence for a longitudinal association between DNAm GrimAge and cognitive decline from age 70 to 79. Sixty-nine of 137 health- and brain-related phenotypes tested were significantly associated with GrimAge. Adjusting all models for childhood intelligence attenuated to non-significance a small number of associations (12/69 associations; 6 of which were cognitive traits), but not the association with general cognitive ability (33.9% attenuation). Higher DNAm GrimAge associates with lower cognitive ability and brain vascular lesions in older age, independently of early-life cognitive ability. This epigenetic predictor of mortality associates with different measures of brain health and may aid in the prediction of age-related cognitive decline.

Maintained memory and long-term potentiation in a mouse model of Alzheimer's disease with both amyloid pathology and human tau.

One of the key knowledge gaps in the field of Alzheimer's disease research is the lack of understanding of how amyloid beta and tau cooperate to cause neurodegeneration. We recently generated a mouse model (APP/PS1 + Tau) that develops amyloid plaque pathology and expresses human tau in the absence of endogenous murine tau. These mice exhibit an age-related behavioural hyperactivity phenotype and transcriptional deficits which are ameliorated by tau transgene suppression. We hypothesized that these mice would also display memory and hippocampal synaptic plasticity deficits as has been reported for many plaque bearing mouse models which express endogenous mouse tau. We observed that our APP/PS1 + Tau model does not exhibit novel object memory or robust long-term potentiation deficits with age, whereas the parent APP/PS1 line with mouse tau did develop the expected deficits. These data are important as they highlight potential functional differences between mouse and human tau and the need to use multiple models to fully understand Alzheimer's disease pathogenesis and develop effective therapeutic strategies.

Structural brain correlates of serum and epigenetic markers of inflammation in major depressive disorder.

Inflammatory processes are implicated in the aetiology of Major Depressive Disorder (MDD); however, the relationship between peripheral inflammation, brain structure and depression remains unclear, partly due to complexities around the use of acute/phasic inflammatory biomarkers. Here, we report the first large-scale study of both serological and methylomic signatures of CRP (considered to represent acute and chronic measures of inflammation respectively) and their associations with depression status/symptoms, and structural neuroimaging phenotypes (T1 and diffusion MRI) in a large community-based sample (Generation Scotland; NMDD cases = 271, Ncontrols = 609). Serum CRP was associated with overall MDD severity, and specifically with current somatic symptoms- general interest (ß = 0.145, PFDR = 6 × 10-4) and energy levels (ß = 0.101, PFDR = 0.027), along with reduced entorhinal cortex thickness (ß = -0.095, PFDR = 0.037). DNAm CRP was significantly associated with reduced global grey matter/cortical volume and widespread reductions in integrity of 16/24 white matter tracts (with greatest regional effects in the external and internal capsules, ßFA= -0.12 to -0.14). In general, the methylation-based measures showed stronger associations with imaging metrics than serum-based CRP measures (ßaverage = -0.15 versus ßaverage = 0.01 respectively). These findings provide evidence for central effects of peripheral inflammation from both serological and epigenetic markers of inflammation, including in brain regions previously implicated in depression. This suggests that these imaging measures may be involved in the relationship between peripheral inflammation and somatic/depressive symptoms. Notably, greater effects on brain morphology were seen for methylation-based rather than serum-based measures of inflammation, indicating the importance of such measures for future studies.

Cognitive impairment in sporadic cerebral small vessel disease: A systematic review and meta-analysis.

This paper is a proposal for an update on the characterization of cognitive impairments associated with sporadic cerebral small vessel disease (SVD). We pose a series of questions about the nature of SVD-related cognitive impairments and provide answers based on a comprehensive review and meta-analysis of published data from 69 studies. Although SVD is thought primarily to affect executive function and processing speed, we hypothesize that SVD affects all major domains of cognitive ability. We also identify low levels of education as a potentially modifiable risk factor for SVD-related cognitive impairment. Therefore, we propose the use of comprehensive cognitive assessments and the measurement of educational level both in clinics and research settings, and suggest several recommendations for future research.

Application of n-of-1 treatment trials in schizophrenia: systematic review.

BACKGROUND: Single patient or 'n-of-1' trials are a pragmatic method to achieve optimal, evidence-based treatments for individual patients. Such trials could be particularly valuable in chronic, heterogeneous, difficult to treat illnesses such as schizophrenia.AimsTo identify how often, and in what way, n-of-1 trials have been used in schizophrenia. METHOD: We performed a systematic search in the major electronic databases for studies adopting n-of-1 methodology in schizophrenia, published in English from the start of records until the end of January 2017. RESULTS: We identified six studies meeting inclusion criteria. There was wide variability in study methodology and analysis. Each trial reported positive outcomes for their respective intervention, but all studies were at high risk of bias. CONCLUSIONS: In conclusion, n-of-1 trials are currently underutilised in schizophrenia. Existing trials suggest the method is well tolerated and potentially effective in achieving optimal treatments for patients, but more standardised methods of design, execution and analysis are required in future trials.Declaration of interestS.M.L. has received grants and personal fees from Janssen, and personal fees from Otsuka and Sunovion, in the past 3 years, outside the submitted work.

Pauci Immune crescentic glomerulonephritis in a patient with T-cell lymphoma and argyria.

BACKGROUND: Silver is a transition metal, toxic when ingested in significant amounts, causing argyria (skin deposition) and argyrosis (eye deposition). It is excreted mainly via the gastrointestinal tract with only small amounts eliminated by the kidneys, and rarely have cases of nephrotoxicity due to silver been reported. Here we present the case of a woman who used colloidal silver as an alternative remedy for a T cell lymphoma, who subsequently developed argyria and a pauci-immune crescentic glomerulonephritis with evidence of extensive glomerular basement membrane silver deposition. CASE PRESENTATION: A 47 year old woman of Indo-Asian descent with a T-cell lymphoma who refused conventional chemotherapy for 18 months but self-medicated with a remedy containing colloidal silver, was admitted with acute dialysis-dependent kidney injury. A kidney biopsy demonstrated a pauci-immune crescentic glomerulonephritis with deposition of silver particles in the mesangium and along the glomerular basement membranes. The patient was treated with intravenous methylprednisolone and intravenous cyclophosphamide and recovered independent renal function. CONCLUSION: Chronological evolution of the the pauci-immune glomerulonephritis suggests that a cellular immune-mediated process was induced, potentially mediated by lymphomatous T cells directed at the glomerular basement membrane, following silver deposition. Immunosuppressive therapy improved the situation and allowed cessation of haemodialysis, supporting the hypothesis of an immune-mediated process.

The accuracy and diagnostic value of gram staining joint aspirates in suspected joint infections.

BACKGROUND: Septic arthritis is a debilitating condition with prolonged treatment and adverse outcomes. A gram stain is often performed from the joint aspirate sample, followed by a definitive culture. In our study, we assessed the accuracy of gram staining for suspected septic arthritis and explored factors associated with positive culture growth and false negatives in the gram stain. METHODS: We retrospectively reviewed joint aspirates performed from 2015-2021 at a major trauma centre. Aspirates not cultured for septic arthritis were excluded. Data collected included aspirate site, gram stain and culture result delay, patient demographics, orthopaedic/rheumatological history, and comorbidities. Outcomes measured were gram stain sensitivity and specificity. Factors influencing positive cultures and false negative gram stain results were analysed using logistic regression. RESULTS: Of 408 joint aspirates meeting the criteria, 37 did not undergo initial gram staining. Gram stain sensitivity was 30.4%, specificity was 97.6%. The delay from aspirate to definitive gram stain and culture results was 1.1 and 5.4 days, respectively Logistic regression identified that prosthetic joint(p = 0.007), past joint infections(p = 0.006), arthritis(p < 0.001), hypertension(p = 0.007), diabetes(p = 0.019) were positively associated with positive cultures. Past joint infections(p = 0.004) were positively associated with false negative gram stain results. Patients on antibiotics during the aspirate had a higher risk of false negative gram stain results (OR = 5.538, 95%CI, 2.802-10.948; p < 0.001). CONCLUSIONS: In conclusion, the initial gram stain has limited sensitivity and caution should be exercised when interpreting negative results. Vigilance is crucial when the highlighted comorbidities or antibiotic use are present, to assess patients with potential joint infections.

MiniMovers: An Initial Pilot and Feasibility Study to Investigate the Impact of a Mobile Application on Children's Motor Skills and Parent Support for Physical Development.

The MiniMovers (MM) APP combines motor development theory with creativity expertise and has been designed to provide parents with developmentally appropriate activities to support children's motor skills. This study investigates how MiniMovers activities enabled parents to support their children's physical development. Families participated in an 8-week MM programme of activities from the MM APP (Mini, Mighty and Mega levels), with pre- and post-intervention data collected using multiple tools (e.g., motion capture system, force plate, eye-tracking glasses, and videos). Mixed research methods were applied among children (N = 8; aged 21-79 months) and their parents, providing quantitative analysis on children's performance (running, throwing, jumping, kicking, balancing and catching), as well as qualitative analysis on parents' attitude and behaviour (two-weekly feedback surveys and interviews). Lab-based measures showed significant improvements in run time, underarm throwing distance, and horizontal jump distance. Test of Gross Motor Development-3 showed a significant gain in running, underarm and overarm throwing, horizontal jump and kicking. Further, developmental stages indicated significant improvements in running, kicking and catching. Parents reported increased enjoyment and knowledge, children's enjoyment, independence and confidence. This pilot study provides support for the research and development of the MM App and suggests more research into the use of APPs to support home activities among families with young children.

Airborne transmission: a new paradigm with major implications for infection control and public health.

Recognition of airborne transmission of SARS-CoV-2 and other respiratory viruses is a paradigm shift in the Infection Prevention and Control (IPC) field, contributed to by New Zealand's experience in Managed Isolation Quarantine Facilities (MIQF). Slowness to embrace this shift by the World Health Organization (WHO) and other international bodies highlights the importance of applying the precautionary principle and subjecting established theories to the same level of critical scrutiny as those challenging the status quo. Improving indoor air quality to reduce infection risk and provide other health benefits is a new frontier, requiring much additional work at both grassroots and policy levels. Existing technologies such as masks, air cleaners and opening windows can improve air quality of many environments now. To achieve sustained, comprehensive improvements in air quality that provide meaningful protection, we also need additional actions that do not rely on individual human's behaviour.

Human astrocytes and microglia show augmented ingestion of synapses in Alzheimer's disease via MFG-E8.

Synapse loss correlates with cognitive decline in Alzheimer's disease (AD). Data from mouse models suggests microglia are important for synapse degeneration, but direct human evidence for any glial involvement in synapse removal in human AD remains to be established. Here we observe astrocytes and microglia from human brains contain greater amounts of synaptic protein in AD compared with non-disease controls, and that proximity to amyloid-ß plaques and the APOE4 risk gene exacerbate this effect. In culture, mouse and human astrocytes and primary mouse and human microglia phagocytose AD patient-derived synapses more than synapses from controls. Inhibiting interactions of MFG-E8 rescues the elevated engulfment of AD synapses by astrocytes and microglia without affecting control synapse uptake. Thus, AD promotes increased synapse ingestion by human glial cells at least in part via an MFG-E8 opsonophagocytic mechanism with potential for targeted therapeutic manipulation.

Plasma Myeloperoxidase as a Potential Biomarker of Patient Response to Anti-Dementia Treatment in Alzheimer's Disease.

BACKGROUND: Myeloperoxidase (MPO), a neutrophil-derived pro-inflammatory protein, co-localizes with amyloid-ß (Aß) plaques in Alzheimer's disease (AD). Anti-dementia treatment may facilitate efflux of Aß and associated plaque proteins from the brain to the peripheral circulation, therefore providing potential biomarkers for the monitoring of donor response to drug treatment. OBJECTIVE: We investigated the diagnostic utility of MPO as a biomarker of AD, and how anti-dementia treatment alters plasma MPO concentration. METHODS: Thirty-two AD patients were recruited, and plasma collected pre-drug administration (baseline), and 1- and 6-months post-treatment. All patients received cholinesterase inhibitors (ChEIs). At baseline and 6 months, patients underwent neuropsychological assessment. Forty-nine elderly healthy individuals with normal cognitive status served as controls. Plasma MPO concentration was measured by ELISA. RESULTS: AD drug naïve patients had similar plasma MPO concentration to their control counterparts (p > 0.05). Baseline MPO levels positively correlated with Neuropsychiatric Inventory score (r = 0.5080; p = 0.011) and carer distress (r = 0.5022; p = 0.012). Following 1-month ChEI treatment, 84.4% of AD patients exhibited increased plasma MPO levels (p < 0.001), which decreased at 6 months (p < 0.001). MPO concentration at 1 month was greatest in AD patients whose memory deteriorated during the study period (p = 0.028), and for AD patients with deterioration in Cornell assessment score (p = 0.044). CONCLUSION: Whereas baseline MPO levels did not differentiate between healthy and AD populations, baseline MPO positively correlated with initial Neuropsychiatric Inventory evaluation. Post-treatment, transient MPO upregulation in ChEI-treated patients may reflect worse therapeutic outcome. Further studies are required to assess the potential of plasma MPO as an AD therapeutic biomarker.