Preanalytical stability of plasma biomarkers for Alzheimer's disease pathology

INTRODUCTION: Plasma tests have demonstrated high diagnostic accuracy for identifying Alzheimer's disease pathology. To facilitate the transition to clinical utility, we assessed whether plasma storage duration and temperature affect the biomarker concentrations. METHODS: Plasma samples from 13 participants were stored at +4°C and +18°C. Concentrations of six biomarkers were measured after 2, 4, 6, 8, 10, and 24 h by single molecule array assays. RESULTS: Phosphorylated tau 181 (p-tau181), phosphorylated tau 231 (p-tau231), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) concentrations were unchanged both when stored at +4°C and +18°C. Amyloid-β 40 (Aβ40) and amyloid-β 42 (Aβ42) concentrations were stable for 24 h at +4°C but declined when stored at +18°C for longer than 6 h. This decline did not affect the Aβ42/Aβ40 ratio. DISCUSSION: Plasma samples can be stored for 24 h at +4°C or +18°C and result in valid assay results for p-tau181, p-tau231, Aβ42/Aβ40 ratio, GFAP, and NfL. HIGHLIGHTS: Plasma samples were stored for 24 h at +4°C and +18°C, mimicking clinical practice.Concentrations for Alzheimer's disease biomarkers were measured at six time-points.p-tau181, p-tau231, NfL, and GFAP concentrations were unchanged during the experiment.Storage at +18°C affected Aβ40 and Aβ42 concentrations while storage at +4°C did not. The Aβ42/Aβ40 ratio was unaffected.These plasma tests seem suitable for use in general practice

Serum TCA cycle metabolites in Lewy bodies dementia and Alzheimer's disease: Network analysis and cognitive prognosis

Se han documentado anomalías en el ciclo del ácido tricarboxílico (TCA) en la demencia. A través del análisis de redes, los metabolitos del ciclo TCA podrían reflejar indirectamente anomalías conocidas relacionadas con la demencia en las vías bioquímicas, y los metabolitos clave podrían estar asociados con el pronóstico. Este estudio analizó los metabolitos del ciclo de TCA como predictores del deterioro cognitivo en una cohorte de demencia leve y exploró las posibles interacciones con el diagnóstico de demencia con cuerpos de Lewy (LBD) o enfermedad de Alzheimer (EA) y el genotipo APOE-ε4. Se incluyeron 145 pacientes con demencia leve (LBD = 59; AD = 86). Los metabolitos del ciclo de TCA en suero se analizaron al inicio del estudio y se realizaron redes de correlación parcial. El rendimiento cognitivo se midió anualmente durante 5 años con el Mini-examen del estado mental. Los modelos Tobit de efectos mixtos longitudinales evaluaron cada metabolito de referencia como predictor del deterioro cognitivo a los 5 años. Se exploraron las interacciones APOE-ε4 y de diagnóstico. Los resultados mostraron concentraciones de metabolitos comparables en LBD y AD. Las redes corregidas de pruebas múltiples mostraron coeficientes más grandes para una correlación negativa entre piruvato-succinato y correlaciones positivas entre fumarato-malato y citrato-isocitrato tanto en LBD como en AD. En la muestra total, los modelos mixtos ajustados mostraron asociaciones significativas entre la concentración inicial de citrato y las puntuaciones longitudinales del MMSE. En los portadores de APOE-ε4, el isocitrato inicial predijo las puntuaciones del MMSE. Concluimos que, en la demencia leve, las concentraciones de citrato sérico podrían estar asociadas con el deterioro cognitivo posterior, así como las concentraciones de isocitrato en los portadores de APOE-ε4. La regulación a la baja de la actividad enzimática en la primera mitad del ciclo TCA (deshidrogenasas descarboxiladoras), con regulación al alza en la segunda mitad (solo deshidrogenasas), podría reflejarse indirectamente en las redes de metabolitos del ciclo TCA sérico.Q2Abnormalities in the Tri-Carboxylic-Acid (TCA) cycle have been documented in dementia. Through network analysis, TCA cycle metabolites could indirectly reflect known dementia-related abnormalities in biochemical pathways, and key metabolites might be associated with prognosis. This study analyzed TCA cycle metabolites as predictors of cognitive decline in a mild dementia cohort and explored potential interactions with the diagnosis of Lewy Body Dementia (LBD) or Alzheimer's Disease (AD) and APOE-ε4 genotype. We included 145 mild dementia patients (LBD = 59; AD = 86). Serum TCA cycle metabolites were analyzed at baseline, and partial correlation networks were conducted. Cognitive performance was measured annually over 5-years with the Mini-mental State Examination. Longitudinal mixed-effects Tobit models evaluated each baseline metabolite as a predictor of 5-year cognitive decline. APOE-ε4 and diagnostic interactions were explored. Results showed comparable metabolite concentrations in LBD and AD. Multiple testing corrected networks showed larger coefficients for a negative correlation between pyruvate – succinate and positive correlations between fumarate – malate and citrate – Isocitrate in both LBD and AD. In the total sample, adjusted mixed models showed significant associations between baseline citrate concentration and longitudinal MMSE scores. In APOE-ε4 carriers, baseline isocitrate predicted MMSE scores. We conclude that, in mild dementia, serum citrate concentrations could be associated with subsequent cognitive decline, as well as isocitrate concentrations in APOE-ε4 carriers. Downregulation of enzymatic activity in the first half of the TCA cycle (decarboxylating dehydrogenases), with upregulation in the latter half (dehydrogenases only), might be indirectly reflected in serum TCA cycle metabolites' networks.https://orcid.org/0000-0001-5832-0603https://scholar.google.com/citations?user=MrICwaMAAAAJ&hl=enhttps://scienti.minciencias.gov.co/cvlac/visualizador/generarCurriculoCv.do?cod_rh=0001429659Revista Internacional - IndexadaS

Cognitive and Motor Decline in Dementia with Lewy Bodies and Parkinson's Disease Dementia

Funding Information: The University of Stavanger supported M.C.G. The CamPaIGN study has received funding from the Wellcome Trust, the Medical Research Council, the Patrick Berthoud Trust, and the NIHR Cambridge Biomedical Research Centre (BRC‐1215‐20014). The ICICLE‐PD study was funded by Parkinson's UK (J‐0802, G‐1301, G‐1507) and supported by the Lockhart Parkinson's Disease Research Fund, National Institute for Health Research (NIHR) Newcastle Biomedical Research Unit and Centre based at Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University. The PICNICS study was funded by the Cure Parkinson's Trust, the Van Geest Foundation, the Medical Research Council, Parkinson's UK, and the NIHR Cambridge Biomedical Research Centre (BRC‐1215‐20014). The NYPUM study was supported by grants from the Swedish Medical Research Council, Erling‐Persson Foundation, the Swedish Brain Foundation (Hjärnfonden), Umeå University, Västerbotten County Council, King Gustaf V and Queen Victoria Freemason Foundation, Swedish Parkinson Foundation, Swedish Parkinson Research Foundation, Kempe Foundation, Swedish PD Association, the European Research Council, and the Knut and Alice Wallenberg Foundation. The PINE study was funded by Parkinson's UK (grant numbers G0502, G0914, and G1302), the Scottish Chief Scientist Office (CAF/12/05, PCL/17/10), Academy of Medical Sciences, NHS Grampian endowments, the BMA Doris Hillier award, RS Macdonald Trust, the BUPA Foundation, and SPRING. The PARKWEST study was supported by the Research Council of Norway (grant# 177966), the Western Norway Regional Health Authority (grant# 911218 and # 911949), Reberg legacy and the Norwegian Parkinson's Research Foundation. The PICC collaboration has been supported by The Chief Scientist Office of the Scottish Government (PCL/17/10), the Academy of Medical Sciences, Parkinson's UK (initial collaborator meeting) and the Norwegian Association for Public Health. The DEMVEST Study was supported by the regional health authorities of Western Norway, Helse‐Vest (grant# 911973). Motol University Hospital's Czech Brain Aging Study was supported by the National Institute for Neurological Research (Programme EXCELES, ID Project No. LX22NPO5107)—Funded by the European Union—Next Generation EU and by Charles University grant PRIMUS 22/MED/011. The Sant Pau Initiative on Neurodegeration (SPIN) cohort was supported by the Fondo de Investigaciones Sanitario (FIS), Instituto de Salud Carlos III (PI14/01126, PI17/01019 and PI20/01473 to JF, PI13/01532 and PI16/01825 to RB, PI18/00335 to MCI, PI18/00435 and INT19/00016 to DA, PI17/01896 and AC19/00103to AL) and the CIBERNED program (Program 1, Alzheimer Disease to AL), jointly funded by Fondo Europeo de Desarrollo Regional, Unión Europea, “Una manera de hacer Europa”. It was also supported by the National Institutes of Health (NIA grants 1R01AG056850‐01A1; R21AG056974; and R01AG061566), by Generalitat de Catalunya (2017‐SGR‐547, SLT006/17/125, SLT006/17/119, SLT002/16/408) and “Marató TV3” foundation grants 20141210, 044412 and 20142610. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. The sponsors were not involved in the study design, in the collection, analysis, and interpretation of data, in the writing of the report, or in the decision to submit the article for publication. The authors declare that there are no conflicts of interest relevant to this work. Funding Sources and Conflicts of Interest:Peer reviewedPublisher PD

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Hippocampal subfields and decline in activities of daily living in Alzheimer's disease and dementia with Lewy bodies

Background: Hippocampal atrophy is presented in Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB). Cognition, dual-tasks, muscular function, goal-related behaviors and neuropsychiatric symptoms are linked to hippocampal volumes and may lead to functional decline in activities of daily living. We examined the association between baseline hippocampal subfield volumes (HSv) in mild AD and DLB, and functional decline. Materials & methods: 12 HSv were computed from structural magnetic resonance images using Freesurfer 6.0 segmentation. Functional decline was assessed using the rapid disability rating scale score. Linear regressions were conducted. Results: In AD, HSv were smaller bilaterally. However, HSv were not associated with functional decline. Conclusion: Functional decline does not depend on HSv in mild AD and DL