Increasing the Survival of a Neuronal Model of Alzheimer's Disease Using Docosahexaenoic Acid, Restoring Endolysosomal Functioning by Modifying the Interactions between the Membrane Proteins C99 and Rab5.

Docosahexaenoic acid (DHA, C22:6 ω3) may be involved in various neuroprotective mechanisms that could prevent Alzheimer's disease (AD). Its influence has still been little explored regarding the dysfunction of the endolysosomal pathway, known as an early key event in the physiopathological continuum triggering AD. This dysfunction could result from the accumulation of degradation products of the precursor protein of AD, in particular the C99 fragment, capable of interacting with endosomal proteins and thus contributing to altering this pathway from the early stages of AD. This study aims to evaluate whether neuroprotection mediated by DHA can also preserve the endolysosomal function. AD-typical endolysosomal abnormalities were recorded in differentiated human SH-SY5Y neuroblastoma cells expressing the Swedish form of human amyloid precursor protein. This altered phenotype included endosome enlargement, the reduced secretion of exosomes, and a higher level of apoptosis, which confirmed the relevance of the cellular model chosen for studying the associated deleterious mechanisms. Second, neuroprotection mediated by DHA was associated with a reduced interaction of C99 with the Rab5 GTPase, lower endosome size, restored exosome production, and reduced neuronal apoptosis. Our data reveal that DHA may influence protein localization and interactions in the neuronal membrane environment, thereby correcting the dysfunction of endocytosis and vesicular trafficking associated with AD.

Clinical reporting following the quantification of cerebrospinal fluid biomarkers in Alzheimer's disease: An international overview.

INTRODUCTION: The current practice of quantifying cerebrospinal fluid (CSF) biomarkers as an aid in the diagnosis of Alzheimer's disease (AD) varies from center to center. For a same biochemical profile, interpretation and reporting of results may differ, which can lead to misunderstandings and raises questions about the commutability of tests. METHODS: We obtained a description of (pre-)analytical protocols and sample reports from 40 centers worldwide. A consensus approach allowed us to propose harmonized comments corresponding to the different CSF biomarker profiles observed in patients. RESULTS: The (pre-)analytical procedures were similar between centers. There was considerable heterogeneity in cutoff definitions and report comments. We therefore identified and selected by consensus the most accurate and informative comments regarding the interpretation of CSF biomarkers in the context of AD diagnosis. DISCUSSION: This is the first time that harmonized reports are proposed across worldwide specialized laboratories involved in the biochemical diagnosis of AD.

Alzheimer's Disease: Treatment Strategies and Their Limitations.

Alzheimer's disease (AD) is the most frequent case of neurodegenerative disease and is becoming a major public health problem all over the world. Many therapeutic strategies have been explored for several decades; however, there is still no curative treatment, and the priority remains prevention. In this review, we present an update on the clinical and physiological phase of the AD spectrum, modifiable and non-modifiable risk factors for AD treatment with a focus on prevention strategies, then research models used in AD, followed by a discussion of treatment limitations. The prevention methods can significantly slow AD evolution and are currently the best strategy possible before the advanced stages of the disease. Indeed, current drug treatments have only symptomatic effects, and disease-modifying treatments are not yet available. Drug delivery to the central nervous system remains a complex process and represents a challenge for developing therapeutic and preventive strategies. Studies are underway to test new techniques to facilitate the bioavailability of molecules to the brain. After a deep study of the literature, we find the use of soft nanoparticles, in particular nanoliposomes and exosomes, as an innovative approach for preventive and therapeutic strategies in reducing the risk of AD and solving problems of brain bioavailability. Studies show the promising role of nanoliposomes and exosomes as smart drug delivery systems able to penetrate the blood-brain barrier and target brain tissues. Finally, the different drug administration techniques for neurological disorders are discussed. One of the promising therapeutic methods is the intranasal administration strategy which should be used for preclinical and clinical studies of neurodegenerative diseases.

Targeted Suppression of Lipoprotein Receptor LSR in Astrocytes Leads to Olfactory and Memory Deficits in Mice.

Perturbations of cholesterol metabolism have been linked to neurodegenerative diseases. Glia-neuron crosstalk is essential to achieve a tight regulation of brain cholesterol trafficking. Adequate cholesterol supply from glia via apolipoprotein E-containing lipoproteins ensures neuronal development and function. The lipolysis-stimulated lipoprotein receptor (LSR), plays an important role in brain cholesterol homeostasis. Aged heterozygote Lsr+/- mice show altered brain cholesterol distribution and increased susceptibility to amyloid stress. Since LSR expression is higher in astroglia as compared to neurons, we sought to determine if astroglial LSR deficiency could lead to cognitive defects similar to those of Alzheimer's disease (AD). Cre recombinase was activated in adult Glast-CreERT/lsrfl/fl mice by tamoxifen to induce astroglial Lsr deletion. Behavioral phenotyping of young and old astroglial Lsr KO animals revealed hyperactivity during the nocturnal period, deficits in olfactory function affecting social memory and causing possible apathy, as well as visual memory and short-term working memory problems, and deficits similar to those reported in neurodegenerative diseases, such as AD. Furthermore, GFAP staining revealed astroglial activation in the olfactory bulb. Therefore, astroglial LSR is important for working, spatial, and social memory related to sensory input, and represents a novel pathway for the study of brain aging and neurodegeneration.

Synthesis of New Water Soluble ß-Cyclodextrin@Curcumin Conjugates and In Vitro Safety Evaluation in Primary Cultures of Rat Cortical Neurons.

Self-aggregation of Curcumin (Cur) in aqueous biological environment decreases its bioavailability and in vivo therapeutic efficacy, which hampers its clinical use as candidate for reducing risk of neurodegenerative diseases. Here, we focused on the design of new Cur- ß-Cyclodextrin nanoconjugates to improve the solubility and reduce cell toxicity of Cur. In this study, we described the synthesis, structural characterization, photophysical properties and neuron cell toxicity of two new water soluble ß-CD/Cur nanoconjugates as new strategy for reducing risks of neurodegenerative diseases. Cur was coupled to one or two ß-CD molecules via triazole rings using CuAAC click chemistry strategy to yield ß-CD@Cur and (ß-CD)2@Cur nanoconjugates, respectively. The synthesized nanoconjugates were found to be able to self-assemble in aqueous condition and form nano-aggregates of an average diameter size of around 35 and 120 nm for ß-CD@Cur and (ß-CD)2@Cur, respectively. The photophysical properties, water solubility and cell toxicity on rat embryonic cortical neurons of the designed nanoconjugates were investigated and compared to that of Cur alone. The findings revealed that both new nanoconjugates displayed better water solubility and in vitro biocompatibility than Cur alone, thus making it possible to envisage their use as future nano-systems for the prevention or risk reduction of neurodegenerative diseases.

Use of Active Salmon-Lecithin Nanoliposomes to Increase Polyunsaturated Fatty Acid Bioavailability in Cortical Neurons and Mice.

Omega-3 polyunsaturated fatty acids (n-3 PUFAs) play an important role in the development, maintenance, and function of the brain. Dietary supplementation of n-3 PUFAs in neurological diseases has been a subject of particular interest in preventing cognitive deficits, and particularly in age-related neurodegeneration. Developing strategies for the efficient delivery of these lipids to the brain has presented a challenge in recent years. We recently reported the preparation of n-3 PUFA-rich nanoliposomes (NLs) from salmon lecithin, and demonstrated their neurotrophic effects in rat embryo cortical neurons. The objective of this study was to assess the ability of these NLs to deliver PUFAs in cellulo and in vivo (in mice). NLs were prepared using salmon lecithin rich in n-3 PUFAs (29.13%), and characterized with an average size of 107.90 ± 0.35 nm, a polydispersity index of 0.25 ± 0.01, and a negative particle-surface electrical charge (-50.4 ± 0.2 mV). Incubation of rat embryo cortical neurons with NLs led to a significant increase in docosahexaenoic acid (DHA) (51.5%, p < 0.01), as well as palmitic acid, and a small decrease in oleic acid after 72 h (12.2%, p < 0.05). Twenty mice on a standard diet received oral administration of NLs (12 mg/mouse/day; 5 days per week) for 8 weeks. Fatty acid profiles obtained via gas chromatography revealed significant increases in cortical levels of saturated, monounsaturated, and n-3 (docosahexaenoic acid,) and n-6 (docosapentaenoic acid and arachidonic acid) PUFAs. This was not the case for the hippocampus or in the liver. There were no effects on plasma lipid levels, and daily monitoring confirmed NL biocompatibility. These results demonstrate that NLs can be used for delivery of PUFAs to the brain. This study opens new research possibilities in the development of preventive as well as therapeutic strategies for age-related neurodegeneration.

Long-term ACE Inhibitor/ARB Use Is Associated With Severe Renal Dysfunction and Acute Kidney Injury in Patients With Severe COVID-19: Results From a Referral Center Cohort in the Northeast of France.

BACKGROUND: In patients with severe coronavirus disease 2019 (COVID-19), data are scarce and conflicting regarding whether chronic use of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) influences disease outcomes. In patients with severe COVID-19, we assessed the association between chronic ACEI/ARB use and the occurrence of kidney, lung, heart, and liver dysfunctions and the severity of the inflammatory reaction as evaluated by biomarkers kinetics, and their association with disease outcomes. METHODS: We performed a retrospective longitudinal cohort study on consecutive patients with newly diagnosed severe COVID-19. Independent predictors were assessed through receiver operating characteristic analysis, time-series analysis, logistic regression analysis, and multilevel modeling for repeated measures. RESULTS: On the 149 patients included in the study 30% (44/149) were treated with ACEI/ARB. ACEI/ARB use was independently associated with the following biochemical variations: phosphorus >40 mg/L (odds ratio [OR], 3.35, 95% confidence interval [CI], 1.83-6.14), creatinine >10.1 mg/L (OR, 3.22, 2.28-4.54), and urea nitrogen (UN) >0.52 g/L (OR, 2.65, 95% CI, 1.89-3.73). ACEI/ARB use was independently associated with acute kidney injury stage ≥1 (OR, 3.28, 95% CI, 2.17-4.94). The daily dose of ACEI/ARB was independently associated with altered kidney markers with an increased risk of +25 to +31% per each 10 mg increment of lisinopril-dose equivalent. In multivariable multilevel modeling, UN >0.52 g/L was independently associated with the risk of acute respiratory failure (OR, 3.54, 95% CI, 1.05-11.96). CONCLUSIONS: Patients chronically treated with ACEI/ARB who have severe COVID-19 are at increased risk of acute kidney injury. In these patients, the increase in UN associated with ACEI/ARB use could predict the development of acute respiratory failure.

Immunoglobulin Preparations Can Mislead Clinical Decision-Making in Follow-Up of Differentiated Thyroid Cancer.

OBJECTIVE: Intravenous and subcutaneous immunoglobulins are commonly used for immune substitution or as immune modulators in a variety of inflammatory and autoimmune disorders. Exogenous thyroid-specific thyroglobulin (Tg) antibodies present in the donor plasma may interfere with the interpretation of measurements of Tg autoantibodies (Tg-Abs) in the recipient's plasma and potentially trigger an immune response in the recipient's immune cells. Levels of antibodies causing bioassay interferences or those leading to clinically relevant changes in patient outcomes are not known. Tg is used as a biomarker in the long-term surveillance of patients with differentiated thyroid cancer (DTC) following total thyroidectomy and radioactive iodine ablation. However, the presence of Tg-Abs in the circulation interferes with Tg measurements. Assessment of levels of Tg-Abs is thus recommended as a part of standard follow-up of DTC together with Tg testing. METHODS: To understand the potential mechanisms and pathophysiologic significance of possible interferences associated with administration immunoglobulin preparations and Tg measurement, we overview the current knowledge on interactions between Tg autoimmunity and immunoglobulin preparations and illustrate diagnostic challenges and perspectives for follow-up of patients with DTC treated with exogenous immunoglobulins. RESULTS: In patients with DTC treated with immunoglobulin preparations, monitoring of thyroid cancer using Tg and Tg-Abs is challenging due to possible analytical interferences through passive transfer of exogenous antibodies from immunoglobulin preparations. CONCLUSION: Analytical interferences must be suspected when a discrepancy exists between clinical examination and diagnostic tests. Collaboration between endocrinologists, biologists, and pharmacologists is fundamental to avoid misdiagnosis and unnecessary medical or radiologic procedures. ABBREVIATIONS: CT = computed tomography; DTC = differentiated thyroid cancer; FNAB = fine-needle aspiration biopsy; HAb = heterophile antibody; IMA = immunometric assay; IVIg = intravenous immunoglobulin; RAI = radioactive iodine; RIA = radioimmunoassay; SCIg = subcutaneous immunoglobulin; Tg = thyroglobulin; Tg-Ab = thyroglobulin autoantibody; Tg-MS = thyroglobulin mass spectrometry; TPO-Ab = thyroid peroxidase autoantibody; TSHR-Ab = thyrotropin receptor autoantibody.

Neurotrophic Effect of Fish-Lecithin Based Nanoliposomes on Cortical Neurons.

Lipids play multiple roles in preserving neuronal function and synaptic plasticity, and polyunsaturated fatty acids (PUFAs) have been of particular interest in optimizing synaptic membrane organization and function. We developed a green-based methodology to prepare nanoliposomes (NL) from lecithin that was extracted from fish head by-products. These NL range between 100-120 nm in diameter, with an n-3/n-6 fatty acid ratio of 8.88. The high content of n-3 PUFA (46.3% of total fatty acid content) and docosahexanoic acid (26%) in these NL represented a means for enrichment of neuronal membranes that are potentially beneficial for neuronal growth and synaptogenesis. To test this, the primary cultures of rat embryo cortical neurons were incubated with NL on day 3 post-culture for 24 h, followed by immunoblots or immunofluorescence to evaluate the NL effects on synaptogenesis, axonal growth, and dendrite formation. The results revealed that NL-treated cells displayed a level of neurite outgrowth and arborization on day 4 that was similar to those of untreated cells on day 5 and 6, suggesting accelerated synapse formation and neuronal development in the presence of NL. We propose that fish-derived NL, by virtue of their n-3 PUFA profile and neurotrophic effects, represent a new innovative bioactive vector for developing preventive or curative treatments for neurodegenerative diseases.

18F-FDG PET can effectively rule out conversion to dementia and the presence of CSF biomarker of neurodegeneration: a real-world data analysis.

BACKGROUND: Precisely defining the delay in onset of dementia is a particular challenge for early diagnosis. Brain [18F] fluoro-2-deoxy-2-D-glucose (18F-FDG) Positron Emission Tomography (PET) is a particularly interesting tool for the early diagnosis of neurodegenerative diseases, through the measurement of the cerebral glucose metabolic rate. There is currently a lack of longitudinal studies under real-life conditions, with sufficient patients, to accurately evaluate the predictive values of brain 18F-FDG PET scans. Here, we aimed to estimate the value of brain 18F-FDG PET for predicting the risk of dementia conversion and the risk of occurrence of a neurodegenerative pathology. METHODS: Longitudinal data for a cohort of patients with no diagnosis of dementia at the time of recruitment referred by a tertiary memory clinic for brain 18F-FDG PET were matched with (Prince M, Wimo A, Guerchet Maëlenn, Ali G-C, Wu Y-T et al. World Alzheimer Report 2015. The Global Impact of Dementia: An analysis of prevalence, incidence, cost and trends. [Research Report] Alzheimer's Disease International. 2015. 2015.) data from the French National Health Data System (NHDS), (Jack CR, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, et al. NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease. Alzheimers Dement. 2018;14(4):535-62.) data from the National Alzheimer Bank (NAB), and (Davis M, O`Connell T, Johnson S, Cline S, Merikle E, Martenyi F, et al. Estimating Alzheimer's Disease Progression Rates from Normal Cognition Through Mild Cognitive Impairment and Stages of Dementia. CAR. 2018;15(8):777-88.) lumbar puncture (LP) biomarker data. The criteria for dementia conversion were the designation, within the three years after the brain 18F-FDG PET scan, of a long-term condition for dementia in the NHDS and a dementia stage of cognitive impairment in the NAB. The criterion for the identification of a neurodegenerative disease in the medical records was the determination of LP biomarker levels. RESULTS: Among the 403 patients (69.9 ± 11.4 years old, 177 women) from the initial cohort with data matched with the NHDS data, 137 were matched with the NAB data, and 61 were matched with LP biomarker data. Within three years of the scan, a 18F-FDG PET had negative predictive values of 85% for dementia conversion (according to the NHDS and NAB datasets) and 95% for the presence of LP neurodegeneration biomarkers. CONCLUSION: A normal brain 18F-FDG PET scan can help rule out the risk of dementia conversion and the presence of cerebrospinal fluid (CSF) biomarker of neurodegeneration early with high certainty, allowing modifications to patient management regimens in the short term. TRIAL REGISTRATION: Clinical Trials database (NCT04804722). March 18, 2021. Retrospectively registered.

Molecular Insights for Alzheimer's Disease: An Unexplored Storyline on the Nanoscale Impact of Nascent Aß1-42 toward the Lipid Membrane.

Deciphering the mechanism of Alzheimer's disease is a key element for designing an efficient therapeutic strategy. Molecular dynamics (MD) calculations, atomic force microscopy, and infrared spectroscopy were combined to investigate ß-amyloid (Aß1-42) peptide interactions with supported lipid bilayers (SLBs). The MD simulations showed that nascent Aß1-42 monomers remain anchored within a model phospholipid bilayer's hydrophobic core, which suggests their stability in their native environment. We tested this prediction experimentally by studying the behavior of Aß1-42 monomers and oligomers when interacting with SLBs. When Aß1-42 monomers and oligomers were self-assembled with a lipid bilayer and deposited as an SLB, they remain within the bilayers. Their presence in the bilayers induces destabilization of the model membranes. No specific interactions between Aß1-42 and the SLBs were detected when SLBs free of Aß1-42 were exposed to Aß1-42. This study suggests that Aß can remain in the membrane after cleavage by γ-secretase and cause severe damage to the membrane.

Soluble TREM-1 plasma concentration predicts poor outcome in COVID-19 patients.

BACKGROUND: The immuno-receptor Triggering Expressed on Myeloid cells-1 (TREM-1) is activated during bacterial infectious diseases, where it amplifies the inflammatory response. Small studies suggest that TREM-1 could be involved in viral infections, including COVID-19. We here aim to decipher whether plasma concentration of the soluble form of TREM-1 (sTREM-1) could predict the outcome of hospitalized COVID-19 patients. METHODS: We conducted a multicentre prospective observational study in 3 university hospitals in France. Consecutive hospitalized patients with confirmed infection with SARS-CoV-2 were enrolled. Plasma concentration of sTREM-1 was measured on admission and then at days 4, 6, 8, 14, 21, and 28 in patients admitted into an ICU (ICU cohort: ICUC) or 3 times a week for patients hospitalized in a medical ward (Conventional Cohort: ConvC). Clinical and biological data were prospectively recorded and patients were followed-up for 90 days. For medical ward patients, the outcome was deemed complicated in case of requirement of increased oxygen supply > 5 L/min, transfer to an ICU, or death. For Intensive Care Unit (ICU) patients, complicated outcome was defined by death in the ICU. RESULTS: Plasma concentration of sTREM-1 at inclusion was higher in ICU patients (n = 269) than in medical ward patients (n = 562) (224 pg/mL (IQR 144-320) vs 147 pg/mL (76-249), p < 0.0001), and higher in patients with a complicated outcome in both cohorts: 178 (94-300) vs 135 pg/mL (70-220), p < 0.0001 in the ward patients, and 342 (288-532) vs 206 pg/mL (134-291), p < 0.0001 in the ICU patients. Elevated sTREM-1 baseline concentration was an independent predictor of complicated outcomes (Hazard Ratio (HR) = 1.5 (1.1-2.1), p = 0.02 in ward patients; HR = 3.8 (1.8-8.0), p = 0.0003 in ICU patients). An sTREM-1 plasma concentration of 224 pg/mL had a sensitivity of 42%, and a specificity of 76% in the ConvC for complicated outcome. In the ICUC, a 287 pg/mL cutoff had a sensitivity of 78%, and a specificity of 74% for death. The sTREM-1 concentrations increased over time in the ConvC patients with a complicated outcome (p = 0.017), but not in the ICUC patients. CONCLUSIONS: In COVID-19 patients, plasma concentration of sTREM-1 is an independent predictor of the outcome, although its positive and negative likelihood ratio are not good enough to guide clinical decision as a standalone marker.

Neuroprotective Effect of Curcumin-Loaded RGD Peptide-PEGylated Nanoliposomes.

Curcumin is known for its anti-inflammatory, neuroprotective, and antioxidant properties, but its use in biological applications is hindered by its sensitivity to light, oxygen, and temperature. Furthermore, due to its low water solubility, curcumin has a poor pharmacokinetic profile and bioavailability. In this study, we evaluated the potential application of curcumin as a neuroprotective agent encapsulated in RGD peptide-PEGylated nanoliposomes developed from salmon-derived lecithin. Salmon lecithin, rich in polyunsaturated fatty acids, was used to formulate empty or curcumin-loaded nanoliposomes. Transmission electron microscopy, dynamic light scattering, and nanoparticle tracking analysis characterizations indicated that the marine-derived peptide-PEGylated nanoliposomes were spherical in shape, nanometric in size, and with an overall negative charge. Cytotoxicity tests of curcumin-loaded nanoliposomes revealed an improved tolerance of neurons to curcumin as compared to free curcumin. Wild-type SH-SY5Y were treated for 24 h with curcumin-loaded nanoliposomes, followed by 24 h incubation with conditioned media of SH-SY5Y expressing the Swedish mutation of APP containing a high ratio of Aß40/42 peptides. Our results revealed significantly lower Aß-induced cell toxicity in cells pre-treated with RGD peptide-PEGylated curcumin-loaded nanoliposomes, as compared to controls. Thus, our data highlight the potential use of salmon lecithin-derived RGD peptide PEGylated nanoliposomes for the efficient drug delivery of curcumin as a neuroprotective agent.

Transfer Phenomena of Nanoliposomes by Live Imaging of Primary Cultures of Cortical Neurons.

Soft nanoparticles, and in particular, nanoliposomes (NL), have attracted increasing interest for their use in food, nutraceuticals, and in particular, in pharmaceutics for drug delivery. Recent data using salmon lecithin NL suggest that these NL, rich in omega-3 (n-3) fatty acids, can improve the bioavailability and transport of molecules through the blood brain barrier (BBB) to target the brain for the prevention and treatment of neurodegenerative diseases. The objective of this study was to characterize the physicochemical properties and analyze the transfer phenomena of salmon lecithin NL over time in neurons to better understand the behavior of NL in an intracellular environment. To test this, primary cultures of cortical neurons from rat embryos were incubated with salmon lecithin NL from day 3 after cell culture, for up to 104 h. The physicochemical properties of NL such as size, speed, morphology and the diffusion coefficient in the live cultures, were studied over time. Image analysis of cell morphology showed dendritic growth and neuronal arborization after 48 h of exposure to NL, for up to 104 h. Results showed an NL stability in size, speed and diffusion coefficient over time, with a peak at 48 h, and then a return to baseline value at the end of incubation. The average speed and diffusion coefficient achieved provided important information on the mode of entry of NL into neurons, and on the slow diffusion rate of NL into the cells. Analysis of videos from 2 h to 104 h showed that significant levels of NL were already internalized by neurons after 3 h incubation. NL appearance and intracellular distribution indicated that they were packed in intracellular compartments similar to endocytic vesicles, suggesting internalization by an active endocytic-like process. The results obtained here demonstrate internalization of NL by cortical neurons by an active endocytic-like process, and suggest the potential use of NL for time-release of therapeutics aimed towards prevention or treatment of neurodegenerative diseases.

Prognostic Impact of 18-F-Florbetaben Amyloid PET Imaging in Patients with Isolated Increases in Cerebrospinal Fluid Phospho-Tau Biomarkers: A Longitudinal Study.

This longitudinal study evaluates the prognostic impact of amyloid PET in patients suspected of Alzheimer's disease and presenting with isolated cerebrospinal fluid (CSF) increases in P-Tau proteins (NCT02556502). The rate of conversion, based on the DSM-5 criteria and all collected data (average follow-up of 39.2±13.2 months), was determined by a panel of experts blinded to the PET results and was 75%(6/8) for positive and 35%(6/17) for negative baseline amyloid PET. In this population with isolated CSF increases in P-Tau, a positive baseline amyloid PET was associated with greater than twice the proportion of dementia conversions within the following three years.

Clinical impact of digital and conventional PET control databases for semi-quantitative analysis of brain 18F-FDG digital PET scans.

PURPOSE: Digital PET cameras markedly improve sensitivity and spatial resolution of brain 18F-FDG PET images compared to conventional cameras. Our study aimed to assess whether specific control databases are required to improve the diagnostic performance of these recent advances. METHODS: We retrospectively selected two groups of subjects, twenty-seven Alzheimer's Disease (AD) patients and twenty-two healthy control (HC) subjects. All subjects underwent a brain 18F-FDG PET on a digital camera (Vereos, Philips®). These two group (AD and HC) are compared, using a Semi-Quantitative Analysis (SQA), to two age and sex matched controls acquired with a digital PET/CT (Vereos, Philips®) or a conventional PET/CT (Biograph 6, Siemens®) camera, at group and individual levels. Moreover, individual visual interpretation of SPM T-maps was provided for the positive diagnosis of AD by 3 experienced raters. RESULTS: At group level, SQA using digital controls detected more marked hypometabolic areas in AD (+ 116 cm3 at p < 0.001 uncorrected for the voxel, corrected for the cluster) than SQA using conventional controls. At the individual level, the accuracy of SQA for discriminating AD using digital controls was higher than SQA using conventional controls (86% vs. 80%, p < 0.01, at p < 0.005 uncorrected for the voxel, corrected for the cluster), with higher sensitivity (89% vs. 78%) and similar specificity (82% vs. 82%). These results were confirmed by visual analysis (accuracies of 84% and 82% for digital and conventional controls respectively, p = 0.01). CONCLUSION: There is an urgent need to establish specific digital PET control databases for SQA of brain 18F-FDG PET images as such databases improve the accuracy of AD diagnosis.

The spectrum of biochemical alterations associated with organ dysfunction and inflammatory status and their association with disease outcomes in severe COVID-19: A longitudinal cohort and time-series design study.

BACKGROUND: In patients with severe COVID-19, no data are available on the longitudinal evolution of biochemical abnormalities and their ability to predict disease outcomes. METHODS: Using a retrospective, longitudinal cohort study design on consecutive patients with severe COVID-19, we used an extensive biochemical dataset of serial data and time-series design to estimate the occurrence of organ dysfunction and the severity of the inflammatory reaction and their association with acute respiratory failure (ARF) and death. FINDINGS: On the 162 studied patients, 1151 biochemical explorations were carried out for up to 59 biochemical markers, totaling 15,260 biochemical values. The spectrum of biochemical abnormalities and their kinetics were consistent with a multi-organ involvement, including lung, kidney, heart, liver, muscle, and pancreas, along with a severe inflammatory syndrome. The proportion of patients who developed an acute kidney injury (AKI) stage 3, increased significantly during follow-up (0·9%, day 0; 21·4%, day 14; P<0·001). On the 20 more representative biochemical markers (>250 iterations), only CRP >90 mg/L (odds ratio [OR] 6·87, 95% CI, 2·36-20·01) and urea nitrogen >0·36 g/L (OR 3·91, 95% CI, 1·15-13·29) were independently associated with the risk of ARF. Urea nitrogen >0·42 g/L was the only marker associated with the risk of COVID-19 related death. INTERPRETATION: Our results point out the lack of the association between the inflammatory markers and the risk of death but rather highlight a significant association between renal dysfunction and the risk of COVID-19 related acute respiratory failure and death.

High performance of cerebrospinal fluid immunoglobulin G analysis for diagnosis of multiple sclerosis.

BACKGROUND: The 2017 revision of the McDonald criteria highlights the usefulness of cerebrospinal fluid (CSF) immunoglobulin G (IgG) analysis to diagnose multiple sclerosis (MS). The objective of this study was to assess the diagnostic performances of CSF IgG analysis in the absence of a gold standard. METHODS: All patients who underwent CSF IgG analysis for events suggestive of MS in Nancy University Hospital (France) from 2008 to 2011 were retrospectively included. A latent class analysis with Bayesian approach was used to infer MS prevalence (latent variable) as well as the diagnostic properties of the 2005 and 2010 McDonald criteria and CSF IgG analysis (observed variables). RESULTS: Data from 673 patients were analysed. For CSF IgG analysis, the Bayesian latent class analysis estimated sensitivity of 0.93 (95% CrI 0.89-0.96) and specificity of 0.81 (95% CrI 0.77-0.85). The true prevalence estimate was 36% (95% CrI 0.33-0.40). Sensitivity and specificity estimates for patients with events suggestive of remitting-onset MS were similar to those for the whole sample-0.92 (95% CrI 0.85-0.96) and 0.80 (95% CrI 0.76-0.84), respectively-but higher for patients with signs of progressive-onset MS-0.95 (95% CrI 0.84-0.99) and 0.88 (95% CrI 0.78-0.94), respectively. CONCLUSIONS: In the absence of a gold standard, latent class analysis indicates good diagnostic properties of CSF IgG analysis for MS. This test could thus be useful, especially for patients who tested negative for the 2005 and 2010 McDonald criteria. These findings deserve to be confirmed prospectively.

Amyloid PETs are commonly negative in suspected Alzheimer's disease with an increase in CSF phosphorylated-tau protein concentration but an Aß42 concentration in the very high range: a prospective study.

BACKGROUND: Atypical cerebrospinal fluid (CSF) patterns, involving an increase in the concentration of phosphorylated-tau (P-tau) proteins but normal amyloid-ß concentration, are not uncommon in patients with mild neurocognitive disorders and suspected Alzheimer's disease (AD). In these conditions, however, AD diagnosis may be ruled out in the absence of any amyloid deposition at positron-emission tomography (PET). This pilot cross-sectional study was aimed to determine whether this negativity of amyloid PET can be predicted by CSF profiles in such patients. METHODS: Twenty-five patients (73 [68-80] years, 10 women) with mild neurocognitive disorders, suspected AD and an increase in the CSF concentration of P-tau proteins but normal Aß42 concentration and Aß42/Aß40 ratio were prospectively included and referred to a 18F-florbetaben PET. The latter was considered as definitively negative with the conjunction of both visual (brain amyloid plaque load score) and quantified (standard uptake value ratios) criteria. Predictors of a negative PET were searched among current CSF biomarkers (Aß42, Aß40, T-tau, P-tau, Aß42/Aß40, Aß42/p-tau). RESULTS: Amyloid PET was negative in 15 patients (60%) with a CSF Aß42 concentration being the sole independent predictor of this negativity. The criterion of an Aß42 concentration in the very high range (> 843 pg/mL), observed in 60% (15/25) of the study patients, was associated with a negative amyloid PET in 93% (14/15) of cases. CONCLUSIONS: In mild neurocognitive disorders patients with suspected AD and showing an increase in CSF P-tau protein level, amyloid PETs are commonly negative, when Aß42 concentration is in the very high range. In such case, AD diagnosis based on biomarkers can be ruled out with reasonable certainty, without the need for additional CSF second-line assays or results from amyloid PET.

Age-related changes in regiospecific expression of Lipolysis Stimulated Receptor (LSR) in mice brain.

The regulation of cholesterol, an essential brain lipid, ensures proper neuronal development and function, as demonstrated by links between perturbations of cholesterol metabolism and neurodegenerative diseases, including Alzheimer's disease. The central nervous system (CNS) acquires cholesterol via de novo synthesis, where glial cells provide cholesterol to neurons. Both lipoproteins and lipoprotein receptors are key elements in this intercellular transport, where the latter recognize, bind and endocytose cholesterol containing glia-produced lipoproteins. CNS lipoprotein receptors are like those in the periphery, among which include the ApoB, E binding lipolysis stimulated lipoprotein receptor (LSR). LSR is a multimeric protein complex that has multiple isoforms including α and α', which are seen as a doublet at 68 kDa, and ß at 56 kDa. While complete inactivation of murine lsr gene is embryonic lethal, studies on lsr +/- mice revealed altered brain cholesterol distribution and cognitive functions. In the present study, LSR profiling in different CNS regions revealed regiospecific expression of LSR at both RNA and protein levels. At the RNA level, the hippocampus, hypothalamus, cerebellum, and olfactory bulb, all showed high levels of total lsr compared to whole brain tissues, whereas at the protein level, only the hypothalamus, olfactory bulb, and retina showed the highest levels of total LSR. Interestingly, major regional changes in LSR expression were observed in aged mice which suggests changes in cholesterol homeostasis in specific structures in the aging brain. Immunocytostaining of primary cultures of mature murine neurons and glial cells isolated from different CNS regions showed that LSR is expressed in both neurons and glial cells. However, lsr RNA expression in the cerebellum was predominantly higher in glial cells, which was confirmed by the immunocytostaining profile of cerebellar neurons and glia. Based on this observation, we would propose that LSR in glial cells may play a key role in glia-neuron cross talk, particularly in the feedback control of cholesterol synthesis to avoid cholesterol overload in neurons and to maintain proper functioning of the brain throughout life.