[On the road to biological blood diagnosis of Alzheimer's disease?] / Vers un diagnostic biologique sanguin de la maladie d'Alzheimer ?

The growing number of people suffering from Alzheimer's disease (AD) represents a major public health problem. The diagnosis of AD is multidisciplinary and involves the use of amyloid and tau biomarkers measured in cerebrospinal fluid. Recent advances in analytical techniques now allow us to measure these biomarkers in blood. Blood biomarkers offer particularly promising potential for early, minimally invasive detection of AD, as well as for differential diagnosis of dementia and patient follow-up. The aim of this review is to provide an overview of current and candidate blood biomarkers for AD, their informative value, and their potential to be integrated into clinical practice in the near future.

Title: Vers un diagnostic biologique sanguin de la maladie d'Alzheimer ? Abstract: Le nombre croissant de personnes atteintes de la maladie d'Alzheimer (MA) représente un problème majeur de santé publique. Le diagnostic de la MA est multidisciplinaire et intègre des marqueurs biologiques dosés dans le liquide cérébrospinal1. Les progrès techniques et analytiques récents permettent de disposer désormais de nouveaux biomarqueurs sanguins prometteurs pour la détection précoce et peu invasive de la MA, mais aussi pour le diagnostic différentiel de la démence et pour le suivi des patients. L'objectif de cette synthèse est de fournir une vue d'ensemble des biomarqueurs sanguins actuels et candidats de la MA, de leur valeur informative et de leur potentiel à être intégrés prochainement à la pratique clinique.

Clinical value of plasma ALZpath pTau217 immunoassay for assessing mild cognitive impairment.

BACKGROUND: Among plasma biomarkers for Alzheimer's disease (AD), pTau181 and pTau217 are the most promising. However, transition from research to routine clinical use will require confirmation of clinical performance in prospective cohorts and evaluation of cofounding factors. METHOD: pTau181 and pTau217 were quantified using, Quanterix and ALZpath, SIMOA assays in the well-characterised prospective multicentre BALTAZAR (Biomarker of AmyLoid pepTide and AlZheimer's diseAse Risk) cohort of participants with mild cognitive impairment (MCI). RESULTS: Among participants with MCI, 55% were Aß+ and 29% developed dementia due to AD. pTau181 and pTau217 were higher in the Aß+ population with fold change of 1.5 and 2.7, respectively. MCI that converted to AD also had higher levels than non-converters, with HRs of 1.38 (1.26 to 1.51) for pTau181 compared with 8.22 (5.45 to 12.39) for pTau217. The area under the curve for predicting Aß+ was 0.783 (95% CI 0.721 to 0.836; cut-point 2.75 pg/mL) for pTau181 and 0.914 (95% CI 0.868 to 0.948; cut-point 0.44 pg/mL) for pTau217. The high predictive power of pTau217 was not improved by adding age, sex and apolipoprotein E ε4 (APOEε4) status, in a logistic model. Age, APOEε4 and renal dysfunction were associated with pTau levels, but the clinical performance of pTau217 was only marginally altered by these factors. Using a two cut-point approach, a 95% positive predictive value for Aß+ corresponded to pTau217 >0.8 pg/mL and a 95% negative predictive value at <0.23 pg/mL. At these two cut-points, the percentages of MCI conversion were 56.8% and 9.7%, respectively, while the annual rates of decline in Mini-Mental State Examination were -2.32 versus -0.65. CONCLUSIONS: Plasma pTau217 and pTau181 both correlate with AD, but the fold change in pTau217 makes it better to diagnose cerebral amyloidosis, and predict cognitive decline and conversion to AD dementia.

Blood Neurofilament Levels Predict Cognitive Decline across the Alzheimer's Disease Continuum.

Neurofilament light chain (NfL) is a potential diagnostic and prognostic plasma biomarker for numerous neurological diseases including Alzheimer's disease (AD). In this study, we investigated the relationship between baseline plasma concentration of Nfl and Mild Cognitive Impairment in participants who did and did not have a clinically determined diagnosis of dementia by the end of the three-year study. Additionally, we explored the connection between baseline plasma concentration of NfL and AD dementia patients, considering their demographics, clinical features, and cognitive profiles. A total of 350 participants from the Biomarker of AmyLoid pepTide and AlZheimer's diseAse Risk (BALTAZAR) multicenter prospective study were investigated: 161 AD dementia participants and 189 MCI participants (of which 141 had amnestic MCI and 48 non-amnestic MCI). Plasma biomarkers were measured at baseline and the progression of clinical and cognitive profiles was followed over the three years of follow-up. Baseline plasma NfL concentration increased across the Alzheimer's disease continuum with a mean NfL value of 17.1 ng/mL [SD = 6.1] in non-amnestic MCI, 20.7 ng/mL [SD = 12.0] in amnestic MCI, and 23.1 ng/mL [SD = 22.7] in AD dementia patients. Plasma NfL concentration correlated with age, body mass index (BMI), and global cognitive performance and decline, as measured by the Mini-Mental State Examination (MMSE). MMSE scores decreased in parallel with increasing plasma NfL concentration, independently of age and BMI. However, NfL concentration did not predict MCI participants' conversion to dementia within three years. Discussion: Baseline plasma NfL concentration is associated with cognitive status along the AD continuum, suggesting its usefulness as a potential informative biomarker for cognitive decline follow-up in patients.

Head-to-Head Comparison of Two Plasma Phospho-tau Assays in Predicting Conversion of Mild Cognitive Impairment to Dementia.

BACKGROUND: Among blood biomarkers, phospho-tau181 (pTau181) is one of the most efficient in detecting Alzheimer disease across its continuum. However, transition from research to routine clinical use will require confirmation of clinical performance in prospective cohorts and evaluation of cofounding factors. METHODS: Here we tested the Lumipulse assay for plasma pTau181 in mild cognitive impairment (MCI) participants from the Baltazar prospective cohort. We compared the performance of this assay to the corresponding Simoa assay for the prediction of conversion to dementia. We also evaluated the association with various routine blood parameters indicative of comorbidities. RESULTS: Lumipulse and Simoa gave similar results overall, with hazard ratios for conversion to dementia of 3.48 (95% CI, 2.23-5.45) and 3.70 (95%CI, 2.39-5.87), respectively. However, the 2 tests differ somewhat in terms of the patients identified, suggesting that their use may be complementary. When combined with age, sex, and apolipoprotein E (APOE)ε4 status, areas under the curves for conversion detection were 0.736 (95% CI, 0.682-0.791) for Lumipulse and 0.733 (95% CI, 0.679-0.788) for Simoa. Plasma pTau181 was independently associated with renal dysfunction (assessed by creatinine and glomerular filtration) for both assays. Cardiovascular factors (adiponectin and cholesterol), nutritional, and inflammatory markers (total protein content, C-reactive protein) also impacted plasma pTau181 concentration, although more so with the Simoa than with the Lumipulse assay. CONCLUSIONS: Plasma pTau181 measured using the fully automated Lumipulse assay performs as well as the Simoa assay for detecting conversion to dementia of MCI patients within 3 years and Lumipulse is less affected by comorbidities. This study suggests a pathway to routine noninvasive in vitro diagnosis-approved testing to contribute to the management of Alzheimer disease. CLINICALTRIALS.GOV REGISTRATION NUMBER: NCT01315639.

Plasma phosphorylated tau 181 predicts amyloid status and conversion to dementia stage dependent on renal function.

OBJECTIVES: Plasma P-tau181 is an increasingly established diagnostic marker for Alzheimer's disease (AD). Further validation in prospective cohorts is still needed, as well as the study of confounding factors that could influence its blood level. METHODS: This study is ancillary to the prospective multicentre Biomarker of AmyLoid pepTide and AlZheimer's diseAse Risk cohort that enrolled participants with mild cognitive impairment (MCI) who were examined for conversion to dementia for up to 3 years. Plasma Ptau-181 was measured using the ultrasensitive Quanterix HD-X assay. RESULTS: Among 476 MCI participants, 67% were amyloid positive (Aß+) at baseline and 30% developed dementia. Plasma P-tau181 was higher in the Aß+ population (3.9 (SD 1.4) vs 2.6 (SD 1.4) pg/mL) and in MCI that converted to dementia (3.8 (SD 1.5) vs 2.9 (SD 1.4) pg/mL). The addition of plasma P-tau181 to a logistic regression model combining age, sex, APOEε4 status and Mini Mental State Examination improved predictive performance (areas under the curve 0.691-0.744 for conversion and 0.786-0.849 for Aß+). The Kaplan-Meier curve of conversion to dementia, according to the tertiles of plasma P-tau181, revealed a significant predictive value (Log rank p<0.0001) with an HR of 3.8 (95% CI 2.5 to 5.8). In addition, patients with plasma P-Tau(181) ≤2.32 pg/mL had a conversion rate of less than 20% over a 3-year period. Using a linear regression approach, chronic kidney disease, creatinine and estimated glomerular filtration rate were independently associated with plasma P-tau181 concentrations. CONCLUSIONS: Plasma P-tau181 effectively detects Aß+ status and conversion to dementia, confirming the value of this blood biomarker for the management of AD. However, renal function significantly modifies its levels and may thus induce diagnostic errors if not taken into account.

Serum neurofilament light chain cut-off definition for clinical diagnosis and prognosis of amyotrophic lateral sclerosis.

BACKGROUND: The neurofilament light chain (NfL) assay is gradually becoming an essential diagnostic tool for the diagnosis of many neurological diseases including amyotrophic lateral sclerosis (ALS). Different methods for the determination of this biomarker in serum have been developed in recent years. METHODS: We measured blood NfL in 429 patients referred to the tertiary ALS center of Montpellier, France using two different ultrasensitive methods (Ella™ and Simoa™) and we compared the clinical performances of these two approaches. We also converted NfL values into age and body mass index-adjusted Z-scores to assess cut-off values of this biomarker in this clinical context. RESULTS: We show comparable diagnostic and prognostic performance of Ella™ and Simoa™ technologies in ALS, with specificities and sensitivities exceeding 80% for both. We propose cut-off values for serum NfL in this clinical context, thus enabling the routine clinical use of this biomarker. CONCLUSION: The use of NfL in routine clinical practice will help predict survival and improve diagnostic accuracy by distinguishing ALS from other neurological diseases and motor neuron disease mimics.

The alternative proteome in neurobiology.

Translation involves the biosynthesis of a protein sequence following the decoding of the genetic information embedded in a messenger RNA (mRNA). Typically, the eukaryotic mRNA was considered to be inherently monocistronic, but this paradigm is not in agreement with the translational landscape of cells, tissues, and organs. Recent ribosome sequencing (Ribo-seq) and proteomics studies show that, in addition to currently annotated reference proteins (RefProt), other proteins termed alternative proteins (AltProts), and microproteins are encoded in regions of mRNAs thought to be untranslated or in transcripts annotated as non-coding. This experimental evidence expands the repertoire of functional proteins within a cell and potentially provides important information on biological processes. This review explores the hitherto overlooked alternative proteome in neurobiology and considers the role of AltProts in pathological and healthy neuromolecular processes.

Neurofilaments: a key new biomarker for clinicians. Part 1: Importance of neurofilaments in the management of neurodegenerative diseases / Les neurofilaments : un nouveau biomarqueur clé pour les cliniciens. Partie 1 : Intérêt des neurofilaments dans la prise en charge des maladies neurodégénératives

Neurological biomarkers are of great use for clinicians, as they can be used for numerous purposes: guiding clinical diagnosis, estimating prognosis, assessing disease stage and monitoring progression or response to treatment. This field of neurology has evolved considerably in recent years due to analytical improvements in assay methods, now allowing the detection of biomarkers not only in cerebrospinal fluid (CSF) but also in blood. This progress greatly facilitates the repeated quantification of biomarkers, the collection of blood being much less invasive than that of CSF. Among the various informative biomarkers of neurological disorders, neurofilaments light chains (NfL) have proven to be particularly attractive in many contexts, in particular for the diagnosis and prognosis of neurodegenerative diseases (which this review will present), but also in other contexts of neurological disorders (which will be detailed in part 2). We further address the added value of NfL compared to other biomarkers commonly used to monitor the diseases described in this review.

Les biomarqueurs neurologiques sont d'une grande utilité, car ils peuvent être utilisés à de nombreuses fins : orienter le diagnostic clinique, estimer le pronostic, évaluer le stade de la maladie et surveiller la progression ou la réponse au traitement. Ce domaine de la neurologie a considérablement évolué ces dernières années grâce à l'amélioration des méthodes de dosage, permettant désormais la détection de biomarqueurs non seulement dans le liquide cérébro-spinal (LCS) mais aussi dans le sang. Ce progrès facilite la quantification répétée des biomarqueurs, le prélèvement de sang étant beaucoup moins invasif que celui du LCS. Parmi les différents biomarqueurs informatifs des troubles neurologiques, la chaîne légère des neurofilaments (NfL) s'est révélée particulièrement intéressante dans de nombreux contextes, notamment pour le diagnostic et le pronostic des maladies neurodégénératives (que cette revue présentera), mais aussi dans d'autres contextes de troubles neurologiques (qui seront détaillés dans la partie 2). La valeur ajoutée du NfL par rapport aux autres biomarqueurs couramment utilisés est analysée.

Neurofilaments: a key new biomarker for clinicians. Part 2: Neurofilaments, an asset beyond neurodegenerative diseases / Les neurofilaments : un nouveau biomarqueur clé pour les cliniciens. Partie 2 : Neurofilaments, un intérêt au-delà des maladies neurodégénératives.

Neurofilaments (Nf) are proteins selectively expressed in the cytoskeleton of neurons, and their increase is a marker of neuronal damage. The potential utility of neurofilament light chain (NfL) has recently increased considerably, well beyond neurodegenerative diseases, due to analytical advances that allow measurement of their concentrations (even low ones) in cerebrospinal fluid and blood. This article completes the first part, in which we presented the interest of NfL in the context of neurodegenerative diseases. Here we focus our review on other clinical contexts of neurological injury (such as traumatic brain injury, multiple sclerosis, stroke, and cancer) and present the potential value of NfL assay in the management of these patients, for both diagnosis and prognosis. We also discuss the added value of the NfL assay compared to other biomarkers commonly used in the described clinical situations.

Les neurofilaments (Nf) sont des protéines sélectivement exprimées dans le cytosquelette des neurones, dont l'augmentation est un marqueur de dommages neuronaux. L'utilité potentielle de la chaîne légère des neurofilaments (NfL) s'est récemment considérablement accrue, bien au-delà des maladies neurodégénératives, grâce aux progrès analytiques permettant de mesurer leurs niveaux (mêmes faibles) dans le liquide cérébro-spinal et le sang. Cet article complète la première partie, dans laquelle nous avions présenté l'intérêt des NfL dans le contexte des maladies neurodégénératives. Nous axons ici notre revue sur d'autres contextes cliniques de lésions neurologiques (tels que les traumatismes crâniens, la sclérose en plaques, les accidents vasculaires cérébraux et le cancer) et présentons l'intérêt potentiel du dosage des NfL pour la prise en charge de ces patients, tant au niveau diagnostique que pronostique. Nous discutons également de la plus-value du dosage des NfL par rapport aux autres biomarqueurs couramment utilisés dans les contextes cliniques décrits.

ß-Synuclein as a candidate blood biomarker for synaptic degeneration in Alzheimer's disease.

Synaptic degeneration is an early event closely associated with the course of Alzheimer's disease (AD). The identification of synaptic blood biomarkers is, therefore, of great interest and clinical relevance. The levels of most synaptic proteins are increased in the cerebrospinal fluid (CSF) of patients with AD, but their detection in blood is hitherto either unavailable or not very informative. This paradigm is related to their low concentration, their peripheral origin, or the presence of highly abundant blood proteins that hinder detection. In recent years, significant progress has been made in detecting the presynaptic protein ß-synuclein. This mini-review summarizes the results that highlight the role of ß-synuclein as a candidate blood marker for synaptic degeneration in AD.

Neurofilaments contribution in clinic: state of the art.

Neurological biomarkers are particularly valuable to clinicians as they can be used for diagnosis, prognosis, or response to treatment. This field of neurology has evolved considerably in recent years with the improvement of analytical methods, allowing the detection of biomarkers not only in cerebrospinal fluid (CSF) but also in less invasive fluids like blood. These advances greatly facilitate the repeated quantification of biomarkers, including at asymptomatic stages of the disease. Among the various informative biomarkers of neurological disorders, neurofilaments (NfL) have proven to be of particular interest in many contexts, such as neurodegenerative diseases, traumatic brain injury, multiple sclerosis, stroke, and cancer. Here we discuss these different pathologies and the potential value of NfL assay in the management of these patients, both for diagnosis and prognosis. We also describe the added value of NfL compared to other biomarkers currently used to monitor the diseases described in this review.

The Aß1-42/Aß1-40 ratio in CSF is more strongly associated to tau markers and clinical progression than Aß1-42 alone.

BACKGROUND: Cerebrospinal fluid (CSF) Aß1-42 levels and the Aß1-42/Aß1-40 ratio are markers of amyloid pathology, but previous studies suggest that their levels might be influenced by additional pathophysiological processes. AIMS: To compare Aß1-42 and the Aß1-42/Aß1-40 ratio in CSF in different neurodegenerative disorders and study their association with other biomarkers (tTau, pTau181, and NfL) and with cognitive and functional progression. METHODS: We included all participants from the Sant Pau Initiative on Neurodegeneration (SPIN) with CSF Aß1-42 and Aß1-42/Aß1-40. Participants had diagnoses of Alzheimer's disease (AD), dementia with Lewy bodies, frontotemporal lobar degeneration-related syndromes, non-neurodegenerative conditions, or were cognitively normal. We classified participants as "positive" or "negative" according to each marker. We compared CSF levels of tTau, pTau181, and NfL between concordant and discordant groups through ANCOVA and assessed differences in cognitive (MMSE, FCSRT) and functional (GDS, CDR-SOB) progression using Cox regression and linear-mixed models. RESULTS: In the 1791 participants, the agreement between Aß1-42 and Aß1-42/Aß1-40 was 78.3%. The Aß1-42/Aß1-40 ratio showed a stronger correlation with tTau and pTau181 than Aß1-42 and an agreement with tTau and pTau181 of 73.1% and 77.1%, respectively. Participants with a low Aß1-42/Aß1-40 ratio showed higher tTau and pTau181 and worse cognitive and functional prognosis, regardless of whether they were positive or negative for Aß1-42. The results were consistent across stages, diagnostic categories, and use of different cutoffs. CONCLUSION: Although Aß1-42 and Aß1-42/Aß1-40 are considered markers of the same pathophysiological pathway, our findings provide evidence favoring the use of the Aß1-42/Aß1-40 ratio in clinical laboratories in the context of AD.

Blood amyloid and tau biomarkers as predictors of cerebrospinal fluid profiles.

INTRODUCTION: Blood biomarkers represent a major advance for improving the management, diagnosis, and monitoring of Alzheimer's disease (AD). However, their context of use in relation to routine cerebrospinal fluid (CSF) analysis for the quantification of amyloid peptides and tau proteins remains to be determined. METHODS: We studied in two independent cohorts, the performance of blood biomarkers in detecting "nonpathological" (A-/T-/N-), amyloid (A+) or neurodegenerative (T+ /N+) CSF profiles. RESULTS: Plasma Aß1-42/Aß1-40 ratio and phosphorylated tau (p-tau(181)) were independent and complementary predictors of the different CSF profile and in particular of the nonpathological (A-/T-/N-) profile with a sensitivity and specificity close to 85%. These performances and the corresponding biomarker thresholds were significantly different from those related to AD detection. CONCLUSION: The use of blood biomarkers to identify patients who may benefit from secondary CSF testing represents an attractive stratification strategy in the clinical management of patients visiting memory clinics. This could reduce the need for lumbar puncture and foreshadow the use of blood testing on larger populations.

Comparison of cerebrospinal fluid tau, ptau(181), synuclein, and 14-3-3 for the detection of Creutzfeldt-Jakob disease in clinical practice.

Creutzfeldt-Jakob disease (CJD) is the leading human prion disease and is a major public health concern, with the risk of secondary iatrogenic transmission. Screening for CJD is often based on the detection of 14-3-3 protein in cerebrospinal fluid (CSF) through western blot assay and, in a second step, on a more specific method such as RT-QuIC (Real-Time Quaking-Induced Conversion). Alternatives to the detection of 14-3-3 in CSF have recently been proposed, specifically CSF tau proteins, tau/p-tau(181) ratio, and alpha-synuclein. In the present work, we compare the diagnostic performance of these biomarkers with that of 14-3-3 protein in a cohort of suspected CJD patients. Our results indicate that tau detection is the most effective and suitable approach for routine disease detection in a clinical setting. Combination with other biomarkers does not improve overall performance, while the tau/p-tau(181) ratio remains useful for differentiating Alzheimer's from CJD. In the end, the performance of tau protein detection in CSF reached 78% sensitivity and 80% specificity for the detection of CJD. It is interesting to note that the use of an automated method with a high concentration range allows for rapid and accurate results, which is very useful in clinical practice and allows for confirmatory testing such as RT-QuIC without delay.

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.

Cytokines as new biomarkers of skin wound vitality.

BACKGROUND: The diagnosis of skin wound vitality is currently based on standard histology, but histological findings lack sensitivity in case of a short survival time. New reliable biomarkers of vitality are therefore strongly needed. We assessed the ability of 10 candidate cytokines (IFN-γ, IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, TNF-α) to discriminate between vital and early post-mortem wounds. METHODS: Twenty-four cadavers with a recent open skin wound (< 3 h) were included (20 men, 4 women, mean age = 51.0 ± 24.3 years). An early post-mortem wound was performed in an uninjured skin area, and both wounds were sampled at the autopsy (post-mortem interval (PMI) = 66.3 ± 28.3 h). Needle-puncture sites related to resuscitation cares were included as very early post-mortem wounds (n = 6). In addition to standard histology, cytokines levels were simultaneously measured in each sample using a multiplex sandwich immunoassay, then normalized on healthy skin levels. A quantitative evaluation of IL-8-positive cells in ante- and post-mortem wound samples was also performed. RESULTS: In the training set of samples (n = 72), cytokine levels were significantly higher in vital wounds (mean age = 47 ± 53 min) than in post-mortem wounds (mean PMI = 6.9 ± 9.0 h) (p < 0.2), except for two cytokines (IFN-γ and IL-2). IL-8 was the best discriminatory cytokine (Se = 54%, Sp = 100%, AUC = 0.79), while a multivariate model combining IL-4 and IL12p70 was a bit more discriminant (Se = 55%, Sp = 100%, AUC = 0.84). In the validation set (n = 72), the discriminatory power of the cytokines and the predictive model was slightly lower, with IL-8 remaining the best cytokine (Se = 46%, Sp = 96%, AUC = 0.75). The predictive model remained highly specific (Sp = 100%). Both the cytokines and the predictive model allowed the iatrogenic injuries to be correctly classified as post-mortem wounds. Standard histology and immunohistochemistry showed 21% sensitivity and a specificity of 79% and 100%, respectively. Only two iatrogenic wounds could be properly categorized histologically. CONCLUSION: This study suggests that cytokines could be useful biomarkers of skin wound vitality and that the immunoassay method could be more sensitive than immunohistochemistry to identify wounds with a short survival time. Further research is underway to confirm these preliminary data.

Use of plasma biomarkers for AT(N) classification of neurodegenerative dementias.

OBJECTIVES: All categories included in the AT(N) classification can now be measured in plasma. However, their agreement with cerebrospinal fluid (CSF) markers is not fully established. A blood signature to generate the AT(N) classification would facilitate early diagnosis of patients with Alzheimer's disease (AD) through an easy and minimally invasive approach. METHODS: We measured Aß, pTau181 and neurofilament light (NfL) in 150 plasma samples of the Sant Pau Initiative on Neurodegeneration cohort including patients with mild cognitive impairment, AD dementia, frontotemporal dementia, dementia with Lewy bodies and cognitively normal participants. We classified participants in the AT(N) categories according to CSF biomarkers and studied the diagnostic value of plasma biomarkers within each category individually and in combination. RESULTS: The plasma Aß composite, pTau181 and NfL yielded areas under the curve (AUC) of 0.75, 0.78 and 0.88 to discriminate positive and negative participants in their respective A, T and N categories. The combination of all three markers did not outperform pTau181 alone (AUC=0.81) to discriminate A+T+ from A-T- participants. There was a moderate correlation between plasma Aß composite and CSF Aß1-42/Aß1-40 (Rho=-0.5, p<0.001) and between plasma pTau181 and CSF pTau181 in the entire cohort (Rho=0.51, p<0.001). NfL levels in plasma showed high correlation with those in CSF (Rho=0.78, p<0.001). CONCLUSIONS: Plasma biomarkers are useful to detect the AT(N) categories, and their use can differentiate patients with pathophysiological evidence of AD. A blood AT(N) signature may facilitate early diagnosis and follow-up of patients with AD through an easy and minimally invasive approach.

Analytical comparison of ELISA and mass spectrometry for quantification of serum hepcidin in critically ill patients.

Aim: To compare methods of quantifying serum hepcidin (based on MS and ELISA) and their ability to diagnose true iron deficiency anemia in critically ill patients. Materials & methods: Serum hepcidin was measured in 119 critically ill patients included in the HEPCIDANE clinical trial, using either an ultra-sensitive ELISA kit (from DRG) or two different MS methods. Results: The results show a good correlation between the different methods studied. The Bland-Altman analysis and the Kappa test for clinical groups show a good or very good agreement between the different tests. Conclusion: ELISA or MS show a satisfactory commutability to quantify serum hepcidin. This is of great importance for the determination of therapeutic strategies in iron deficiency.

NFL strongly correlates with TNF-R1 in the plasma of AD patients, but not with cognitive decline.

Peripheral inflammation mechanisms involved in Alzheimer's disease (AD) have yet to be accurately characterized and the identification of blood biomarker profiles could help predict cognitive decline and optimize patient care. Blood biomarkers described to date have failed to provide a consensus signature, which is mainly due to the heterogeneity of the methods used or the cohort. The present work aims to describe the potential informativity of peripheral inflammation in AD, focusing in particular on the potential association between the level of plasma neurofilament light (NFL), peripheral inflammation (by quantifying IL-1ß, IL-6, TNFα, CCL5, TNF-R1, sIL-6R, TIMP-1, IL-8 in blood) and cognitive decline (assessed by the MMSE and ADAScog scales) through a 2-year follow-up of 40 AD patients from the Cytocogma cohort (CHU Poitiers, Pr M. Paccalin). Our results show for the first time a strong correlation between plasma NFL and TNF-R1 at each time of follow-up (baseline, 12 and 24 months), thus opening an interesting perspective for the prognosis of AD patients.

Tau protein in cerebrospinal fluid: a novel biomarker of the time of death?

BACKGROUND: Tau proteins are recognized biomarkers of neurodegeneration and neuronal damage in the cerebrospinal fluid (CSF). It has also been suggested that these CSF proteins could increase post-mortem due to neuronal death. The aim of this study was to investigate the changes in CSF total and phosphorylated tau (p-tau) levels in the early post-mortem interval (PMI), to determine whether these proteins could be relevant biomarkers of time since death. METHODS: Tau and p-tau levels were measured by ELISA in lumbar and cisternal CSF samples from 82 corpses (46 men, 36 women, mean age: 72.4 ± 15.2 years) with a PMI < 12 h. Forty-eight of them were considered neurologically healthy at the time of death. Rectal and tympanic temperatures were also measured in 37 individuals, and two validated temperature-based methods of PMI estimation were applied (Henssge's nomogram and Baccino's method). RESULTS: CSF tau and p-tau levels were significantly increased, with respective median values of 3315 pg/mL and 68.5 pg/mL in the whole cohort, while lower but still increased levels were observed in neurologically healthy patients. Sub-occipital punctures systematically provided higher tau and p-tau values (p < 0.0001). Despite a great inter-individual variability, the concentrations of both biomarkers were positively correlated with the early PMI, with the highest correlation for cisternal p-tau (r = 0.50, p < 0.0001 in the whole cohort; r = 0.58, p = 0.0003 in the neurologically healthy patients). Higher levels of CSF biomarkers were observed for PMI > 6 h versus PMI ≤ 6 h, the discriminatory power of the biomarkers being higher in the subgroup of neurologically healthy patients. Based on cut-off values obtained by ROC curve analysis, the CSF biomarkers could rectify or adjust the time interval provided by the temperature-based methods in a significant number of cases. A predictive model combining tympanic temperature and cisternal tau values was found to be particularly accurate to assign individuals according to their PMI (≤ or > 6 h), with a Se of 83% and a Sp of 100% (AUC = 0.95). CONCLUSION: Our findings suggest that CSF tau and p-tau proteins could serve as potential biomarkers of time since death, in association with tympanic temperature. The practical applicability of such an integrated approach has to be assessed by further studies.