Opsoclonus-Ataxia Syndrome in a Patient With Small-Cell Lung Cancer Treated With Immune Checkpoint Inhibitors.

OBJECTIVES: To describe a case of post-immune checkpoint inhibitor (ICI) opsoclonus-myoclonus-ataxia syndrome (OMAS), with complete clinical remission after treatment. METHODS: A 52-year-old man was admitted because of subacute-onset vertigo, dysarthria, vomiting, and weight loss. He was under atezolizumab (anti-PD-L1) monotherapy (23 cycles) for metastatic small-cell lung cancer, with excellent response. RESULTS: On examination (1 month after symptom onset), the patient had opsoclonus, dysarthria, severe truncal and gait ataxia, and mild appendicular ataxia without myoclonus (SARA score 26/40). Brain MRI showed mild cerebellar atrophy, and CSF analysis disclosed pleocytosis and oligoclonal bands. Anti-SOX1 antibodies were detected in serum and CSF. Atezolizumab was stopped, and corticosteroids and monthly IV immunoglobulins were administered. Chemotherapy (carboplatin and etoposide) was also started because of cancer progression. Three months later, examination showed regression of the opsoclonus, truncal ataxia, and dysarthria and persistence of very mild gait ataxia (SARA score 3.5/40), which completely regressed at last examination (20 months after onset). DISCUSSION: The clinical pattern and reversibility bring the present case close to a few patients with paraneoplastic OMAS described before the ICI era. More research is needed to clarify the pathogenesis and outcomes of OMAS in the context of ICI.

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.

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.

Investigating Predictive Factors of Suicidal Re-attempts in Adolescents and Young Adults After a First Suicide Attempt, a Prospective Cohort Study. Study Protocol of the SURAYA Project.

Introduction: Suicide is the fourth leading cause of death in youth. Previous suicide attempts are among the strongest predictors of future suicide re-attempt. However, the lack of data and understanding of suicidal re-attempt behaviors in this population makes suicide risk assessment complex and challenging in clinical practice. The primary objective of this study is to determine the rate of suicide re-attempts in youth admitted to the emergency department after a first suicide attempt. The secondary objectives are to explore the clinical, socio-demographic, and biological risk factors that may be associated with re-attempted suicide in adolescents and young adults. Methods: We have developed a single-center prospective and naturalistic study that will follow a cohort of 200 young people aged 16 to 25 years admitted for a first suicide attempt to the emergency department of Lyon, France. The primary outcome measure will be the incidence rate of new suicide attempts during 3 months of follow-up. Secondary outcomes to investigate predictors of suicide attempts will include several socio-demographic, clinical and biological assessments: blood and hair cortisol levels, plasma pro- and mature Brain-Derived Neurotrophic Factor (BDNF) isoforms proportion, previous infection with toxoplasma gondii, and C-Reactive Protein (CRP), orosomucoid, fibrinogen, interleukin (IL)-6 inflammatory markers. Discussion: To our knowledge, the present study is the first prospective study specifically designed to assess the risk of re-attempting suicide and to investigate the multidimensional predictive factors associated with re-attempting suicide in youth after a first suicide attempt. The results of this study will provide a unique opportunity to better understand whether youth are an at-risk group for suicide re-attempts, and will help us identify predictive factors of suicide re-attempt risk that could be translated into clinical settings to improve psychiatric care in this population. Clinical Trial Registration: ClinicalTrials.gov, identifier: NCT03538197, first registered on 05/29/2018. The first patient was enrolled 05/22/2018.

Proteinopathies associated to repeat expansion disorders.

The most common neurodegenerative disorders, such as Alzheimer's or Parkinson's diseases, are characterized by synaptic dysfunction, neuronal loss and proteinaceous aggregates in central nervous system. The deposition of misfolded proteins constitutes neuropathological hallmarks of these diseases, grouped in the generic term of proteinopathies. Apart from these, other neurodegenerative diseases are characterized by genetic abnormalities like unstable repetitive simple sequence tracts (microsatellites) dispersed throughout the human genome. They are called repeat expansion disorders and include, for example, Huntington's disease or frontotemporal dementia/amyotrophic lateral sclerosis phenotypes associated to an expansion in C9ORF72. The presence of the expanded DNA tract leads to molecular alterations at the DNA, RNA and protein levels associated to distinct mechanisms, such as loss-of-function (LOF), gain-of-function (GOF) including misfolding of physiological or mutant proteins, favoring their polymerization and aggregation. Therefore, specific proteinopathies also arise from these repeat expansion disorders. The molecular description of the nature and location of expanded tracts, highlighting the consequences onto clinical phenotypes will be first described. Specific focuses on the three pathomechanisms of the repeat expansions associated to proteinopathies will then be addressed. Lastly, we will show how progress in the understanding of these different mechanisms has led to recent advances in new/innovative therapeutic approaches and emergence of associated biomarkers.

Core cerebrospinal fluid biomarker profile in anti-LGI1 encephalitis.

OBJECTIVE: To compare CSF biomarkers' levels in patients suffering from anti-Leucine-rich Glioma-Inactivated 1 (LGI1) encephalitis to neurodegenerative [Alzheimer's disease (AD), Creutzfeldt-Jakob's disease (CJD)] and primary psychiatric (PSY) disorders. METHODS: Patients with LGI1 encephalitis were retrospectively selected from the French Reference Centre database between 2010 and 2019 and enrolled if CSF was available for biomarkers analysis including total tau (T-tau), phosphorylated tau (P-tau), amyloid-beta Aß1-42, and neurofilaments light chains (Nf L). Samples sent for biomarker determination as part of routine practice, and formally diagnosed as AD, CJD, and PSY, were used as comparators. RESULTS: Twenty-four patients with LGI1 encephalitis were compared to 39 AD, 20 CJD and 20 PSY. No significant difference was observed in T-tau, P-tau, and Aß1-42 levels between LGI1 encephalitis and PSY patients. T-Tau and P-Tau levels were significantly lower in LGI1 encephalitis (231 and 43 ng/L) than in AD (621 and 90 ng/L, p < 0.001) and CJD patients (4327 and 55 ng/L, p < 0.001 and p < 0.01). Nf L concentrations of LGI1 encephalitis (2039 ng/L) were similar to AD (2,765 ng/L) and significantly higher compared to PSY (1223 ng/L, p < 0.005), but significantly lower than those of CJD (13,457 ng/L, p < 0.001). Higher levels of Nf L were observed in LGI1 encephalitis presenting with epilepsy (3855 ng/L) compared to LGI1 without epilepsy (1490 ng/L, p = 0.02). No correlation between CSF biomarkers' levels and clinical outcome could be drawn. CONCLUSION: LGI encephalitis patients showed higher Nf L levels than PSY, comparable to AD, and even higher when presenting epilepsy suggesting axonal or synaptic damage linked to epileptic seizures.

Comparative diagnosis interest of NfL and pNfH in CSF and plasma in a context of FTD-ALS spectrum.

OBJECTIVE: The 'Frontotemporal dementia-Amyotrophic lateral sclerosis Spectrum' (FAS) encompasses different phenotypes, including cognitive disorders (frontotemporal dementia, FTD) and/or motor impairments (amyotrophic lateral sclerosis, ALS). The aim of this study was to apprehend the specific uses of neurofilaments light chain (NfL) and phosphorylated neurofilaments heavy chain (pNfH) in a context of FAS. METHODS: First, NfL and pNfH were measured in 39 paired cerebrospinal fluid (CSF) and plasma samples of FAS and primary psychiatric disorders (PPD) patients, considered as controls. Secondly, additional plasma samples were included to examine a larger cohort of 81 samples composed of symptomatic FAS and PPD patients, presymptomatic and non-carrier relatives individuals. The measures were performed using Simoa technology. RESULTS: There was a positive correlation between CSF and plasma values for NfL (p < 0.0001) and for pNfH (p = 0.0036). NfL values were higher for all phenotypes of symptomatic FAS patients compared to PPD patients (p = 0.0016 in CSF; p = 0.0003 in plasma). On the contrary, pNfH values were solely increased in FAS patients exhibiting motor impairment. Unlike symptomatic FAS patients, presymptomatic cases had comparable concentrations with non-carrier individuals. CONCLUSION: NfL, but not pNfH, appeared to be useful in a context of differential diagnosis between FTD and psychiatric patients. Nevertheless, pNfH seem more specific for the diagnosis and follow-up of motor impairments. In each specific indication, measures in CSF and plasma will provide identical interpretations.

Change in Expression of 5-HT6 Receptor at Different Stages of Alzheimer's Disease: A Postmortem Study with the PET Radiopharmaceutical [18F]2FNQ1P.

BACKGROUND: The 5-HT6 receptor is one of the most recently identified serotonin receptors in the central nervous system. Because of its role in memory and cognitive process, this receptor might be implicated in Alzheimer's disease (AD) and associated disorders. OBJECTIVE: The aim of this study was to investigate the binding of [18F]2FNQ1P, a new specific radiotracer of 5-HT6 receptors, and to quantify 5-HT6 receptor density in caudate nucleus in a population of patients with different AD stages. METHODS: Patients were classified according to the "ABC" NIA-AA classification. In vitro binding assays were performed in postmortem brain tissue from the healthy control (HC; n = 8) and severe AD ("High"; n = 8) groups. In vitro quantitative autoradiography was performed in human brain tissue (caudate nucleus) from patients with different stages of AD: HC (n = 15), "Low" (n = 18), "Int" (n = 20), and "High" (n = 15). RESULTS: In vitro binding assays did not show significant differences for the KD and Bmax parameters between "High" and HC groups. In vitro quantitative autoradiography showed a significant difference between the "High" and HC groups (p = 0.0025). We also showed a progressive diminution in [18F]2FNQ1P specific binding, which parallels 5-HT6 receptors expression, according to increasing AD stage. Significant differences were observed between the HC group and all AD stages combined ("Low", "Intermediate", and "High") (p = 0.011). CONCLUSION: This study confirms the interest of investigating the role of 5-HT6 receptors in AD and related disorders. [18F]2FNQ1P demonstrated specific binding to 5-HT6 receptors.

The standardization of cerebrospinal fluid markers and neuropathological diagnoses brings to light the frequent complexity of concomitant pathology in Alzheimer's disease: The next challenge for biochemical markers?

During the last two decades, neuropathological examination of the brain has evolved both technically and scientifically. The increasing use of immunohistochemistry to detect protein aggregates paralleled a better understanding of neuroanatomical progression of protein deposition. As a consequence, an international effort was achieved to standardize hyperphosphorylated-Tau (phospho-TAU), ßAmyloid (Aß), alpha syncuclein (alpha-syn), phosphorylated transactive response DNA-binding protein 43 (phospho-TDP43) and vascular pathology detection. Meanwhile harmonized staging systems emerged in order to increase inter rater reproducibility. Therefore, a refined definition of Alzheimer's disease was recommended., a clearer picture of the neuropathological lesions diversity emerged secondarily to the systematic assessment of concomitant pathology highlighting finally a low rate of pure AD pathology. This brings new challenges to laboratory medicine in the field of cerebrospinal fluid (CSF) markers of Alzheimer's disease: how to further validate total Tau, phospho-TAU, Aß40 and Aß42 and new marker level cut-offs while autopsy rates are declining?

Development of an automated capillary nano-immunoassay-Simple Western assay-to quantify total TDP43 protein in human platelet samples.

Frontotemporal lobar degeneration syndrome is the second cause of young-onset dementia. Unfortunately, reliable biomarkers are currently lacking for the diagnosis of this disease. As TDP43 protein is one of the proteins pathologically involved in frontotemporal lobar degeneration, many studies have been performed to assess TDP43 protein diagnostic performances. Mixed results were obtained using cerebrospinal fluid and plasma samples so far. The aim of the study was to develop an automated capillary nano-immunoassay-Simple Western assay-to detect and quantify TDP43 protein simultaneously in human blood-based samples. Simple Western assay was developed with two different cell lysates used as positive controls and was compared to Western blot. TDP43 protein profiles in plasma samples were disappointing, as they were discordant to our positive controls. On the contrary, similar TDP43 patterns were obtained between platelet samples and cell lysates using both assays. Simple Western assay provided good quantitative performances in platelet samples: a linearity of signals could be observed (r2 = 0.994), associated to a within-run variability at 5.7%. Preliminary results based on a cohort of patients suffering from frontotemporal lobar degeneration showed large inter-individual variations superior to Simple Western's analytical variability. Simple Western assay seems to be suitable for detecting and quantifying TDP43 protein in platelet samples, providing a potential candidate biomarker in this disease. Further confirmation studies should now be performed on larger cohorts of patients to assess diagnostic performances of TDP43 protein in platelet samples.

C9orf72 Protein Plasmatic Concentrations Are Similar between C9ORF72 Expansion Carriers and Noncarriers in Frontotemporal Dementia.

BACKGROUND/AIMS: The aim of the study was to assess the theory of haploinsufficiency in C9ORF72 expansion carriers, the most frequent causative gene of frontotemporal dementia. METHODS: Plasmatic concentrations of C9orf72 protein were measured in 33 patients suspected of familial frontotemporal dementia using an enzyme-linked immunosorbent assay. RESULTS: No difference was observed between C9ORF72 expansion carriers (21.2% of patients) and noncarriers (78.8% of patients). C9orf72 protein determination is not a suitable biomarker for screening C9ORF72 expansion carriers. CONCLUSION: Our results provide new evidence against the hypothesis of haploinsufficiency leading to frontotemporal dementia in C9ORF72 expansion carriers.

Multicenter Analytical Validation of Aß40 Immunoassays.

BACKGROUND: Before implementation in clinical practice, biomarker assays need to be thoroughly analytically validated. There is currently a strong interest in implementation of the ratio of amyloid-ß peptide 1-42 and 1-40 (Aß42/Aß40) in clinical routine. Therefore, in this study, we compared the analytical performance of six assays detecting Aß40 in cerebrospinal fluid (CSF) in six laboratories according to a recently standard operating procedure (SOP) developed for implementation of ELISA assays for clinical routine. METHODS: Aß40 assays of six vendors were validated in up to three centers per assay according to recently proposed international consensus validation protocols. The performance parameters included sensitivity, precision, dilutional linearity, recovery, and parallelism. Inter-laboratory variation was determined using a set of 20 CSF samples. In addition, test results were used to critically evaluate the SOPs that were used to validate the assays. RESULTS: Most performance parameters of the different Aß40 assays were similar between labs and within the predefined acceptance criteria. The only exceptions were the out-of-range results of recovery for the majority of experiments and of parallelism by three laboratories. Additionally, experiments to define the dilutional linearity and hook-effect were not executed correctly in part of the centers. The inter-laboratory variation showed acceptable low levels for all assays. Absolute concentrations measured by the assays varied by a factor up to 4.7 for the extremes. CONCLUSION: All validated Aß40 assays appeared to be of good technical quality and performed generally well according to predefined criteria. A novel version of the validation SOP is developed based on these findings, to further facilitate implementation of novel immunoassays in clinical practice.

Cerebrospinal Fluid Aß40 Improves the Interpretation of Aß42 Concentration for Diagnosing Alzheimer's Disease.

The combination of decreased amyloid ß42 (Aß42) and increased total tau proteins (T-Tau) and phosphorylated tau (P-Tau) in cerebrospinal fluid (CSF) has recently been considered as a biological diagnostic criterion of Alzheimer's disease (AD). Previous studies showed significant heterogeneity in CSF Aß42 levels to discriminate AD from non-AD patients. It was also suggested that the CSF amyloid peptide ß42/ß40 ratio has better diagnostic performance than Aß42 alone. The objective of the present study was to investigate the potential added value of determining CSF amyloid ß40 peptide (Aß40) for biological diagnosis of AD when CSF Aß42 levels failed. CSF AD biomarkers were run in 2,171 samples from 1,499 AD and 672 non-AD patients. The following pathologic thresholds were used to define an AD-positive CSF biomarker profile: T-Tau ≥ 400 ng/L, P-Tau181 ≥ 60 ng/L, and Aß42 ≤ 700 ng/L. CSF Aß40 was assayed in AD patients with CSF Aß42 levels above 700 ng/L and non-AD patients with CSF Aß42 levels below 700 ng/L. CSF Aß40 levels were higher in AD than non-AD patients. The receiver operator characteristic curves of CSF Aß40 and the Aß42/Aß40 ratio defined AD cut-off values at 12,644 ng/L and 0.06, respectively. In AD patients with non-pathological CSF Aß42, CSF Aß40 concentration was able to correct 76.2% of cases when expressed as CSF Aß42/Aß40 ratio and 94.7% of cases when used alone. Using CSF Aß42 and then CSF Aß40, the percentage of misinterpreted AD patients fell to 1.0%. CSF Aß40 concentration improved interpretation of Aß42 level for the diagnosis of AD. CSF Aß40 alone showed better diagnostic performance than the amyloid peptide Aß42/Aß40 ratio. The added value of determining CSF Aß40 in AD diagnosis now needs confirming in a cohort of definite AD patients and to be completed with novel amyloid cascade biomarkers.

Pre-analytical and analytical factors influencing Alzheimer's disease cerebrospinal fluid biomarker variability.

A panel of cerebrospinal fluid (CSF) biomarkers including total Tau (t-Tau), phosphorylated Tau protein at residue 181 (p-Tau) and ß-amyloid peptides (Aß42 and Aß40), is frequently used as an aid in Alzheimer's disease (AD) diagnosis for young patients with cognitive impairment, for predicting prodromal AD in mild cognitive impairment (MCI) subjects, for AD discrimination in atypical clinical phenotypes and for inclusion/exclusion and stratification of patients in clinical trials. Due to variability in absolute levels between laboratories, there is no consensus on medical cut-off value for the CSF AD signature. Thus, for full implementation of this core AD biomarker panel in clinical routine, this issue has to be solved. Variability can be explained both by pre-analytical and analytical factors. For example, the plastic tubes used for CSF collection and storage, the lack of reference material and the variability of the analytical protocols were identified as important sources of variability. The aim of this review is to highlight these pre-analytical and analytical factors and describe efforts done to counteract them in order to establish cut-off values for core CSF AD biomarkers. This review will give the current state of recommendations.

Chasing the Effects of Pre-Analytical Confounders - A Multicenter Study on CSF-AD Biomarkers.

INTRODUCTION: Core cerebrospinal fluid (CSF) biomarkers - Aß42, Tau, and phosphorylated Tau (pTau) - have been recently incorporated in the revised criteria for Alzheimer's disease (AD). However, their widespread clinical application lacks standardization. Pre-analytical sample handling and storage play an important role in the reliable measurement of these biomarkers across laboratories. AIM: In this study, we aim to surpass the efforts from previous studies, by employing a multicenter approach to assess the impact of less studied CSF pre-analytical confounders in AD-biomarkers quantification. METHODS: Four different centers participated in this study and followed the same established protocol. CSF samples were analyzed for three biomarkers (Aß42, Tau, and pTau) and tested for different spinning conditions [temperature: room temperature (RT) vs. 4°C; speed: 500 vs. 2000 vs. 3000 g], storage volume variations (25, 50, and 75% of tube total volume), as well as freezing-thaw cycles (up to five cycles). The influence of sample routine parameters, inter-center variability, and relative value of each biomarker (reported as normal/abnormal) was analyzed. RESULTS: Centrifugation conditions did not influence biomarkers levels, except for samples with a high CSF total protein content, where either non-centrifugation or centrifugation at RT, compared to 4°C, led to higher Aß42 levels. Reducing CSF storage volume from 75 to 50% of total tube capacity decreased Aß42 concentration (within analytical CV of the assay), whereas no change in Tau or pTau was observed. Moreover, the concentration of Tau and pTau appears to be stable up to five freeze-thaw cycles, whereas Aß42 levels decrease if CSF is freeze-thawed more than three times. CONCLUSION: This systematic study reinforces the need for CSF centrifugation at 4°C prior to storage and highlights the influence of storage conditions in Aß42 levels. This study contributes to the establishment of harmonized standard operating procedures that will help reducing inter-lab variability of CSF-AD biomarkers evaluation.

Alzheimer's disease--Recent biomarker developments in relation to updated diagnostic criteria.

Alzheimer's disease (AD) is the most common cause of dementia and is characterized by neuroaxonal and synaptic degeneration accompanied by intraneuronal neurofibrillary tangles and accumulation of extracellular plaques in specific brain regions. These features are reflected in the AD cerebrospinal fluid (CSF) by increased concentrations of total tau (t-tau) and phosphorylated tau (p-tau), together with decreased concentrations of ß-amyloid (Aß42), respectively. In combination, Aß42, p-tau and t-tau are 85-95% sensitive and specific for AD in both prodromal and dementia stages of the disease and they are now included in the diagnostic research criteria for AD. However, to fully implement these biomarkers into clinical practice, harmonization of data is needed. This work is ongoing through the standardization of analytical procedures between clinical laboratories and the production of reference materials for CSF Aß42, p-tau and t-tau. To monitor other aspects of AD neuropathology, e.g., synaptic dysfunction and/or to develop markers of progression, identifying novel candidate biomarkers is of great importance. Based on knowledge from the established biomarkers, exemplified by Aß and its many variants, and emerging data on neurogranin fragments as biomarker candidate(s), a thorough protein characterization in order to fully understand the diagnostic value of a protein is a suggested approach for successful biomarker discovery.

Efficacy of intranasal administration of artesunate in experimental cerebral malaria.

BACKGROUND: Improving management of patients suffering from cerebral malaria is needed to reduce the devastating mortality and morbidity of the disease in endemic areas. Intravenous artesunate is currently the first-line treatment, but the lack of material and skills in the field make it difficult to implement in endemic areas. Intranasal route provides a very easy and direct gateway to blood and brain to deliver medications, by-passing the brain blood barrier. Therefore, it could be helpful and suitable to administer artesunate in the context of cerebral malaria, especially in young children. In this study, intranasal administration of artesunate to rescue from cerebral malaria using a murine model was tested. METHODS: CBA/J mice infected with Plasmodium berghei ANKA strain received artesunate (20 mg/kg) or a placebo solution intranasally, either on day 5, 6 or 7 post-infection, during a controlled, blinded, randomized trial. Primary endpoint was mortality on day 12 post-infection. Secondary endpoints were parasitaemia and clinical stage. Pharmacokinetics data following administration were collected in blood and brains of treated mice. Local toxicity was evaluated by histopathologic examination of brain and nasal sections in blinded manner. RESULTS: Intranasal administration of artesunate dramatically reduced the mortality rate (p < 0.001), preventing death in most cases. Parasitaemia loads decreased by 88.7% (61.8-100%) within 24 hours after administration. Symptoms of cerebral malaria were prevented or reversed. Dihydroartemisinin was detected in mice blood and brain within 15 minutes of intranasal administration. No direct nasal or brain toxicity was detected. CONCLUSION: Intranasal delivery is an efficient route to timely and efficiently administer artesunate and therefore may contribute to decreasing malaria-related mortality.