Diagnostic and prognostic biomarkers in immune checkpoint inhibitor-related encephalitis: a retrospective cohort study.

Background: Immune checkpoint inhibitor-related encephalitis (ICI-encephalitis) is not well characterised and diagnostic and prognostic biomarkers are lacking. We aimed to comprehensively characterise ICI-encephalitis and identify diagnostic biomarkers and outcome predictors. Methods: This retrospective observational study included all patients with ICI-encephalitis studied in the French Reference Centre on Paraneoplastic Neurological Syndromes (PNS) and Autoimmune Encephalitis (2015-2023). ICI encephalitis was considered definite in case of inflammatory findings at paraclinical tests and/or well-characterised neural antibodies. Predictors of immune-related adverse event (irAE) treatment response, defined as a Common Terminology Criteria for Adverse Events v5.0 grade < 3 at any time after therapeutic intervention, were assessed by logistic regression analysis, and predictors of mortality by Cox regression analysis. Neurofilament light chain (NfL) was measured by enzyme-linked immunosorbent assay. Findings: Sixty-seven patients with definite encephalitis were identified (median age, 69 years; 66% male). A focal syndrome was observed in 43/67 patients (64%; limbic encephalitis, cerebellar ataxia, and/or brainstem encephalitis), while 24/67 (36%) had meningoencephalitis, a non-focal syndrome with altered mental status (22/24 patients, 92%) and pleocytosis (24/24 patients, 100%). Patients with focal encephalitis more frequently had abnormal brain MRI (26/42, 62% versus 8/24, 33%, p = 0.025), PNS-related antibodies (36/43, 84% versus 1/24, 4%, p < 0.001), and neuroendocrine cancers (22/43, 51% versus 1/24, 4%; p < 0.001) than patients with meningoencephalitis. Focal encephalitis patients had a lower rate of irAE treatment response (7/39, 18%) and higher mortality (27/43, 63%) compared to meningoencephalitis patients (12/22, 77% and 5/24, 21%, respectively, p < 0.001 each). PNS-related antibodies were associated with less irAE treatment response, independently of age, sex, and baseline severity (adjusted OR 0.05; 95%CI [0.01; 0.19]; p < 0.001) as well as higher mortality, independently of age and cancer type (adjusted HR 5.07; 95% CI [2.12; 12.12]; p < 0.001). Serum NfL discriminated patients with definite ICI-encephalitis (n = 27) from cancer-matched controls (n = 16; optimal cut-off >273.5 pg/mL, sensitivity 81%, specificity 88%, AUC 0.87, 95% CI [0.76; 0.98]) and irAE treatment responders (n = 10) from non-responders (n = 17, optimal cut-off >645 pg/mL, sensitivity 90%, specificity 65%; AUC 0.75, 95% CI [0.55; 0.94]). Interpretation: ICI-encephalitis corresponds to a set of clinically-recognisable syndromes. Patients with focal encephalitis, PNS-related antibodies, and/or higher serum NfL have low irAE treatment response rates. Research is needed on the underlying immunopathogenesis to foster therapeutic innovations. Funding: Agence Nationale de la Recherche.

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.