Diagnostic biomarkers from proteomic characterization of cerebrospinal fluid in patients with brain malignancies.

Recent technological advances in molecular diagnostics through liquid biopsies hold the promise to repetitively monitor tumor evolution and treatment response of brain malignancies without the need of invasive surgical tissue accrual. Here, we implemented a mass spectrometry-based protein analysis pipeline which identified hundreds of proteins in 251 cerebrospinal fluid (CSF) samples from patients with four types of brain malignancies (glioblastoma, lymphoma, brain metastasis, and leptomeningeal disease [LMD]) and from healthy individuals with a focus on glioblastoma in a retrospective and confirmatory prospective observational study. CSF proteome deregulation via disruption of the blood brain barrier appeared to be largely conserved across brain tumor entities. CSF analysis of glioblastoma patients identified two proteomic clusters that correlated with tumor size and patient survival. By integrating CSF data with proteomic analyses of matching glioblastoma tumor tissue and primary glioblastoma cells, we identified potential CSF biomarkers for glioblastoma, in particular chitinase-3-like protein 1 (CHI3L1) and glial fibrillary acidic protein (GFAP). Key findings were validated in a prospective cohort consisting of 35 glioma patients. Finally, in LMD patients who frequently undergo repeated CSF work-up, we explored our proteomic pipeline as a mean to profile consecutive CSF samples. Therefore, proteomic analysis of CSF in brain malignancies has the potential to reveal biomarkers for diagnosis and therapy monitoring.

Gap junctions between interneurons are required for normal spatial coding in the hippocampus and short-term spatial memory.

Gap junctions containing connexin 36 electrically couple interneurons in many brain regions and synchronize their activity. We used connexin-36 knock-out mice (Cx36(-/-)) to study the importance of electrical coupling between interneurons for spatial coding in the hippocampus and for different forms of hippocampus-dependent spatial memory. Recordings in behaving mice revealed that the spatial selectivity of hippocampal pyramidal neurons was reduced and less stable in Cx36(-/-) mice. Altered network activity was reflected in slower theta oscillations in the mutants. Temporal coding, assessed by determining the presence and characteristics of theta phase precession, had different dynamics in Cx36(-/-) mice compared with controls. At the behavioral level, Cx36(-/-) mice displayed impaired short-term spatial memory but normal spatial reference memory. These results highlight the functional role of electrically coupled interneurons for spatial coding and cognition. Moreover, they suggest that the precise spatial selectivity of place cells is not essential for normal performance on spatial tasks assessing associative long-term memory.

Diagnostic Accuracy in Teleneurological Stroke Consultations.

BACKGROUND: The accuracy of diagnosing acute cerebrovascular disease via a teleneurology service and the characteristics of misdiagnosed patients are insufficiently known. METHODS: A random sample (n = 1500) of all teleneurological consultations conducted between July 2015 and December 2017 was screened. Teleneurological diagnosis and hospital discharge diagnosis were compared. Diagnoses were then grouped into two main categories: cerebrovascular disease (CVD) and noncerebrovascular disease. Test characteristics were calculated. RESULTS: Out of 1078 consultations, 52% (n = 561) had a final diagnosis of CVD. Patients with CVD could be accurately identified via teleneurological consultation (sensitivity 95.2%, 95% CI 93.2-96.8), but we observed a tendency towards false-positive diagnosis (specificity 77.4%, 95% CI 73.6-80.8). Characteristics of patients with a false-negative CVD diagnosis were similar to those of patients with a true-positive diagnosis, but patients with a false-negative CVD diagnosis had ischemic heart disease less frequently. In retrospect, one patient would have been considered a candidate for intravenous thrombolysis (0.2%). CONCLUSIONS: Teleneurological consultations are accurate for identifying patients with CVD, and there is a very low rate of missed candidates for thrombolysis. Apart from a lower prevalence of ischemic heart disease, characteristics of "stroke chameleons" were similar to those of correctly identified CVD patients.

Development and validation of the Heidelberg Neurological Triage System (HEINTS).

BACKGROUND/OBJECTIVE: Neurological syndromes are underrepresented in existing triage systems which are not validated for neurological patients; therefore, we developed and validated the new Heidelberg Neurological Triage System (HEINTS) in a prospective, single-center observational study. METHODS: Patients were triaged according to the new triage system by nurses and physicians (stage 1) as well as trained nurses (stage 2). In stage 1, all patients presenting to the neurological emergency room (ER) were triaged by nurses and physicians. In stage 2, three specially trained nurses triaged patients according to HEINTS. The main outcomes comprised interrater agreement between nurses' and physicians' triage (stage 1), sensitivity and specificity to detect emergencies (stages 1 and 2), and improvement in triage quality as a result of training (stage 2), as well as correlation of HEINTS with hospital admissions and resource utilization. RESULTS: In stage 1 (n = 2423 patients), sensitivity and specificity to detect neurological emergencies were 84.2% (SD 0.8%) and 85.4% (SD 0.8%) for nurses, as well as 92.4% (SD 0.6%) and 84.1% (SD 0.9%) for physicians, respectively. The interrater-reliability between nurses and physicians in stage 1 was moderate [Cohen's kappa 0.44, standard deviation (SD) 0.02]. In stage 2 (n = 506 patients), sensitivity of trained nurses increased to 94.3% (SD 1.0%), while specificity decreased to 74.8% (SD 1.9%). Correlation of HEINTS triage with hospital admission and resource utilization in both stages was highly significant. CONCLUSIONS: HEINTS predicted hospital admissions and resource utilization. Agreement between nurses and physicians was moderate. HEINTS, applied by physicians and by nurses after training, reliably detected neurological emergencies.