Introduction: Synaptic dysfunction and degeneration are central events in Alzheimer’s disease (AD) pathophysiology that are thought to occur early in disease progression. Synaptic pathology may be studied by examining protein biomarkers specific for different synaptic elements. We recently showed that the dendritic protein neurogranin (Ng), including the endogenous Ng peptide 48 to 76 (Ng_48–76), is markedly increased in cerebrospinal fluid (CSF) in AD and that Ng_48–76 is the dominant peptide in human brain tissue. The aim of this study was to characterize Ng in plasma and CSF using mass spectrometry and to investigate the performance of plasma Ng as an AD biomarker. Methods: Paired plasma and CSF samples from patients with AD (n = 25) and healthy controls (n = 20) were analyzed in parallel using an immunoassay developed in-house on the Meso Scale Discovery platform and hybrid immunoaffinity-mass spectrometry (HI-MS). A second plasma material from patients with AD (n = 13) and healthy controls (n = 17) was also analyzed with HI-MS. High-resolution mass spectrometry was used for identification of endogenous plasma Ng peptides. Results: Ng in human plasma is present as several endogenous peptides. Of the 16 endogenous Ng peptides identified, seven were unique for plasma and not detectable in CSF. However, Ng_48–76 was not present in plasma. CSF Ng was significantly increased in AD compared with controls (P < 0.0001), whereas the plasma Ng levels were similar between the groups in both studies. Plasma and CSF Ng levels showed no correlation. CSF Ng was stable during storage at −20°C for up to 2 days, and no de novo generation of peptides were detected. Conclusions: For the first time, to our knowledge, we have identified several endogenous Ng peptides in human plasma. In agreement with previous studies, we show that CSF Ng is significantly increased in AD as compared with healthy controls. The origin of Ng in plasma and its possible use as a biomarker need to be further investigated. The results suggest that CSF Ng, in particular Ng_48–76, might reflect the neurodegenerative processes within the brain, indicating a role for Ng as a potential novel clinical biomarker for synaptic function in AD.

Introduction: Neuroinflammation and synaptic degeneration are major neuropathological hallmarks in Alzheimer’s disease (AD). Neurogranin and YKL-40 in cerebrospinal fluid (CSF) are newly discovered markers indicating synaptic damage and microglial activation, respectively. Methods: CSF samples from 95 individuals including 39 patients with AD dementia (AD-D), 13 with mild cognitive impairment (MCI) due to AD (MCI-AD), 29 with MCI not due to AD (MCI-o) and 14 patients with non-AD dementias (non-AD-D) were analyzed for neurogranin and YKL-40. Results: Patients with dementia or MCI due to AD showed elevated levels of CSF neurogranin (p < 0.001 for AD-D and p < 0.05 for MCI-AD) and YKL-40 (p < 0.05 for AD-D and p = 0.15 for MCI-AD) compared to mildly cognitively impaired subjects not diagnosed with AD. CSF levels of neurogranin and YKL-40 did not differ between MCI not due to AD and non-AD dementias. In AD subjects no correlation between YKL-40 and neurogranin was found. The CSF neurogranin levels correlated moderately with tau and p-tau but not with Aβ₄₂ or the MMSE in AD samples. No relevant associations between YKL-40 and MMSE or the core AD biomarkers, Aβ₄₂, t-tau and p-tau were found in AD subjects. Conclusions: Neurogranin and YKL-40 are promising AD biomarkers, independent of and complementary to the established core AD biomarkers, reflecting additional pathological changes in the course of AD.

Objectives: To assess the predictive value of multiparametric MRI for treatment response evaluation of induction chemo-immunotherapy in locally advanced head and neck squamous cell carcinoma.Methods: Twenty-two patients with locally advanced, histologically confirmed head and neck squamous cell carcinoma who were enrolled in the prospective multicenter phase II CheckRad-CD8 trial were included in the current analysis. In this unplanned secondary single-center analysis, all patients who received contrast-enhanced MRI at baseline and in week 4 after single-cycle induction therapy with cisplatin/docetaxel combined with the immune checkpoint inhibitors tremelimumab and durvalumab were included. In week 4, endoscopy with representative re-biopsy was performed to assess tumor response. All lesions were segmented in the baseline and restaging multiparametric MRI, including the primary tumor and lymph node metastases. The volume of interest of the respective lesions was volumetrically measured, and time-resolved mean intensities of the golden-angle radial sparse parallel-volume-interpolated gradient-echo perfusion (GRASP-VIBE) sequence were extracted. Additional quantitative parameters including the T1 ratio, short-TI inversion recovery ratio, apparent diffusion coefficient, and dynamic contrast-enhanced (DCE) values were measured. A model based on parallel random forests incorporating the MRI parameters from the baseline MRI was used to predict tumor response to therapy. Receiver operating characteristic (ROC) curves were used to evaluate the prognostic performance.Results: Fifteen patients (68.2%) showed pathologic complete response in the re-biopsy, while seven patients had a residual tumor (31.8%). In all patients, the MRI-based primary tumor volume was significantly lower after treatment. The baseline DCE parameters of time to peak and wash-out were significantly different between the pathologic complete response group and the residual tumor group (p < 0.05). The developed model, based on parallel random forests and DCE parameters, was able to predict therapy response with a sensitivity of 78.7% (95% CI 71.24–84.93) and a specificity of 78.6% (95% CI 67.13–87.48). The model had an area under the ROC curve of 0.866 (95% CI 0.819–0.914).Conclusions: DCE parameters indicated treatment response at follow-up, and a random forest machine learning algorithm based on DCE parameters was able to predict treatment response to induction chemo-immunotherapy.

Purpose: The necessity of providing endovascular recanalization of acutely thrombosed arteriovenous access (AV access) during weekend is questionable, since hemodialysis can alternatively be achieved by temporarily placed non-tunneled central venous catheters (CVC). Interventional therapy of acutely thrombosed AV access is provided only on weekdays in the study center. This study aimed to compare outcomes in patients admitted on weekdays and on the weekend. Methods: A total of 355 endovascular procedures for thrombosed AV access performed in a single tertiary center from 2007 to 2017 were retrospectively analyzed for technical and clinical success, complications, rate of CVC and length of hospitalization. Technical success was defined as adequate blood flow with less than 30% residual stenosis, clinical success was defined as at least one successful hemodialysis after recanalization. There were two groups: patients who had to wait at least 2 days for recanalization due to admission at the weekend (n = 59, at-the-weekend group, ATW group) and patients receiving therapy no later than the day after admission (n = 296, on a working day group, OAW group). Results: The technical/clinical success rate was 96.6%/88.1% in the ATW and 89.1%/84.6% in the OAW group (p > .05). Complications did not differ among groups (p > .05). Despite a higher rate of CVC, no attributed additional adverse events or complications were observed in the ATW group (p > .05). Conclusion: Despite a longer time until treatment and a higher rate of short-term CVC, it seems to be justified to provide recanalization of dialysis shunts only during weekdays. Graphical