slan-defined subsets of CD16-positive monocytes: impact of granulomatous inflammation and M-CSF receptor mutation.

Human monocytes are subdivided into classical, intermediate, and nonclassical subsets, but there is no unequivocal strategy to dissect the latter 2 cell types. We show herein that the cell surface marker 6-sulfo LacNAc (slan) can define slan-positive CD14(+)CD16(++) nonclassical monocytes and slan-negative CD14(++)CD16(+) intermediate monocytes. Gene expression profiling confirms that slan-negative intermediate monocytes show highest expression levels of major histocompatibility complex class II genes, whereas a differential ubiquitin signature is a novel feature of the slan approach. In unsupervised hierarchical clustering, the slan-positive nonclassical monocytes cluster with monocytes and are clearly distinct from CD1c(+) dendritic cells. In clinical studies, we show a selective increase of the slan-negative intermediate monocytes to >100 cells per microliter in patients with sarcoidosis and a fivefold depletion of the slan-positive monocytes in patients with hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS), which is caused by macrophage colony-stimulating factor (M-CSF) receptor mutations. These data demonstrate that the slan-based definition of CD16-positive monocyte subsets is informative in molecular studies and in clinical settings.

The PROMESA-protocol: progression rate of multiple system atrophy under EGCG supplementation as anti-aggregation-approach.

Formation of toxic α-synuclein oligomers appears to be a key underlying pathological mechanism of synucleinopathies such as Parkinson's disease or multiple system atrophy (MSA). Given that Epigallocatechin-gallate has been shown to inhibit α-synuclein aggregation, it might represent a causal treatment option. Therefore, we set out to evaluate the safety, tolerability and a potential disease-modifying effect of Epigallocatechin-gallate in patients with MSA after 48 weeks of treatment. Power calculation was performed on existing natural history data on the progression of the Unified MSA Rating Scale as primary readout parameter. To assess the efficacy of Epigallocatechin-gallate versus placebo regarding the reduction of disease progression measured during the study period (80 % power, 5 % p level, 50 % effect size) 36 patients per group are needed. Considering a drop-out rate of 20 % a total of 86 patients will be recruited in this multicentre study. These data provide a solid rationale to investigate whether supplementation of Epigallocatechin-gallate can delay the progression of the MSA-related disability.

Faster and Better: How Anomaly Detection Can Accelerate and Improve Reporting of Head Computed Tomography.

BACKGROUND: Most artificial intelligence (AI) systems are restricted to solving a pre-defined task, thus limiting their generalizability to unselected datasets. Anomaly detection relieves this shortfall by flagging all pathologies as deviations from a learned norm. Here, we investigate whether diagnostic accuracy and reporting times can be improved by an anomaly detection tool for head computed tomography (CT), tailored to provide patient-level triage and voxel-based highlighting of pathologies. METHODS: Four neuroradiologists with 1-10 years of experience each investigated a set of 80 routinely acquired head CTs containing 40 normal scans and 40 scans with common pathologies. In a random order, scans were investigated with and without AI-predictions. A 4-week wash-out period between runs was included to prevent a reminiscence effect. Performance metrics for identifying pathologies, reporting times, and subjectively assessed diagnostic confidence were determined for both runs. RESULTS: AI-support significantly increased the share of correctly classified scans (normal/pathological) from 309/320 scans to 317/320 scans (p = 0.0045), with a corresponding sensitivity, specificity, negative- and positive- predictive value of 100%, 98.1%, 98.2% and 100%, respectively. Further, reporting was significantly accelerated with AI-support, as evidenced by the 15.7% reduction in reporting times (65.1 ± 8.9 s vs. 54.9 ± 7.1 s; p < 0.0001). Diagnostic confidence was similar in both runs. CONCLUSION: Our study shows that AI-based triage of CTs can improve the diagnostic accuracy and accelerate reporting for experienced and inexperienced radiologists alike. Through ad hoc identification of normal CTs, anomaly detection promises to guide clinicians towards scans requiring urgent attention.

Impact of normative brain volume reports on the diagnosis of neurodegenerative dementia disorders in neuroradiology: A real-world, clinical practice study.

Background: Normative brain volume reports (NBVR) are becoming more available in the work-up of patients with suspected dementia disorders, potentially leveraging the value of structural MRI in clinical settings. The present study aims to investigate the impact of NBVRs on the diagnosis of neurodegenerative dementia disorders in real-world clinical practice. Methods: We retrospectively analyzed data of 112 memory clinic patients, who were consecutively referred for MRI and 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) during a 12-month period. Structural MRI was assessed by two residents with 2 and 3 years of neuroimaging experience. Statements and diagnostic confidence regarding the presence of a neurodegenerative disorder in general (first level) and Alzheimer's disease (AD) pattern in particular (second level) were recorded without and with NBVR information. FDG-PET served as the reference standard. Results: Overall, despite a trend towards increased accuracy, the impact of NBVRs on diagnostic accuracy was low and non-significant. We found a significant drop of sensitivity (0.75-0.58; p < 0.001) and increase of specificity (0.62-0.85; p < 0.001) for rater 1 at identifying patients with neurodegenerative dementia disorders. Diagnostic confidence increased for rater 2 (p < 0.001). Conclusions: Overall, NBVRs had a limited impact on diagnostic accuracy in real-world clinical practice. Potentially, NBVR might increase diagnostic specificity and confidence of neuroradiology residents. To this end, a well-defined framework for integration of NBVR in the diagnostic process and improved algorithms of NBVR generation are essential.

Safety and efficacy of epigallocatechin gallate in multiple system atrophy (PROMESA): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Multiple system atrophy is a rare neurodegenerative disease characterised by aggregation of α-synuclein in oligodendrocytes and neurons. The polyphenol epigallocatechin gallate inhibits α-synuclein aggregation and reduces associated toxicity. We aimed to establish if epigallocatechin gallate could safely slow disease progression in patients with multiple system atrophy. METHODS: We did a randomised, double-blind, parallel group, placebo-controlled clinical trial at 12 specialist centres in Germany. Eligible participants were older than 30 years; met consensus criteria for possible or probable multiple system atrophy and could ambulate independently (ie, were at Hoehn and Yahr stages 1-3); and were on stable anti-Parkinson's, anti-dysautonomia, anti-dementia, and anti-depressant regimens (if necessary) for at least 1 month. Participants were randomly assigned (1:1) to epigallocatechin gallate or placebo (mannitol) via a web-generated permuted blockwise randomisation list (block size=2) that was stratified by disease subtype (parkinsonism-predominant disease vs cerebellar-ataxia-predominant disease). All participants and study personnel were masked to treatment assignment. Participants were given one hard gelatin capsule (containing either 400 mg epigallocatechin gallate or mannitol) orally once daily for 4 weeks, then one capsule twice daily for 4 weeks, and then one capsule three times daily for 40 weeks. After 48 weeks, all patients underwent a 4-week wash-out period. The primary endpoint was change in motor examination score of the Unified Multiple System Atrophy Rating Scale (UMSARS) from baseline to 52 weeks. Efficacy analyses were done in all people who received at least one dose of study medication. Safety was analysed in all people who received at least one dose of the study medication to which they had been randomly assigned. This trial is registered with ClinicalTrials.gov (NCT02008721) and EudraCT (2012-000928-18), and is completed. FINDINGS: Between April 23, 2014, and Sept 3, 2015, 127 participants were screened and 92 were randomly assigned-47 to epigallocatechin gallate and 45 to placebo. Of these, 67 completed treatment and 64 completed the study (altough one of these patients had a major protocol violation). There was no evidence of a difference in the mean change from baseline to week 52 in motor examination scores on UMSARS between the epigallocatechin gallate (5·66 [SE 1·01]) and placebo (6·60 [0·99]) groups (mean difference -0·94 [SE 1·41; 95% CI -3·71 to 1·83]; p=0·51). Four patients in the epigallocatechin gallate group and two in the placebo group died. Two patients in the epigallocatechin gallate group had to stop treatment because of hepatotoxicity. INTERPRETATION: 48 weeks of epigallocatechin gallate treatment did not modify disease progression in patients with multiple system atrophy. Epigallocatechin gallate was overall well tolerated but was associated with hepatotoxic effects in some patients, and thus doses of more than 1200 mg should not be used. FUNDING: ParkinsonFonds Deutschland, German Parkinson Society, German Neurology Foundation, Lüneburg Foundation, Bischof Dr Karl Golser Foundation, and Dr Arthur Arnstein Foundation.

Multivariate Analysis of 18F-DMFP PET Data to Assist the Diagnosis of Parkinsonism.

An early and differential diagnosis of parkinsonian syndromes still remains a challenge mainly due to the similarity of their symptoms during the onset of the disease. Recently, 18F-Desmethoxyfallypride (DMFP) has been suggested to increase the diagnostic precision as it is an effective radioligand that allows us to analyze post-synaptic dopamine D2/3 receptors. Nevertheless, the analysis of these data is still poorly covered and its use limited. In order to address this challenge, this paper shows a novel model to automatically distinguish idiopathic parkinsonism from non-idiopathic variants using DMFP data. The proposed method is based on a multiple kernel support vector machine and uses the linear version of this classifier to identify some regions of interest: the olfactory bulb, thalamus, and supplementary motor area. We evaluated the proposed model for both, the binary separation of idiopathic and non-idiopathic parkinsonism and the multigroup separation of parkinsonian variants. These systems achieved accuracy rates higher than 70%, outperforming DaTSCAN neuroimages for this purpose. In addition, a system that combined DaTSCAN and DMFP data was assessed.

3D transcranial ultrasound as a novel intra-operative imaging technique for DBS surgery: a feasibility study.

PURPOSE: Intra-operative image guidance during deep brain stimulation (DBS) surgery is usually avoided due to cost and overhead of intra-operative MRI and CT acquisitions. Recently, there has been interest in the community towards the usage of non-invasive transcranial ultrasound (TCUS) through the preauricular bone window. In this work, we investigate, for the first time, the feasibility of using 3D-TCUS for imaging of already implanted DBS electrodes. As a first step towards this goal, we report imaging methods and electrode localisation errors outside of the operating room on eight previously operated DBS patients. METHODS: We evaluate the feasibility of using 3D-TCUS by registering volumes to pre-operative T1-MRI. US-MRI registration is achieved through a two-step point-based approach. First, a rough surface scan of the subjects' skin surface in 3D-TCUS space is registered to a segmented skin-surface point cloud from MRI. Next, we perform a refinement using rigid registration of multiple pairs of manually marked anatomical landmarks. We validate against post-operative CT scans which are also registered to pre-operative MRI. RESULTS: Qualitative results are given in form of 3D reconstruction examples at 2.5 and 3.5 MHz TCUS image frequency, overlaid on pre-operative T1-MRI and post-operative CT. Quantitative evaluation is performed by reporting the accuracy of electrode tip localisation at 2.5 and 3.5 MHz after our US-MRI approach. As a baseline, we also report RMSE errors for pairs of anatomical landmarks in pre-operative MRI and 3D-TCUS. CONCLUSION: Multiple image examples show the appearance and quality of 3D-TCUS scans, depending on the bone window. Overall accuracy of anatomic point pairs lies on the order of 3.2 mm, using our registration approach. Compared to this baseline, electrode tip localisation in 3D-TCUS has a mean accuracy on the order of 4.8 mm and a precision on the order of 2.3 mm. While insufficient at first glance, we argue why these results are promising nonetheless. Our work motivates further future work in improved TCUS scanning, advanced TCUS-MRI registration and computer-aided electrode detection in 3D-TCUS.