A Case of Beta-propeller Protein-associated Neurodegeneration due to a Heterozygous Deletion of WDR45

Background: Static encephalopathy of childhood with neurodegeneration in adulthood is a phenotypically distinctive, X-linked dominant subtype of neurodegeneration with brain iron accumulation (NBIA). WDR45 mutations were recently identified as causal. WDR45 encodes a beta-propeller scaffold protein with a putative role in autophagy, and the disease has been renamed beta-propeller protein-associated neurodegeneration (BPAN). Case Report: Here we describe a female patient suffering from a classical BPAN phenotype due to a novel heterozygous deletion of WDR45. An initial gene panel and Sanger sequencing approach failed to uncover the molecular defect. Based on the typical clinical and neuroimaging phenotype, quantitative polymerase chain reaction of the WDR45 coding regions was undertaken, and this showed a reduction of the gene dosage by 50% compared with controls. Discussion: An extended search for deletions should be performed in apparently WDR45-negative cases presenting with features of NBIA and should also be considered in young patients with predominant intellectual disabilities and hypertonia/parkinsonism/dystonia

Clinical field-strength MRI of amyloid plaques induced by low-level cholesterol feeding in rabbits

Two significant barriers have limited the development of effective treatment of Alzheimer's disease. First, for many cases the aetiology is unknown and likely multi-factorial. Among these factors, hypercholesterolemia is a known risk predictor and has been linked to the formation of β-amyloid plaques, a pathological hallmark this disease. Second, standardized diagnostic tools are unable to definitively diagnose this disease prior to death; hence new diagnostic tools are urgently needed. Magnetic resonance imaging (MRI) using high field-strength scanners has shown promise for direct visualization of β-amyloid plaques, allowing in vivo longitudinal tracking of disease progression in mouse models. Here, we present a new rabbit model for studying the relationship between cholesterol and Alzheimer's disease development and new tools for direct visualization of β-amyloid plaques using clinical field-strength MRI. New Zealand white rabbits were fed either a low-level (0.125–0.25% w/w) cholesterol diet (n = 5) or normal chow (n = 4) for 27 months. High-resolution (66 × 66 × 100 µm3; scan time = 96 min) ex vivo MRI of brains was performed using a 3-Tesla (T) MR scanner interfaced with customized gradient and radiofrequency coils. β-Amyloid-42 immunostaining and Prussian blue iron staining were performed on brain sections and MR and histological images were manually registered. MRI revealed distinct signal voids throughout the brains of cholesterol-fed rabbits, whereas minimal voids were seen in control rabbit brains. These voids corresponded directly to small clusters of extracellular β-amyloid-positive plaques, which were consistently identified as iron-loaded (the presumed source of MR contrast). Plaques were typically located in the hippocampus, parahippocampal gyrus, striatum, hypothalamus and thalamus. Quantitative analysis of the number of histologically positive β-amyloid plaques (P < 0.0001) and MR-positive signal voids (P < 0.05) found in cholesterol-fed and control rabbit brains corroborated our qualitative observations. In conclusion, long-term, low-level cholesterol feeding was sufficient to promote the formation of extracellular β-amyloid plaque formation in rabbits, supporting the integral role of cholesterol in the aetiology of Alzheimer's disease. We also present the first evidence that MRI is capable of detecting iron-associated β-amyloid plaques in a rabbit model of Alzheimer's disease and have advanced the sensitivity of MRI for plaque detection to a new level, allowing clinical field-strength scanners to be employed. We believe extension of these technologies to an in vivo setting in rabbits is feasible and that our results support future work exploring the role of MRI as a leading imaging tool for this debilitating and life-threatening disease

Exploring individual multiple sclerosis lesion volume change over time: Development of an algorithm for the analyses of longitudinal quantitative MRI measures

Background: Magnetic resonance imaging (MRI) is used to follow-up multiple sclerosis (MS) and evaluate disease progression and therapy response via lesion quantification. However, there is a lack of automated post-processing techniques to quantify individual MS lesion change. Objective: The present study developed a secondary post-processing algorithm for MS lesion segmentation routine to quantify individual changes in volume over time. Methods: An Automatic Follow-up of Individual Lesions (AFIL) algorithm was developed to process time series of pre-segmented binary lesion masks. The resulting consistently labelled lesion masks allowed for the evaluation of individual lesion volumes. Algorithm performance testing was executed in seven early MS patients with four MRI visits, and MS experienced readers verified the accuracy. Results: AFIL distinguished 328 individual MS lesions with a 0.9% error rate to track persistent or new lesions based on expert assessment. A total of 121 new lesions evolved within the observed time period. The proportional courses of 69.1% lesions in the persistent lesion population exhibited varying volume, 16.9% exhibited stable volume, 3.4% exhibiting continuously increasing, and 0.5% exhibited continuously decreasing volume. Conclusion: This algorithm tracked individual lesions to automatically create an individual lesion growth profile of MS patients. This approach may allow for characterization of patients based on their individual lesion progression. Keywords: Multiple sclerosis, Therapy monitoring, Medical image analysis, Lesion tracking, Volumetric assessment, Quantitative magnetic resonance imagin

Rescue therapy with alemtuzumab in B cell/antibody-mediated multiple sclerosis

Alemtuzumab exerts its clinical efficacy by its specific pattern of depletion and repopulation of different immune cell subsets. Recently, single cases of multiple sclerosis patients who developed severe exacerbation after the first alemtuzumab application, accompanied by re-appearance of peripheral B cells, were reported. Here we present a case with underlying B cell-driven multiple sclerosis that impressively improves after alemtuzumab, although peripheral B cell repopulation took place. Our detailed clinical, histopathological, imaging and immunological data suggest that alemtuzumab can act as an effective rescue treatment in highly active B cell-driven and antibody/complement-mediated multiple sclerosis type II patients

Single-subject analysis of regional brain volumetric measures can be strongly influenced by the method for head size adjustment

Purpose Total intracranial volume (TIV) is often a nuisance covariate in MRI-based brain volumetry. This study compared two TIV adjustment methods with respect to their impact on z-scores in single subject analyses of regional brain volume estimates. Methods Brain parenchyma, hippocampus, thalamus, and TIV were segmented in a normal database comprising 5059 T1w images. Regional volume estimates were adjusted for TIV using the residual method or the proportion method. Age was taken into account by regression with both methods. TIV- and age-adjusted regional volumes were transformed to z-scores and then compared between the two adjustment methods. Their impact on the detection of thalamus atrophy was tested in 127 patients with multiple sclerosis. Results The residual method removed the association with TIV in all regions. The proportion method resulted in a switch of the direction without relevant change of the strength of the association. The reduction of physiological between-subject variability was larger with the residual method than with the proportion method. The difference between z-scores obtained with the residual method versus the proportion method was strongly correlated with TIV. It was larger than one z-score point in 5% of the subjects. The area under the ROC curve of the TIV- and age-adjusted thalamus volume for identification of multiple sclerosis patients was larger with the residual method than with the proportion method (0.84 versus 0.79). Conclusion The residual method should be preferred for TIV and age adjustments of T1w-MRI-based brain volume estimates in single subject analyses

Odor-related brain hyper-reactivity in euthymic bipolar disorder: An fMRI and ERP study.

Previous studies on olfactory function in patients with bipolar disorder (BD) are limited and contradictory. The current study aimed to comprehensively analyze the olfactory function of patients with euthymic BD using psychophysical, electrophysiological and neuroimaging techniques. Twenty-one patients with BD in remission and 20 healthy controls were tested with the "Sniffin' Sticks" olfactory test. Block-design fMRI data to a pleasant and an unpleasant stimulus were acquired while recording intensity and hedonic ratings. Olfactory event-related potentials (OERP) to the same stimuli were additionally recorded. Results show no differences between patients and healthy controls in terms of self-rated olfactory function and tested olfactory domains (odor threshold, discrimination or identification) (p>0.05). Compared to healthy controls, patients showed an increased fMRI activation in multiple cortical and subcortical regions as a response to olfactory stimulation, as well as larger amplitudes of OERPs regardless of the hedonic valence of the odor. All in all, patients with euthymic BD showed a stronger central responsiveness to odorous stimuli in fMRI and OERPs despite of normal psychophysical results, indicating the probable existence of an odor-related over-reactive brain network in the remission phase of BD

Automatic segmentation of the thalamus using a massively trained 3D convolutional neural network: higher sensitivity for the detection of reduced thalamus volume by improved inter-scanner stability

Objectives To develop an automatic method for accurate and robust thalamus segmentation in T1w-MRI for widespread clinical use without the need for strict harmonization of acquisition protocols and/or scanner-specific normal databases. Methods A three-dimensional convolutional neural network (3D-CNN) was trained on 1975 T1w volumes from 170 MRI scanners using thalamus masks generated with FSL-FIRST as ground truth. Accuracy was evaluated with 18 manually labeled expert masks. Intra- and inter-scanner test-retest stability were assessed with 477 T1w volumes of a single healthy subject scanned on 123 MRI scanners. The sensitivity of 3D-CNN-based volume estimates for the detection of thalamus atrophy was tested with 127 multiple sclerosis (MS) patients and a normal database comprising 4872 T1w volumes from 160 scanners. The 3D-CNN was compared with a publicly available 2D-CNN (FastSurfer) and FSL. Results The Dice similarity coefficient of the automatic thalamus segmentation with manual expert delineation was similar for all tested methods (3D-CNN and FastSurfer 0.86 +/- 0.02, FSL 0.87 +/- 0.02). The standard deviation of the single healthy subject's thalamus volume estimates was lowest with 3D-CNN for repeat scans on the same MRI scanner (0.08 mL, FastSurfer 0.09 mL, FSL 0.15 mL) and for repeat scans on different scanners (0.28 mL, FastSurfer 0.62 mL, FSL 0.63 mL). The proportion of MS patients with significantly reduced thalamus volume was highest for 3D-CNN (24%, FastSurfer 16%, FSL 11%). Conclusion The novel 3D-CNN allows accurate thalamus segmentation, similar to state-of-the-art methods, with considerably improved robustness with respect to scanner-related variability of image characteristics. This might result in higher sensitivity for the detection of disease-related thalamus atrophy.ISSN:0938-7994ISSN:1432-108

A Case of Beta-propeller Protein-associated Neurodegeneration due to a Heterozygous Deletion of <em>WDR45</em>

<p><strong>Background:</strong>&nbsp;Static encephalopathy of childhood with neurodegeneration in adulthood is a phenotypically distinctive, X-linked dominant subtype of neurodegeneration with brain iron accumulation (NBIA).&nbsp;<em>WDR45</em>&nbsp;mutations were recently identified as causal.&nbsp;<em>WDR45</em>&nbsp;encodes a beta-propeller scaffold protein with a putative role in autophagy, and the disease has been renamed beta-propeller protein-associated neurodegeneration (BPAN).</p><p><strong>Case Report:</strong>&nbsp;Here we describe a female patient suffering from a classical BPAN phenotype due to a novel heterozygous deletion of&nbsp;<em>WDR45</em>. An initial gene panel and Sanger sequencing approach failed to uncover the molecular defect. Based on the typical clinical and neuroimaging phenotype, quantitative polymerase chain reaction of the&nbsp;<em>WDR45</em>&nbsp;coding regions was undertaken, and this showed a reduction of the gene dosage by 50% compared with controls.</p><p><strong>Discussion:</strong>&nbsp;An extended search for deletions should be performed in apparently&nbsp;<em>WDR45-</em>negative cases presenting with features of NBIA and should also be considered in young patients with predominant intellectual disabilities and hypertonia/parkinsonism/dystonia.</p