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Abstract Central nervous system germ cell tumors (CNS-GCT) are malignant neoplasms that arise predominantly during adolescence and young adulthood. These tumors are typically sensitive to treatment, but resulting long-term health deficits are common. Additional clinical challenges include surgical risks associated with tumor biopsy, and need to determine treatment response for adapting radiotherapy protocols. The aim of this study was to establish the detectability of circulating-tumor DNA (ctDNA) from cerebrospinal fluid (CSF) of children with CNS-GCT as a potential biomarker. We obtained CSF from patients with CNS-GCT by lumbar puncture or intra-operatively. Cell-free DNA (cfDNA) was extracted and subjected to low-pass whole genome sequencing (LP-WGS). Copy-number alterations (CNAs) were inferred and served as a marker of measurable residual disease (MRD). Comparisons with imaging findings and tumor marker levels were made. A total of 29 CSF samples from 21 patients (16 with germinoma, 5 with non-germinomatous GCT) were sequenced. Twenty samples from 19 patients were collected at diagnosis, and 9 samples from 7 patients were collected during or after therapy. Among the diagnostic samples, CNAs were detected in samples from 17/19 patients (89%), which included 8 with marker-negative tumors. Specific clinical scenarios suggested that serial cfDNA analysis may carry utility in tracking treatment responses as well as clarifying indeterminate imaging findings. Our results provide evidence for the high-sensitivity in detecting ctDNA from CSF of CNS-GCT patients using LP-WGS, with potential utility for non-invasive diagnosis and disease monitoring in upcoming CNS-GCT studies.

Abstract Background Stroke is a leading cause of mortality and disability worldwide and its occurrence is expected to increase in the future. Blood biomarkers have proven their usefulness in identification and monitoring of the disease. Stroke severity is a major factor for estimation of prognosis and risk of recurrent events, but knowledge on respective blood biomarkers is still scarce. Stroke pathophysiology comprises a multitude of ischemia-induced inflammatory and immune mediated responses. Therefore, the assessment of an immune-related panel in correlation with stroke severity seems promising. Methods In the present cross-sectional evaluation, a set of 92 blood biomarkers of a standardized immune panel were gathered (median 4.6 days after admission) and related to stroke severity measures, assessed at hospital admission of acute stroke patients. Multivariable logistic regression models were used to determine associations between biomarkers and modified Rankin Scale (mRS), linear regression models were used for associations with National Institute of Health Stroke Scale. Results 415 patients (mean age 69 years; 41% female) were included for biomarker analysis. C-type lectin domain family 4 member G (CLEC4G; OR = 2.89, 95% CI [1.49; 5.59], p adj = 0.026, Cytoskeleton-associated protein 4 (CKAP4; OR = 2.38, 95% CI [1.43; 3.98], p adj = 0.019), and Interleukin-6 (IL-6) (IL6; OR = 1.97, 95% CI [1.49; 2.62], p adj

Objective: Intracranial volume (ICV) represents the maximal brain volume for an individual, attained prior to late adolescence and remaining constant throughout life after. Thus, ICV serves as a surrogate marker for brain growth integrity. To assess the potential impact of adult-onset multiple sclerosis (MS) and its preceding prodromal subclinical changes on ICV in a large cohort of monozygotic twins clinically discordant for MS. Methods: FSL software was used to derive ICV estimates from 3D-T1-weighted-3 T-MRI images by using an atlas scaling factor method. ICV were compared between clinically affected and healthy co-twins. All twins were compared to a large healthy reference cohort using standardized ICV z-scores. Mixed models assessed the impact of age at MS diagnosis on ICV. Results: 54 twin-pairs (108 individuals/80female/42.45 ± 11.98 years), 731 individuals (375 non-twins, 109/69 monozygotic/dizygotic twin-pairs; 398female/29.18 ± 0.13 years) and 35 healthy local individuals (20male/31.34 ± 1.53 years). In 45/54 (83 %) twin-pairs, both clinically affected and healthy co-twins showed negative ICV z-scores, i.e., ICVs lower than the average of the healthy reference cohort (M = -1.53 ± 0.11, P 30 years) yielded lower ICVs in those twin pairs with younger age at diagnosis (P = 0.01). Comparison within individual twin-pairs identified lower ICVs in the MS-affected co-twins with younger age at diagnosis compared to their corresponding healthy co-twins (P = 0.003). Conclusion: We offer for the first-time evidence for strong associations between adult-onset MS and lower ICV, which is more pronounced with younger age at diagnosis. This suggests pre-clinical alterations in early neurodevelopment associated with susceptibility to MS both in individuals with and without clinical manifestation of the disease.

Childhood stroke occurs from birth to 18 years of age, ranks among the top ten childhood causes of death, and leaves lifelong neurological impairments. Arterial ischemic stroke in infancy and childhood occurs due to arterial occlusion in the brain, resulting in a focal lesion. Our understanding of mechanisms of injury and repair associated with focal injury in the developing brain remains rudimentary. Neuroimaging can reveal important insights into these mechanisms. In adult stroke population, multi-center neuroimaging studies are common and have accelerated the translation process leading to improvements in treatment and outcome. These studies are centered on the growing evidence that neuroimaging measures and other biomarkers (e.g., from blood and cerebrospinal fluid) can enhance our understanding of mechanisms of risk and injury and be used as complementary outcome markers. These factors have yet to be studied in pediatric stroke because most neuroimaging studies in this population have been conducted in single-centred, small cohorts. By pooling neuroimaging data across multiple sites, larger cohorts of patients can significantly boost study feasibility and power in elucidating mechanisms of brain injury, repair and outcomes. These aims are particularly relevant in pediatric stroke because of the decreased incidence rates and the lack of mechanism-targeted trials.Toward these aims, we developed the Pediatric Stroke Neuroimaging Platform (PEDSNIP) in 2015, funded by The Brain Canada Platform Support Grant, to focus on three identified neuroimaging priorities. These were: developing and harmonizing multisite clinical protocols, creating the infrastructure and methods to import, store and organize the large clinical neuroimaging dataset from multiple sites through the International Pediatric Stroke Study (IPSS), and enabling central searchability. To do this, developed a two-pronged approach that included building 1) A Clinical-MRI Data Repository (standard of care imaging) linked to clinical data and longitudinal outcomes and 2) A Research-MRI neuroimaging data set acquired through our extensive collaborative, multi-center, multidisciplinary network. This dataset was collected prospectively in eight North American centers to test the feasibility and implementation of harmonized advanced Research-MRI, with the addition of clinical information, genetic and proteomic studies, in a cohort of children presenting with acute ischemic stroke.Here we describe the process that enabled the development of PEDSNIP built to provide the infrastructure to support neuroimaging research priorities in pediatric stroke. Having built this Platform, we are now able to utilize the largest neuroimaging and clinical data pool on pediatric stroke data worldwide to conduct hypothesis-driven research. We are actively working on a bioinformatics approach to develop predictive models of risk, injury and repair and accelerate breakthrough discoveries leading to mechanism-targeted treatments that improve outcomes and minimize the burden following childhood stroke. This unique transformational resource for scientists and researchers has the potential to result in a paradigm shift in the management, outcomes and quality of life in children with stroke and their families, with far-reaching benefits for other brain conditions of people across the lifespan.

Introduction: Persistent postural-perceptual dizziness (PPPD) (ICD-11) and anxiety disorders (ANX) share behavioural symptoms like anxiety, avoidance, social withdrawal, hyperarousal, or palpitation as well as neurological symptoms like vertigo, stance and gait disorders. Furthermore, previous studies have shown a bidirectional link between vestibulo-spatial and anxiety neural networks. So far, there have been no neuroimaging-studies comparing these groups. Objectives: The aim of this explorative study was to investigate differences and similarities of neural correlates between these two patient groups and to compare their findings with a healthy control group. Methods: 63 participants, divided in two patient groups (ANX = 20 and PPPD = 14) and two sex and age matched healthy control groups (HC-A = 16, HC-P = 13) were included. Anxiety and dizziness related pictures were shown during fMRI-measurements in a block-design in order to induce emotional responses. All subjects filled in questionnaires regarding vertigo (VSS, VHQ), anxiety (STAI), depression (BDI-II), alexithymia (TAS), and illness-perception (IPQ). After modelling the BOLD response with a standard canonical HRF, voxel-wise t-tests between conditions (emotional-negative vs neutral stimuli) were used to generate statistical contrast maps and identify relevant brain areas (pFDR 30 voxels). ROI-analyses were performed for amygdala, cingulate gyrus, hippocampus, inferior frontal gyrus, insula, supramarginal gyrus and thalamus (p ≤ 0.05). Results: Patient groups differed from both HC groups regarding anxiety, dizziness, depression and alexithymia scores; ratings of the PPPD group and the ANX group did differ significantly only in the VSS subscale ‘vertigo and related symptoms’ (VSS-VER). The PPPD group showed increased neural responses in the vestibulo-spatial network, especially in the supramarginal gyrus (SMG), and superior temporal gyrus (STG), compared to ANX and HC-P group. The PPPD group showed increased neural responses compared to the HC-P group in the anxiety network including amygdala, insula, lentiform gyrus, hippocampus, inferior frontal gyrus (IFG) and brainstem. Neuronal responses were enhanced in visual structures, e.g. fusiform gyrus, middle occipital gyrus, and in the medial orbitofrontal cortex (mOFC) in healthy controls compared to patients with ANX and PPPD, and in the ANX group compared to the PPPD group. Conclusions: These findings indicate that neuronal responses to emotional information in the PPPD and the ANX group are comparable in anxiety networks but not in vestibulo-spatial networks. Patients with PPPD revealed a stronger neuronal response especially in SMG and STG compared to the ANX and the HC group. These results might suggest higher sensitivity and poorer adaptation processes in the PPPD group to anxiety and dizziness related pictures. Stronger activation in visual processing areas in HC subjects might be due to less emotional and more visual processing strategies.

BackgroundChronic fatigue is a common symptom after a stroke. Studies suggested that chronic fatigue is caused by inflammatory or immunological processes but data are limited and contradictory. Thus, the present study aimed to identify specific biomarkers associated with fatigue in post-stroke patients and replicated the findings in a population-based study.MethodsWe investigated associations between 39 circulating biomarkers of inflammation and fatigue in 327 patients after an ischemic stroke included in the Stroke Cohort Augsburg (SCHANA) study and the “Metabolism, Nutrition and Immune System in Augsburg” (MEIA) study (n = 140). The Fatigue Assessment Scale (FAS) was used to assess the severity of fatigue. The serum concentrations of the biomarkers were measured using the Bio-Plex Pro™ Human Cytokine Screening Panel (Bio-Rad, USA). Multiple linear regression models adjusted for possible confounders were used to examine associations.ResultsIn patients with stroke, SCGFb was inversely associated [−1.67, 95% confidence interval (CI) (−3.05; −0.29) p = 0.018], and in healthy subjects, G-CSF was positively associated [1.56, 95% CI (0.26; 2.87), p = 0.020] with an increasing FAS-score, while SCF was positively related in both samples [1.84, 95% CI (0.27; 3.42), p = 0.022 and 1.40, 95% CI (0.29; 2.52), p = 0.015]. However, after correction for multiple testing, all of these associations lost statistical significance.ConclusionThe present findings suggested an association between the growth factor SCF and fatigue. Future research on cytokines as possible markers of fatigue should focus on a longitudinal design including a sufficiently large number of study participants to enable testing associations between certain cytokines and sub-groups of chronic fatigue.

Abstract Background Although convolutional neural networks (CNNs) achieve high diagnostic accuracy for detecting Alzheimer’s disease (AD) dementia based on magnetic resonance imaging (MRI) scans, they are not yet applied in clinical routine. One important reason for this is a lack of model comprehensibility. Recently developed visualization methods for deriving CNN relevance maps may help to fill this gap as they allow the visualization of key input image features that drive the decision of the model. We investigated whether models with higher accuracy also rely more on discriminative brain regions predefined by prior knowledge. Methods We trained a CNN for the detection of AD in N = 663 T1-weighted MRI scans of patients with dementia and amnestic mild cognitive impairment (MCI) and verified the accuracy of the models via cross-validation and in three independent samples including in total N = 1655 cases. We evaluated the association of relevance scores and hippocampus volume to validate the clinical utility of this approach. To improve model comprehensibility, we implemented an interactive visualization of 3D CNN relevance maps, thereby allowing intuitive model inspection. Results Across the three independent datasets, group separation showed high accuracy for AD dementia versus controls (AUC ≥ 0.91) and moderate accuracy for amnestic MCI versus controls (AUC ≈ 0.74). Relevance maps indicated that hippocampal atrophy was considered the most informative factor for AD detection, with additional contributions from atrophy in other cortical and subcortical regions. Relevance scores within the hippocampus were highly correlated with hippocampal volumes (Pearson’s r ≈ −0.86, p < 0.001). Conclusion The relevance maps highlighted atrophy in regions that we had hypothesized a priori. This strengthens the comprehensibility of the CNN models, which were trained in a purely data-driven manner based on the scans and diagnosis labels. The high hippocampus relevance scores as well as the high performance achieved in independent samples support the validity of the CNN models in the detection of AD-related MRI abnormalities. The presented data-driven and hypothesis-free CNN modeling approach might provide a useful tool to automatically derive discriminative features for complex diagnostic tasks where clear clinical criteria are still missing, for instance for the differential diagnosis between various types of dementia.

BackgroundPost-stroke fatigue is a common symptom after stroke. However, studies on the factors associated with early and late fatigue are scarce. The objective of this study was to identify variables associated with early and late fatigue.MethodsIn the German Stroke Cohort Augsburg (SCHANA) study, participants were interviewed during their hospital stay and completed a postal questionnaire 3 and 12 months post-stroke. Fatigue was assessed using the Fatigue Assessement Scale (FAS). In addition, depression was measured by the Patient Health Questionnaire (PHQ-9), general health status by the EQ-5D visual analog scale, and physical activity by the International Physical Activity Questionnaire (IPAQ). Multivariable regression models were used to determine the associations between FAS scores at 3 and 12 months post-stroke and demographic, psychosocial and health-related covariables.ResultsAmong 505 participants, the frequency of fatigue was 31.1% 3 months and 29.1% 12 months post-stroke. Prior stroke (ß = 2.37, p = 0.0076), prior diagnosis of depression (ß = 5.04, p = 0.0001), higher NIHSS (ß = 0.25, p = 0.0360) and higher PHQ-9 scores (ß = 0.55, p < 0.0001) were significantly associated with higher fatigue levels 3 months post-stroke. Additionally, younger age (ß = −0.07, p = 0.0219), a worse rating of general health at baseline (ß = −0.04, p = 0.0287) and low pre-stroke physical activity (ß = −0.0004, p = 0.0089) were significantly associated with higher fatigue levels 12 months after stroke.ConclusionsFatigue is a common and persisting symptom even in patients with mild impairment. Prior depressive disorder and early depressive symptoms were the most relevant predictors of both early and late fatigue.

Abstract Objective Patients with acute central vestibular syndrome suffer from vertigo, spontaneous nystagmus, postural instability with lateral falls, and tilts of visual vertical. Usually, these symptoms compensate within months. The mechanisms of compensation in vestibular infarcts are yet unclear. This study focused on structural changes in gray and white matter volume that accompany clinical compensation. Methods We studied patients with acute unilateral brain stem infarcts prospectively over 6 months. Structural changes were compared between the acute phase and follow‐up with a group of healthy controls using voxel‐based morphometry. Results Restitution of vestibular function following brain stem infarcts was accompanied by downstream structural changes in multisensory cortical areas. The changes depended on the location of the infarct along the vestibular pathways in patients with pathological tilts of the SVV and on the quality of the vestibular percept (rotatory vs graviceptive) in patients with pontomedullary infarcts. Patients with pontomedullary infarcts with vertigo or spontaneous nystagmus showed volumetric increases in vestibular parietal opercular multisensory and (retro‐) insular areas with right‐sided preference. Compensation of graviceptive deficits was accompanied by adaptive changes in multiple multisensory vestibular areas in both hemispheres in lower brain stem infarcts and by additional changes in the motor system in upper brain stem infarcts. Interpretation This study demonstrates multisensory neuroplasticity in both hemispheres along with the clinical compensation of vestibular deficits following unilateral brain stem infarcts. The data further solidify the concept of a right‐hemispheric specialization for core vestibular processing. The identification of cortical structures involved in central compensation could serve as a platform to launch novel rehabilitative treatments such as transcranial stimulations.

Background: Symptomatic and asymptomatic delayed non-ischemic cerebral enhancing (NICE) lesions in magnetic resonance imaging (MRI) have been reported as a rare complication after endovascular therapy (EVT) in recent years with incidence rates between 0.05% and 0.9% in most studies. Information on long-term clinical course and immunotherapies is scarce or has not been reported in detail in the literature. Objective: Aims of our study were to assess the incidence of NICE lesions in patients after cerebral EVT over a period of more than 12 years, describe clinical and EVT characteristics, and immunotherapies applied. Methods: A retrospective chart review of all patients treated by endovascular therapy for symptomatic or asymptomatic aneurysms at the University Hospital of Augsburg from May 1, 2008 to December 31, 2020 was performed. Patients were identified retrospectively and followed-up prospectively where appropriate. In addition, one case treated at another institution was included. Results: Five out of 746 patients, 0.67%, developed NICE lesions after EVT, all with non-ruptured aneurysms and all symptomatic upon detection of NICE lesions by MRI. In total, the disease course of 6 female patients is reported. Symptoms occurred after a mean time of 15 days (±13.42, SD) after EVT with headache (6/6 patients), focal neurological signs (6/6 patients), epileptic seizures (2/6 patients) and cognitive deficits (3/6 patients). All 6 patients received glucocorticosteroids (GCS), 1/6 azathioprine (AZA), 4/6 mycophenolate mofetil (MMF), 1/6 methotrexate (MTX), 1/6 rituximab (RTX), 2/6 cyclophosphamide (CYC) and 3/6 tocilizumab (TCZ). A treatment response could be observed for GCS, TCZ and MMF (in two of four cases), RTX and AZA did not result in disease stabilization. Conclusions: Delayed NICE lesions are a rare complication after EVT, requiring immunotherapies in all patients reported here. Physicians should be aware of this disorder in case of new symptoms or contrast enhancing lesions after EVT.

Objective: The integration of somatosensory, ocular motor and vestibular signals is necessary for self-location in space and goal-directed action. We aimed to detect remote changes in the cerebral cortex after thalamic infarcts to reveal the thalamo-cortical connections necessary for multisensory processing and ocular motor control. Methods: Thirteen patients with unilateral ischemic thalamic infarcts presenting with vestibular, somatosensory, and ocular motor symptoms were examined longitudinally in the acute phase and after six months. Voxel- and surface-based morphometry were used to detect changes in vestibular and multisensory cortical areas and known hubs of central ocular motor processing. The results were compared with functional connectivity data in 50 healthy volunteers. Results: Patients with paramedian infarcts showed impaired saccades and vestibular perception, i.e., tilts of the subjective visual vertical (SVV). The most common complaint in these patients was double vision or vertigo / dizziness. Posterolateral thalamic infarcts led to tilts of the SVV and somatosensory deficits without vertigo. Tilts of the SVV were higher in paramedian compared to posterolateral infarcts (median 11.2° vs 3.8°). Vestibular and ocular motor symptoms recovered within six months. Somatosensory deficits persisted. Structural longitudinal imaging showed significant volume reduction in subcortical structures connected to the infarcted thalamic nuclei (vestibular nuclei region, dentate nucleus region, trigeminal root entry zone, medial lemniscus, superior colliculi). Volume loss was evident in connections to the frontal, parietal and cingulate lobes. Changes were larger in the ipsilesional hemisphere but were also detected in homotopical regions contralesionally. The white matter volume reduction led to deformation of the cortical projection zones of the infarcted nuclei. Conclusions: White matter volume loss after thalamic infarcts reflects sensory input from the brainstem as well the cortical projections of the main affected nuclei for sensory and ocular motor processing. Changes in the cortical geometry seem not to reflect gray matter atrophy but rather reshaping of the cortical surface due to the underlying white matter atrophy.

Abstract CREB (cyclic AMP response element binding protein) binding protein (CBP, CREBBP) is a ubiquitously expressed transcription coactivator with intrinsic histone acetyltransferase (KAT) activity. Germline mutations within the CBP gene are known to cause Rubinstein-Taybi syndrome (RSTS), a developmental disorder characterized by intellectual disability, specific facial features and physical anomalies. Here, we investigate mechanisms of CBP function during brain development in order to elucidate morphological and functional mechanisms underlying the development of RSTS. Due to the embryonic lethality of conventional CBP knockout mice, we employed a tissue specific knockout mouse model (hGFAP-cre::CBP Fl/Fl , mutant mouse) to achieve a homozygous deletion of CBP in neural precursor cells of the central nervous system. Our findings suggest that CBP plays a central role in brain size regulation, correct neural cell differentiation and neural precursor cell migration. We provide evidence that CBP is both important for stem cell viability within the ventricular germinal zone during embryonic development and for unhindered establishment of adult neurogenesis. Prominent histological findings in adult animals include a significantly smaller hippocampus with fewer neural stem cells. In the subventricular zone, we observe large cell aggregations at the beginning of the rostral migratory stream due to a migration deficit caused by impaired attraction from the CBP-deficient olfactory bulb. The cerebral cortex of mutant mice is characterized by a shorter dendrite length, a diminished spine number, and a relatively decreased number of mature spines as well as a reduced number of synapses. In conclusion, we provide evidence that CBP is important for neurogenesis, shaping neuronal morphology, neural connectivity and that it is involved in neuronal cell migration. These findings may help to understand the molecular basis of intellectual disability in RSTS patients and may be employed to establish treatment options to improve patients’ quality of life.

Introduction: As prospective data on long-term patient-reported outcome measures (PROMs) to assess Health related Quality of Life (HRQoL) after stroke are still scarce, this study examined the long-term course of PROMs and investigated influential factors such as recanalization therapies.Materials and Methods: A total of 945 (mean age 69 years; 56% male) stroke patients were enrolled with a personal interview and chart review performed at index event. One hundred forty (15%) patients received thrombolysis (IVT) and 53 (5%) patients received endovascular therapy (ET) or both treatments as bridging therapy (BT). After 3 and 12 months, a follow-up was conducted using a postal questionnaire including subjective quality of life EQ-5D-5L (European Quality of Life 5 Dimensions). At all time-points, Modified Rankin Scale (mRS) was additionally used to quantify functional stroke severity. Differences between therapy groups were identified using post-hoc-tests. Linear and logistic regression analyses were used to identify predictors of outcomes.Results: Recanalization therapies were associated with significant improvements of NIHSS (National Institutes of Health Stroke Scale [regression coefficient IVT 1.21 (p = 0.01) and ET/BT 7.6; p = 0.001] and mRS (modified Rankin Scale) [regression coefficient IVT 0.83; p = 0.001 and ET/BT 2.0; p = 0.001] between admission and discharge compared to patients with stroke unit therapy only, with a trend toward improvement of EQ-5D after 12 months [regression coefficient 4.67 (p = 0.17)] with IVT. HRQoL was considerably impaired by stroke and increased steadily in 3- and 12-months follow-up in patients with (mean EQ-5D from 56 to 68) and without recanalization therapy (mean EQ-5D from 62 to 68). In severe strokes a major and significant improvement was only detected during period of 3 to 12 months (p = 0.03 in patients with and p = 0.005 in patients without recanalization therapy).Conclusions: Despite significant and continuous improvements after stroke the HRQoL after 12 months remained below the age-matched general population, but was still unexpectedly high in view of the accumulation of permanent disabilities in up to 30% of the patients. Especially in severe strokes, it is important to evaluate HRQoL beyond a 3-months follow-up as improvements became significant only between 3 months and 1 year.

In-vivo non-invasive verification of endolymphatic hydrops (ELH) by means of intravenous delayed gadolinium (Gd) enhanced magnetic resonance imaging of the inner ear (iMRI) is rapidly developing into a standard clinical tool to investigate peripheral vestibulo-cochlear syndromes. In this context, methodological comparative studies providing standardization and comparability between labs seem even more important, but so far very few are available. One hundred eight participants [75 patients with Meniere's disease (MD; 55.2 ± 14.9 years) and 33 vestibular healthy controls (HC; 46.4 ± 15.6 years)] were examined. The aim was to understand (i) how variations in acquisition protocols influence endolymphatic space (ELS) MR-signals; (ii) how ELS quantification methods correlate to each other or clinical data; and finally, (iii) how ELS extent influences MR-signals. Diagnostics included neuro-otological assessment, video-oculography during caloric stimulation, head-impulse test, audiometry, and iMRI. Data analysis provided semi-quantitative (SQ) visual grading and automatic algorithmic quantitative segmentation of ELS area [2D, mm2] and volume [3D, mm3] using deep learning-based segmentation and volumetric local thresholding. Within the range of 0.1–0.2 mmol/kg Gd dosage and a 4 h ± 30 min time delay, SQ grading and 2D- or 3D-quantifications were independent of signal intensity (SI) and signal-to-noise ratio (SNR; FWE corrected, p < 0.05). The ELS quantification methods used were highly reproducible across raters or thresholds and correlated strongly (0.3–0.8). However, 3D-quantifications showed the least variability. Asymmetry indices and normalized ELH proved the most useful for predicting quantitative clinical data. ELH size influenced SI (cochlear basal turn p < 0.001), but not SNR. SI could not predict the presence of ELH. In conclusion, (1) Gd dosage of 0.1–0.2 mmol/kg after 4 h ± 30 min time delay suffices for ELS quantification. (2) A consensus is needed on a clinical SQ grading classification including a standardized level of evaluation reconstructed to anatomical fixpoints. (3) 3D-quantification methods of the ELS are best suited for correlations with clinical variables and should include both ears and ELS values reported relative or normalized to size. (4) The presence of ELH increases signal intensity in the basal cochlear turn weakly, but cannot predict the presence of ELH.

Background: Cognitive decline has been found to be associated with gray matter atrophy and disruption of functional neural networks in Alzheimer’s disease (AD) in structural and functional imaging (fMRI) studies. Most previous studies have used single test scores of cognitive performance among monocentric cohorts. However, cognitive domain composite scores could be more reliable than single test scores due to the reduction of measurement error. Adopting a multicentric resting state fMRI (rs-fMRI) and cognitive domain approach, we provide a comprehensive description of the structural and functional correlates of the key cognitive domains of AD. Method: We analyzed MRI, rs-fMRI and cognitive domain score data of 490 participants from an interim baseline release of the multicenter DELCODE study cohort, including 54 people with AD, 86 with Mild Cognitive Impairment (MCI), 175 with Subjective Cognitive Decline (SCD), and 175 Healthy Controls (HC) in the AD-spectrum. Resulting cognitive domain composite scores (executive, visuo-spatial, memory, working memory and language) from the DELCODE neuropsychological battery (DELCODE-NP), were previously derived using confirmatory factor analysis. Statistical analyses examined the differences between diagnostic groups, and the association of composite scores with regional atrophy and network-specific functional connectivity among the patient subgroup of SCD, MCI and AD. Result: Cognitive performance, atrophy patterns and functional connectivity significantly differed between diagnostic groups in the AD-spectrum. Regional gray matter atrophy was positively associated with visuospatial and other cognitive impairments among the patient subgroup in the AD-spectrum. Except for the visual network, patterns of network-specific resting-state functional connectivity were positively associated with distinct cognitive impairments among the patient subgroup in the AD-spectrum. Conclusion: Consistent associations between cognitive domain scores and both regional atrophy and network-specific functional connectivity (except for the visual network), support the utility of a multicentric and cognitive domain approach towards explicating the relationship between imaging markers and cognition in the AD-spectrum.

Objective: Structural reorganization following cerebellar infarcts is not yet known. This study aimed to demonstrate structural volumetric changes over time in the cortical vestibular and multisensory areas (i.e., brain plasticity) after acute cerebellar infarcts with vestibular and ocular motor symptoms. Additionally, we evaluated whether structural reorganization in the patients topographically correlates with cerebello-cortical connectivity that can be observed in healthy participants. Methods: We obtained high-resolution structural imaging in seven patients with midline cerebellar infarcts at two time points. These data were compared to structural imaging of a group of healthy age-matched controls using voxel-based morphometry (2×2 ANOVA approach). The maximum overlap of the infarcts was used as a seed region for a separate resting-state functional connectivity analysis in healthy volunteers. Results: Volumetric changes were detected in the multisensory cortical vestibular areas around the parieto-opercular and (retro-) insular cortex. Furthermore, structural reorganization was evident in parts of the frontal, temporal, parietal, limbic, and occipital lobes and reflected functional connections between the main infarct regions in the cerebellum and the cerebral cortex in healthy individuals. Conclusions: This study demonstrates structural reorganization in the parieto-opercular insular vestibular cortex after acute vestibulo-cerebellar infarcts. Additionally, the widely distributed structural reorganization after midline cerebellar infarcts provides additional in vivo evidence for the multifaceted contribution of cerebellar processing to cortical functions that extend beyond vestibular or ocular motor function.

Multiple genetic and non-heritable factors have been linked to the risk of multiple sclerosis (MS). These factors seem to contribute to disease pathogenesis before the onset of clinical symptoms, as suggested by incidental MRI evidence of subclinical MS neuropathology in individuals without clinical symptoms. Individuals with high familial risk for MS, such as first-degree relatives of patients with MS, can be studied by MRI to characterize the neuropathology during a subclinical period of MS. 16 studies published in English, which performed brain MRI on healthy individuals with high familial risk of MS were included in this scoping review. Studies suggest either no conclusive (5), or inconclusive yet considerable (4), or conclusive evidence (7) for the incidence of subclinical neuropathology, including focal and diffuse tissue damage. Across all studies, white matter lesions fulfilling MS criteria were observed in 86 of 613 individuals (14%). Future research is needed to evaluate the longitudinal dynamics and clinical relevance of preclinical imaging abnormalities in MS.

Abnormal variations of the neonatal brain perfusion can result in long-term neurodevelopmental consequences and cerebral perfusion imaging can play an important role in diagnostic and therapeutic decision-making. To identify at-risk situations, perfusion imaging of the neonatal brain must accurately evaluate both regional and global perfusion. To date, neonatal cerebral perfusion assessment remains challenging. The available modalities such as magnetic resonance imaging (MRI), ultrasound imaging, computed tomography (CT), near-infrared spectroscopy or nuclear imaging have multiple compromises and limitations. Several promising methods are being developed to achieve better diagnostic accuracy and higher robustness, in particular using advanced MRI and ultrasound techniques.The objective of this state-of-the-art review is to analyze the methodology and challenges of neonatal brain perfusion imaging, to describe the currently available modalities, and to outline future perspectives.

Background: Dysfunction of the cholinergic basal forebrain (cBF) is associated with cognitive decline in Alzheimer’s disease (AD). Multimodal MRI allows for the investigation of cBF changes in-vivo. In this study we assessed alterations in cBF functional connectivity (FC), mean diffusivity (MD), and volume across the spectrum of AD. We further assessed effects of amyloid pathology on these changes. Methods: Participants included healthy controls, and subjects with subjective cognitive decline (SCD), mild cognitive impairment (MCI), or AD dementia (ADD) from the multicenter DELCODE study. Resting-state functional MRI (rs-fMRI) and structural MRI data was available for 477 subjects, and a subset of 243 subjects also had DTI data available. Differences between diagnostic groups were investigated using seed-based FC, volumetric, and MD analyses of functionally defined anterior (a-cBF) and posterior (p-cBF) subdivisions of a cytoarchitectonic cBF region-of-interest. In complementary analyses groups were stratified according to amyloid status based on CSF Aβ42/40 biomarker data, which was available in a subset of participants. Results: a-cBF and p-cBF subdivisions showed regional FC profiles that were highly consistent with previously reported patterns, but there were only minimal differences between diagnostic groups. Compared to controls, cBF volumes and MD were significantly different in MCI and ADD but not in SCD. The Aβ42/40 stratified analyses largely matched these results. Conclusions: We reproduced subregion-specific FC profiles of the cBF in a clinical sample spanning the AD spectrum. At least in this multicentric cohort study, cBF-FC did not show marked changes along the AD spectrum, and multimodal MRI did not provide more sensitive measures of AD-related cBF changes compared to volumetry.

Background: Transcranial B-mode sonography (TCS) can detect hyperechogenic speckles in the area of the substantia nigra (SN) in Parkinson's disease (PD). These speckles correlate with iron accumulation in the SN tissue, but an exact volumetric localization in and around the SN is still unknown. Areas of increased iron content in brain tissue can be detected in vivo with magnetic resonance imaging, using quantitative susceptibility mapping (QSM). Methods: In this work, we i) acquire, co-register and transform TCS and QSM imaging from a cohort of 23 PD patients and 27 healthy control subjects into a normalized atlas template space and ii) analyze and compare the 3D spatial distributions of iron accumulation in the midbrain, as detected by a signal increase (TCS+ and QSM+) in both modalities. Results: We achieved sufficiently accurate intra-modal target registration errors (TRE

Abstract Background The distribution of cranio-spinal compliance (CSC) in the brain and spinal cord is a fundamental question, as it would determine the overall role of the compartments in modulating ICP in healthy and diseased states. Invasive methods for measurement of CSC using infusion-based techniques provide overall CSC estimate, but not the individual sub-compartmental contribution. Additionally, the outcome of the infusion-based method depends on the infusion site and dynamics. This article presents a method to determine compliance distribution between the cranium and spinal canal non-invasively using data obtained from patients. We hypothesize that this CSC distribution is indicative of the ICP. Methods We propose a lumped-parameter model representing the hydro and hemodynamics of the cranio-spinal system. The input and output to the model are phase-contrast MRI derived volumetric transcranial blood flow measured in vivo, and CSF flow at the spinal cervical level, respectively. The novelty of the method lies in the model mathematics that predicts CSC distribution (that obeys the physical laws) from the system dc gain of the discrete-domain transfer function. 104 healthy individuals (48 males, 56 females, age 25.4 ± 14.9 years, range 3–60 years) without any history of neurological diseases, were used in the study. Non-invasive MR assisted estimate of ICP was calculated and compared with the cranial compliance to prove our hypothesis. Results A significant negative correlation was found between model-predicted cranial contribution to CSC and MR-ICP. The spinal canal provided majority of the compliance in all the age groups up to 40 years. However, no single sub-compartment provided majority of the compliance in 41–60 years age group. The cranial contribution to CSC and MR-ICP were significantly correlated with age, with gender not affecting the compliance distribution. Spinal contribution to CSC significantly positively correlated with CSF stroke volume. Conclusions This paper describes MRI-based non-invasive way to determine the cranio-spinal compliance distribution in the brain and spinal canal sub-compartments. The proposed mathematics makes the model always stable and within the physiological range. The model-derived cranial compliance was strongly negatively correlated to non-invasive MR-ICP data from 104 patients, indicating that compliance distribution plays a major role in modulating ICP.

Abstract Background Recent evidence derived from functional magnetic resonance imaging (fMRI) studies suggests that functional hubs (i.e., highly connected brain regions) are important for mental health. We found recently that global connectivity of a hub in the left frontal cortex (LFC connectivity) is associated with relatively preserved memory abilities and higher levels of protective factors (education, IQ) in normal aging and Alzheimer’s disease. These results suggest that LFC connectivity supports reserve capacity, alleviating memory decline. An open question, however, is why LFC connectivity is beneficial and supports memory function in the face of neurodegeneration. We hypothesized that higher LFC connectivity is associated with enhanced efficiency in connected major networks involved in episodic memory. We further hypothesized that higher LFC-related network efficiency predicts higher memory abilities. Methods We assessed fMRI during a face-name association learning task performed by 26 healthy, cognitively normal elderly participants. Using beta-series correlation analysis, we computed task-related LFC connectivity to key memory networks, including the default mode network (DMN) and dorsal attention network (DAN). Network efficiency within the DMN and DAN was estimated by the graph theoretical small-worldness statistic. We applied linear regression analyses to test the association between LFC connectivity with the DMN/DAN and small-worldness of these networks. Mediation analysis was applied to test LFC connectivity to the DMN and DAN as a mediator of the association between education and higher DMN and DAN small-worldness. Last, we tested network small-worldness as a predictor of memory performance. Results We found that higher LFC connectivity to the DMN and DAN during successful memory encoding and recognition was associated with higher small-worldness of those networks. Higher task-related LFC connectivity mediated the association between education and higher small-worldness in the DMN and DAN. Further, higher small-worldness of these networks predicted better performance in the memory task. Conclusions The present results suggest that higher education-related LFC connectivity to key memory networks during a memory task is associated with higher network efficiency and thus enhanced reserve of memory abilities in aging.

Introduction: Acute stroke care delivered by interdisciplinary teams is time-sensitive. Simulation-based team training is a promising tool to improve team performance in medical operations. It has the potential to improve process times, team communication, patient safety, and staff satisfaction. We aim to assess whether a multi-level approach consisting of a stringent workflow revision based on peer-to-peer review and 2–3 one-day in situ simulation trainings can improve acute stroke care processing times in high volume neurocenters within a 6 months period.Methods and Analysis: The trial is being carried out in a pre-test-post-test design at 7 tertiary care university hospital neurocenters in Germany. The intervention is directed at the interdisciplinary multiprofessional stroke teams. Before and after the intervention, process times of all direct-to-center stroke patients receiving IV thrombolysis (IVT) and/or endovascular therapy (EVT) will be recorded. The primary outcome measure will be the “door-to-needle” time of all consecutive stroke patients directly admitted to the neurocenters who receive IVT. Secondary outcome measures will be intervention-related process times of the fraction of patients undergoing EVT and effects on team communication, perceived patient safety, and staff satisfaction via a staff questionnaire.Interventions: We are applying a multi-level intervention in cooperation with three “STREAM multipliers” from each center. First step is a central meeting of the multipliers at the sponsor's institution with the purposes of algorithm review in a peer-to-peer process that is recorded in a protocol and an introduction to the principles of simulation training and debriefing as well as crew resource management and team communication. Thereafter, the multipliers cooperate with the stroke team trainers from the sponsor's institution to plan and execute 2–3 one-day simulation courses in situ in the emergency department and CT room of the trial centers whereupon they receive teaching materials to perpetuate the trainings.Clinical Trial Registration: STREAM is a registered trial at https://clinicaltrials.gov/ct2/show/NCT03228251.

ObjectiveVestibular signals are involved in higher cortical functions like spatial orientation and its disorders. Vestibular dysfunction contributes, for example, to spatial neglect which can be transiently improved by caloric stimulation. The exact roles and mechanisms of the vestibular and visual systems for the recovery of neglect are not yet known.MethodsResting-state functional connectivity (fc) magnetic resonance imaging was recorded in a patient with hemispatial neglect during the acute phase and after recovery 6 months later following a right middle cerebral artery infarction before and after caloric vestibular stimulation. Seeds in the vestibular [parietal operculum (OP2)], the parietal [posterior parietal cortex (PPC); 7A, hIP3], and the visual cortex (VC) were used for the analysis.ResultsDuring the acute stage after caloric stimulation the fc of the right OP2 to the left OP2, the anterior cingulum, and the para/hippocampus was increased bilaterally (i.e., the vestibular network), while the interhemispheric fc was reduced between homologous regions in the VC. After 6 months, similar fc increases in the vestibular network were found without stimulation. In addition, fc increases of the OP2 to the PPC and the VC were seen; interhemispherically this was true for both PPCs and for the right PPC to both VCs.ConclusionImprovement of neglect after caloric stimulation in the acute phase was associated with increased fc of vestibular cortex areas in both hemispheres to the para-hippocampus and the dorsal anterior cingulum, but simultaneously with reduced interhemispheric VC connectivity. This disclosed a, to some extent, similar but also distinct short-term mechanism (vestibular stimulation) of an improvement of spatial orientation compared to the long-term recovery of neglect.

ObjectivesTo evaluate the function of the oculomotor and vestibular systems and to correlate these findings with the clinical status of patients with Gaucher disease type 3 (GD3). The goal of this cross-sectional and longitudinal study was to find oculomotor biomarkers for future clinical trials.MethodsTwenty-six patients with GD3 were assessed for eligibility and 21 were able to perform at least one task. Horizontal and vertical reflexive saccades, smooth pursuit, gaze-holding, optokinetic nystagmus, and horizontal vestibulo-ocular reflex (VOR) were examined by video-oculography/video-head impulse test and compared concurrently with 33 healthy controls. The Scale for the Assessment and Rating of Ataxia (SARA), the modified Severity Scoring Tool (mSST), and Grooved Pegboard Test (GPT) were administered to assess overall neurological function. Eleven patients were also re-assessed after 1 year.ResultsNine out of 17 patients exhibited gaze-holding deficits. One patient had upbeat nystagmus. Three patients presented with bilateral abducens palsy in combination with central oculomotor disorders, suggesting a bilateral involvement of the abducens nucleus. Horizontal angular VOR gain was reduced in all patients (0.66 ± 0.37) compared with controls (1.1 ± 0.11, p