Whole-Brain Magnetic Resonance Spectroscopy Reveals Distinct Alterations in Neurometabolic Profile in Progressive Supranuclear Palsy.

BACKGROUND: Progressive supranuclear palsy (PSP) is an atypical Parkinsonian syndrome characterized by supranuclear gaze palsy, early postural instability, and a frontal dysexecutive syndrome. Contrary to normal brain magnetic resonance imaging in Parkinson's disease (PD), PSP shows specific cerebral atrophy patterns and alterations, but these findings are not present in every patient, and it is still unclear if these signs are also detectable in early disease stages. OBJECTIVE: The aim of the present study was to analyze the metabolic profile of patients with clinically diagnosed PSP in comparison with matched healthy volunteers and PD patients using whole-brain magnetic resonance spectroscopic imaging (wbMRSI). METHODS: Thirty-nine healthy controls (HCs), 29 PD, and 22 PSP patients underwent wbMRSI. PSP and PD patients were matched for age and handedness with HCs. Clinical characterization was performed using the Movement Disorder Society Unified Parkinson's Disease Rating Scale, PSP rating scale, and DemTect (test for cognitive assessment). RESULTS: In PSP patients a significant reduction in N-acetyl-aspartate (NAA) was detected in all brain lobes. Fractional volume of the cerebrospinal fluid significantly increased in PSP patients compared to PD and healthy volunteers. CONCLUSIONS: In PSP much more neuronal degeneration and cerebral atrophy have been detected compared with PD. The most relevant alteration is the decrease in NAA in all lobes of the brain, which also showed a partial correlation with clinical symptoms. However, more studies are needed to confirm the additional value of wbMRSI in clinical practice. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Convolutional Neural Network for Fully Automated Cerebellar Volumetry in Children in Comparison to Manual Segmentation and Developmental Trajectory of Cerebellar Volumes.

The purpose of this study was to develop a fully automated and reliable volumetry of the cerebellum of children during infancy and childhood using deep learning algorithms in comparison to manual segmentation. In addition, the clinical usefulness of measuring the cerebellar volume is shown. One hundred patients (0 to 16.3 years old) without infratentorial signal abnormalities on conventional MRI were retrospectively selected from our pool of pediatric MRI examinations. Based on a routinely acquired 3D T1-weighted magnetization prepared rapid gradient echo (MPRAGE) sequence, the cerebella were manually segmented using ITK-SNAP. The data set of all 100 cases was divided into four splits (four-fold cross-validation) to train the network (NN) to delineate the boundaries of the cerebellum. First, the accuracy of the newly created neural network was compared with the manual segmentation. Secondly, age-related volume changes were investigated. Our trained NN achieved an excellent Spearman correlation coefficient of 0.99, a Dice Coefficient of 95.0 ± 2.1%, and an intersection over union (IoU) of 90.6 ± 3.8%. Cerebellar volume increased continuously with age, showing an exponentially rapid growth within the first year of life. Using a convolutional neural network, it was possible to achieve reliable, fully automated cerebellar volume measurements in childhood and infancy, even when based on a relatively small cohort. In this preliminary study, age-dependent cerebellar volume changes could be acquired.

The semi-sitting position in patients with indwelling CSF shunts: perioperative management and avoidance of complications.

OBJECTIVE: Posterior fossa or midline tumors are often associated with hydrocephalus and primary tumor removal with or without perioperative placement of an external ventricular drain (EVD) is commonly accepted as first-line treatment. Shunting prior to posterior fossa surgery (PFS) is mostly reserved for symptomatic cases or special circumstances. There are limited data regarding the anticipated risk for symptomatic pneumocephalus and the perioperative management using the semi-sitting position (SSP) in such a scenario. Here, we therefore assessed the safety of performing PFS in a consecutive series of patients over a period of 15 years to allow the elaboration of recommendations for perioperative management. METHODS: According to specific inclusion and exclusion criteria a total of 13 patients who underwent 17 operations was identified. Supratentorial pneumocephalus was evaluated with semiautomatic-volumetric segmentation. The volume of pneumocephalus was evaluated according to age and ventricular size. RESULTS: Ten of the 13 patients had a programmable valve (preoperative valve setting range 6-14 cmH20; mean 7.5 cmH20) while 3 patients had non programmable valves. A variable amount of supratentorial air collection was evident in all patients postoperatively (range 3.2-331 ml; mean 122.32 ml). Positive predictors for the volume of postoperative pneumocephalus were higher age and a preoperative Evans ratio > 0.3. In our series, we encountered no cases of tension pneumocephalus necessitating an air replacement procedure as well as no obstruction, disconnection, infection or hardware malfunction of the shunt system. CONCLUSIONS: Our findings indicate that a CSF shunt in situ is not a contraindication for performing PFS in the semi-sitting position and it does not increase the pre-existing risk for postoperative tension pneumocephalus. In cases of primary shunting for hydrocephalus associated with posterior fossa tumors a programmable valve set at a medium opening pressure with a gravitational device is a valid option when PFS in the semi-sitting position is opted. In patients with an indwelling shunt diversion system special caution is indicated in order to prevent and detect overdrainage especially in not adjustable valves or shunts without antisiphon devices.

[Comparison of speech understanding taking into account the exact electrode position (SRA/MRA/CA)]. / Vergleich des Sprachverstehens unter Berücksichtigung der genauen Elektrodenposition (SRA/MRA/CA).

Cochlear implantation has been a routine hearing rehabilitation procedure for years. Nevertheless, not all parameters that influence speech understanding after implantation are known. We test the hypothesis whether there is a connection between speech understanding and the position of different electrode types in relation to the modiolus in the cochlea with identical speech processors. For this purpose, in this retrospective study, we compare the hearing results with different electrode types ("Straight Research Array" [SRA], "Modiolar Research Array" [MRA] and "Contour Advance" [CA]) from the manufacturer Cochlear in matched pair groups.After creating three groups using "matched pairs" (n=52 patients per group), the cochlear parameters (length of the outer wall, angle of insertion, insertion depth, cochlear coverage and total length of the electrode in the cochlea, wrapping factor) were measured in the routinely performed manner pre- and post-operative high-resolution CT or DVT. The Freiburg monosyllabic understanding was used as a target variable one year after implantation.In the Freiburg monosyllabic test one year postoperatively, patients with MRA had a monosyllabic understanding of 51.2%, patients with SRA 49.5% and patients with CA 58.0%. It could be shown that with increasing cochlear coverage with MRA and CA, the speech understanding of the patients decreases and with SRA it increases. In addition, it could be shown that the monosyllabic understanding increases with increasing "wrapping factor".The results show that the position of the electrode to the modiolus is not the only factor explaining differences in outcome after cochlear implantation.

Cerebrospinal Fluid Findings in Neurological Diseases Associated with Sjögren's Syndrome.

BACKGROUND: Sjögren's syndrome is a chronic autoimmune-mediated disease that can cause a variety of neurological manifestations. METHODS: This study investigated characteristics of clinical and cerebrospinal fluid (CSF) features in patients with neurological diseases associated with Sjögren's syndrome. Eighty-two patients were examined separately according to the presence of Sjögren's syndrome alone or in combination with other autoimmune diseases. RESULTS: In the 47 patients with primary Sjögren's syndrome, peripheral neuropathy (57%) was found most frequently, followed by the involvement of the central nervous system (CNS; 17%), cranial neuropathy (15%), and myalgia (11%). These patients did not display consistent signs of inflammation in the CSF. Slight pleocytosis of 8-107 cells/µL was found in patients with peripheral neuropathy (9%), cranial neuropathy (20%), and CNS involvement (25%). Oligoclonal bands indicating intrathecal IgG synthesis occurred in 26% of patients with peripheral neuropathy, 20% of patients with cranial neuropathy, and 25% of patients with CNS involvement. CONCLUSIONS: In patients with Sjögren's syndrome and neurological manifestations, inflammatory CSF changes were rarely found and did not show a characteristic pattern irrespective of peripheral or central genesis of neurological deficits. Analysis of the CSF presents therefore an important diagnostic procedure to exclude other autoimmune and infectious diseases.

Clinically Isolated Syndrome According to McDonald 2010: Intrathecal IgG Synthesis Still Predictive for Conversion to Multiple Sclerosis.

While the revised McDonald criteria of 2010 allow for the diagnosis of multiple sclerosis (MS) in an earlier stage, there is still a need to identify the risk factors for conversion to MS in patients with clinically isolated syndrome (CIS). Since the latest McDonald criteria were established, the prognostic role of cerebrospinal fluid (CSF) and visual evoked potentials (VEP) in CIS patients is still poorly defined. We conducted a monocentric investigation including patients with CIS in the time from 2010 to 2015. Follow-ups of 120 patients revealed that 42% converted to MS. CIS patients with positive oligoclonal bands (OCB) were more than twice as likely to convert to MS as OCB negative patients (hazard ratio = 2.6). The probability to develop MS was even higher when a quantitative intrathecal IgG synthesis was detected (hazard ratio = 3.8). In patients with OCB, VEP did not add further information concerning the conversion rate to MS. In patients with optic neuritis and negative OCB, a significantly higher rate converted to MS when VEP were delayed. In conclusion, the detection of an intrathecal IgG synthesis increases the conversion probability to MS. Pathological VEP can help to predict the conversion rate to MS in patients with optic neuritis without an intrathecal IgG synthesis.

Physiological neuronal decline in healthy aging human brain - An in vivo study with MRI and short echo-time whole-brain (1)H MR spectroscopic imaging.

Knowledge of physiological aging in healthy human brain is increasingly important for neuroscientific research and clinical diagnosis. To investigate neuronal decline in normal aging brain eighty-one healthy subjects aged between 20 and 70years were studied with MRI and whole-brain (1)H MR spectroscopic imaging. Concentrations of brain metabolites N-acetyl-aspartate (NAA), choline (Cho), total creatine (tCr), myo-inositol (mI), and glutamine+glutamate (Glx) in ratios to internal water, and the fractional volumes of brain tissue were estimated simultaneously in eight cerebral lobes and in cerebellum. Results demonstrated that an age-related decrease in gray matter volume was the largest contribution to changes in brain volume. Both lobar NAA and the fractional volume of gray matter (FVGM) decreased with age in all cerebral lobes, indicating that the decreased NAA was predominantly associated with decreased gray matter volume and neuronal density or metabolic activity. In cerebral white matter Cho, tCr, and mI increased with age in association with increased fractional volume, showing altered cellular membrane turn-over, energy metabolism, and glial activity in human aging white matter. In cerebellum tCr increased while brain tissue volume decreased with age, showing difference to cerebral aging. The observed age-related metabolic and microstructural variations suggest that physiological neuronal decline in aging human brain is associated with a reduction of gray matter volume and neuronal density, in combination with cellular aging in white matter indicated by microstructural alterations and altered energy metabolism in the cerebellum.

McDonald Criteria 2010 and 2005 Compared: Persistence of High Oligoclonal Band Prevalence Despite Almost Doubled Diagnostic Sensitivity.

The 2010 McDonald criteria were developed to allow a more rapid diagnosis of relapsing-remitting multiple sclerosis (MS) by only one MRI of the brain. Although cerebrospinal fluid (CSF) is not a mandatory part of the latest criteria, the evidence of an intrathecal humoral immunoreaction in the form of oligoclonal bands (OCB) is crucial in the diagnostic workup. To date, the impact of the 2010 McDonald criteria on the prevalence of OCB has not been investigated. We retrospectively evaluated data of 325 patients with a clinical relapse suggestive of demyelination that were treated in a German university hospital between 2010 and 2015. One hundred thirty-six patients (42%) were diagnosed with MS and 189 patients with CIS when the criteria of 2010 were applied. The criteria of 2005 allowed only 70 patients (22%) to be designated as MS. In contrast, the prevalence of OCB was marginal affected in MS patients with 96% for the criteria of 2010 and 98.5% for the criteria of 2005. In conclusion, OCB are prevalent in most MS patients and reflect the chronic inflammatory nature of the disease. We recommend CSF examination to exclude alternative diagnoses and reevaluation of the diagnosis MS in patients with negative OCB.

Cerebral white matter lesions in patients with cirrhosis - causative for hepatic encephalopathy or bystanders?

BACKGROUND & AIMS: Focal white matter lesions mimicking microvascular lesions were connected to the development of hepatic encephalopathy (HE) in patients with cirrhosis. This study aims to assess the relationship between cerebrovascular risk factors and the prevalence and extent of these lesions in patients with cirrhosis, as well as their impact upon cognitive function. METHODS: 55 cirrhotic patients underwent neurological examination, psychometric testing and magnetic resonance imaging. T2-weighted images were reviewed for white matter lesions by a neuroradiologist and a neurologist, independently. Patients were allocated into three groups: (i) no or <5, (ii) 6-15 and (iii) more than 15 lesions. Allocation was confirmed by a senior neuroradiologist blinded for the clinical data. The patient groups were compared concerning age, underlying liver disease, mortality, MELD Score, history of HE, treatment for HE, cerebrovascular risk factors and psychometric test results. Regression analysis was performed to identify risk factors for the presence and extent of white matter lesions. RESULTS: Patient groups 2 and 3 were older and showed worse results in the psychometric tests than group 1 (P < 0.05). Correlation analyses showed a significant relationship between the number of white matter lesions and the grade of HE (P < 0.001) and cognitive function (P < 0.05), but no interrelationship between the lesions and cerebrovascular risk factors or other factors tested. CONCLUSIONS: Focal white matter lesions in patients with cirrhosis do not represent cerebrovascular small-vessel disease but are related to the pathology of HE. Further studies are needed to clarify the mechanisms behind in detail.

Extended Long-Term Outcome After Conservative Decompressive Microsurgery and Routine Adjuvant Fractionated Stereotactic Radiotherapy for Symptomatic Cavernous Sinus Meningiomas.

BACKGROUND AND OBJECTIVES: Cavernous sinus meningiomas (CSM) pose one of the most difficult to treat subgroup of skull base meningiomas. The purpose of this study was to evaluate the efficacy of an interdisciplinary treatment approach for symptomatic CSM which incorporated conservative function preserving microsurgery and routine adjuvant fractionated stereotactic radiotherapy (FSRT). METHODS: A homogenous group of patients with symptomatic primary CSM with extracavernous extension was treated between 2005 and 2012. All patients were available for a minimum follow-up of 5 years. Clinical follow-up included detailed examination of oculomotor deficits, visual status, and endocrinologic function. Radiologic follow-up was conducted by tumor volumetry. RESULTS: Overall, 23 patients were included in this study (78.3% women; median age 58 years). Diplopia was the most common presenting symptom, followed by headache and visual disturbances. Surgical morbidity was low (3/23; 13%). FSRT was applied after a median of 2 months after surgery. At a median clinical follow-up of 113 months, 70.45% of the presenting symptoms had improved, 25% remained unchanged, and in 2 cases (4.54%), worsening occurred. Overall tumor regression was evident in 19/21 World Health Organization 1 and in 1/2 of World Health Organization 2 CSM, respectively, at a median radiological follow-up of 103 months. CONCLUSION: Our findings demonstrate the efficacy of an interdisciplinary treatment approach for symptomatic primary CSM with extracavernous extension with decompression of neurovascular elements followed by FSRT. Precise preoperative planning and intraoperative decision making in combination with routine postoperative radiotherapy can achieve excellent tumor control, improve neurologic function, and minimize long-term morbidity.

Reducing radiation exposure and costs: CT body scout views with an enhanced protocol versus conventional radiography after shunt surgery.

OBJECTIVE: Ventriculoperitoneal shunt implantation has become standard treatment for cerebrospinal fluid diversion, besides endoscopic third ventriculostomy for certain indications. Postoperative X-ray radiography series of skull, chest and abdomen combined with cranial CT are obtained routinely in many institutions to document the shunt position and valve settings in adult patients. Measures to reduce postoperative radiation exposure are needed, however, there is only limited experience with such efforts. Here, we aim to compare routine postoperative cranial CT plus conventional radiography series (retrospective arm) with cranial CT and body scout views only (prospective arm) concerning both diagnostic quality and radiation exposure. PATIENTS AND METHODS: After introduction of an enhanced CT imaging protocol, routine skull and abdomen radiography was no longer obtained after VP shunt surgery. The image studies of 25 patients with routine postoperative cranial CT and conventional radiography (retrospective arm of study) were then compared to 25 patients with postoperative cranial CT and CT body scout views (prospective arm of study). Patient demographics such as age, sex and primary diagnosis were collected. The image quality of conventional radiographic images and computed tomography scout views images were independently analyzed by one neurosurgeon and one neuroradiologist. RESULTS: There were no differences in quality assessments according to three different factors determined by two independent investigators for both groups. There was a statistically significant difference, however, between the conventional radiography series group and the CT body scout view imaging group with regard to radiation exposure. The effective dose estimation calculation yielded a difference of 0.05 mSv (two-tailed t-test, p = 0.044) in favor of CT body scout view imaging. Furthermore, the new enhanced protocol resulted in a reduction of cost and the use of human resources. CONCLUSION: CT body scout view imaging provides sufficient imaging quality to determine shunt positioning and valve settings. With regard to radiation exposure and costs, we suggest that conventional postoperative shunt series may be abandoned.

Effects of the COVID-19 Pandemic on Patients With NMO Spectrum Disorders and MOG-Antibody-Associated Diseases: COPANMO(G)-Study.

BACKGROUND AND OBJECTIVES: To evaluate the effects of the coronavirus disease 2019 (COVID-19) pandemic on the life of patients with neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated diseases (MOGAD). METHODS: This multicenter, cross-sectional study included data of 187 patients recruited from 19 different German and Austrian Neuromyelitis Optica Study Group (NEMOS) centers between July 2021 and March 2022. The effects of the pandemic on immunotherapeutic treatment and access to care, the possible severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and the potential effect of vaccination against SARS-CoV-2 on disease incidence and relapse risk were assessed using a patient questionnaire. Health-related quality of life (HRQoL) was measured with the EuroQoL Group 5-Dimension 5-Level Scale (EQ-5D-5L). Demographic and clinical characteristics were retrieved from the NEMOS database. RESULTS: One hundred eighty-seven patients (75% women; median age 47 [range 21-86] years; median disease duration 5.5 [range 0-67] years; median Expanded Disability Status Scale 2.0 [range 0-8.0]; 51% aquaporin-4 immunoglobulin G (AQP4-IgG)-positive, 36% myelin oligodendrocyte glycoprotein (MOG)-IgG-positive 13% double-seronegative) were analyzed. Most patients maintained excellent access to healthcare services throughout the pandemic. Immunotherapy was not changed in 88% of patients. Ninety-one percent of all patients were satisfied with medical care during the pandemic. Nearly two-thirds (64%) of patients rated their risk of infection with SARS-CoV-2 as low or moderate. Among this study sample, 23 patients (12%) knowingly acquired an infection with SARS-CoV-2 and predominantly had a nonsevere course of illness (n = 22/23, 96%). The SARS-CoV-2 vaccination rate was 89%, with 4 cases of confirmed attack or first manifestation of NMOSD/MOGAD occurring in temporal association with the vaccination (range 2-9 days). The reported HRQoL did not decline compared with a prepandemic assessment (mean EQ-5D-5L index value 0.76, 95% bootstrap confidence interval [CI] 0.72-0.80; mean EQ-VAS 66.5, 95% bootstrap CI 63.5-69.3). DISCUSSION: This study demonstrates that, overall, patients with NMOSD/MOGAD affiliated with specialized centers received ongoing medical care during the pandemic. Patients' satisfaction with medical care and HRQoL did not decrease.

Polysialyltransferase overexpression in Schwann cells mediates different effects during peripheral nerve regeneration.

The polysialic acid (PSA) moiety of the neural cell adhesion molecule (NCAM) has been shown to support dynamic changes underlying peripheral nerve regeneration. Using transgenic mice expressing polysialyltransferase ST8SiaIV under control of a glial-specific (proteolipid protein, PLP) promoter (PLP-ST8SiaIV-transgenic mice), we tested the hypothesis that permanent synthesis of PSA in Schwann cells impairs functional recovery of lesioned peripheral nerves. After sciatic nerve crush, histomorphometric analyses demonstrated impaired remyelination of regenerated axons at the lesion site and in target tissue of PLP-ST8SiaIV-transgenic mice, though the number and size of regenerating unmyelinated axons were not changed. This was accompanied by slower mechanosensory recovery in PLP-ST8SiaIV-transgenic mice. However, the proportion of successfully mono-(re)innervated motor endplates in the foot pad muscle was significantly increased in PLP-ST8SiaIV-transgenic mice when compared with wild-type littermates, suggesting that long-term increase in PSA levels in regenerating nerves may favor selective motor target reinnervation. The combined negative and positive effects of a continuous polysialyltransferase overexpression observed during peripheral nerve regeneration suggest that an optimized time- and differentiation-dependent control of polysialyltransferase expression in Schwann cells may further improve recovery after peripheral nerves injury.

Immunoadsorption therapy for steroid-unresponsive relapses in patients with multiple sclerosis.

BACKGROUND: Therapeutic plasma exchange (TPE) in steroid-unresponsive relapses of patients with multiple sclerosis (MS) is an established therapy with response rates of up to 70%. Immunoadsorption (IA) specifically removes immunoglobulins from the patient's plasma. It is hypothesized that IA therapy might be better tolerated than and as effective as TPE in the treatment of MS relapses. Experiences with IA therapy of steroid-unresponsive MS relapses are limited. METHODS: We report our experiences with IA therapy in a series of 10 patients with steroid-unresponsive MS relapses. RESULTS: A marked to moderate clinical response with clear gain of function was observed in 66% of our patients. IA therapy was well tolerated. CONCLUSIONS: IA therapy is an effective and well-tolerated therapeutic option for steroid-unresponsive MS relapses.

When Fat Hits the Brain: Intraventricular and Subarachnoid Fat Migration Secondary to a Complex Sacropelvic Fracture-Diagnosis and Treatment.

Massive migration of fat droplets in the ventricles and the subarachnoid space is a very rare sequel of spinal trauma. Owing to its rarity, knowledge about treatment and outcome remains limited. We report on the uncommon occurrence of massive subarachnoid and intraventricular fat dissemination in a 41-year-old man who suffered a complex sacropelvic fracture with spondylopelvic dissociation but who had no head injury. We show that early placement of an external ventricular drain with prolonged drainage for washout of the fat depots can prevent chronic hydrocephalus and subsequent shunt dependency.

Advancement of door-to-needle times in acute stroke treatment after repetitive process analysis: never give up!

Background: In acute ischemic stroke, timely treatment is of utmost relevance. Identification of delaying factors and knowledge about challenges concerning hospital structures are crucial for continuous improvement of process times in stroke care. Objective: In this study, we report on our experience in optimizing the door-to-needle time (DNT) at our tertiary care center by continuous quality improvement. Methods: Five hundred forty patients with acute ischemic stroke receiving intravenous thrombolysis (IVT) at Hannover Medical School were consecutively analyzed in two phases. In study phase I, including 292 patients, process times and delaying factors were collected prospectively from May 2015 until September 2017. In study phase II, process times of 248 patients were obtained from January 2019 until February 2021. In each study phase, a new clinical standard operation procedure (SOP) was implemented, considering previously identified delaying factors. Pre- and post-SOP treatment times and delaying factors were analyzed to evaluate the new protocols. Results: In study phase I, SOP I reduced the median DNT by 15 min. The probability to receive treatment within 30 min after admission increased by factor 5.35 [95% confidence interval (CI): 2.46-11.66]. Further development of the SOP with implementation of a mobile thrombolysis kit led to a further decrease of DNT by 5 min in median in study phase II. The median DNT was 29 (25th-75th percentiles: 18-44) min, and the probability to undergo IVT within 15 min after admission increased by factor 4.2 (95% CI: 1.63-10.83) compared with study phase I. Conclusion: Continuous process analysis and subsequent development of targeted workflow adjustments led to a substantial improvement of DNT. These results illustrate that with appropriate vigilance, there is constantly an opportunity for improvement in stroke care.

Insights Into Immunothrombotic Mechanisms in Acute Stroke due to Vaccine-Induced Immune Thrombotic Thrombocytopenia.

During the COVID-19 pandemic, vaccination is the most important countermeasure. Pharmacovigilance concerns however emerged with very rare, but potentially disastrous thrombotic complications following vaccination with ChAdOx1. Platelet factor-4 antibody mediated vaccine-induced immune thrombotic thrombocytopenia (VITT) was described as an underlying mechanism of these thrombotic events. Recent work moreover suggests that mechanisms of immunothrombosis including neutrophil extracellular trap (NET) formation might be critical for thrombogenesis during VITT. In this study, we investigated blood and thrombus specimens of a female patient who suffered severe stroke due to VITT after vaccination with ChAdOx1 in comparison to 13 control stroke patients with similar clinical characteristics. We analyzed cerebral thrombi using histological examination, staining of complement factors, NET-markers, DNase and LL-37. In blood samples at the hyper-acute phase of stroke and 7 days later, we determined cell-free DNA, myeloperoxidase-histone complexes, DNase activity, myeloperoxidase activity, LL-37 and inflammatory cytokines. NET markers were identified in thrombi of all patients. Interestingly, the thrombus of the VITT-patient exclusively revealed complement factors and high amounts of DNase and LL-37. High DNase activity was also measured in blood, implying a disturbed NET-regulation. Furthermore, serum of the VITT-patient inhibited reactive oxygen species-dependent NET-release by phorbol-myristate-acetate to a lesser degree compared to controls, indicating either less efficient NET-inhibition or enhanced NET-induction in the blood of the VITT-patient. Additionally, the changes in specific cytokines over time were emphasized in the VITT-patient as well. In conclusion, insufficient resolution of NETs, e.g. by endogenous DNases or protection of NETs against degradation by embedded factors like the antimicrobial peptide LL-37 might thus be an important factor in the pathology of VITT besides increased NET-formation. On the basis of these findings, we discuss the potential implications of the mechanisms of disturbed NETs-degradation for diagnostic and therapeutic approaches in VITT-related thrombogenesis, other auto-immune disorders and beyond.

Alterations of Striato-Thalamic Metabolism in Normal Aging Human Brain-An MR Metabolic Imaging Study.

Aging effects on striato-thalamic metabolism in healthy human brains were studied in vivo using short-TE whole brain 1H-MR spectroscopic imaging (wbMRSI) on eighty healthy subjects aged evenly between 20 to 70 years at 3T. Relative concentrations of N-acetyl-aspartate (NAA), choline, total creatine (tCr), myo-inositol (mI), glutamate, and glutamine in bilateral caudate nucleus, putamen, pallidum, and thalamus were determined using signal normalization relative to brain tissue water. Linear regression analysis was used to analyze the age-dependence of the metabolite concentrations. The metabolite concentrations revealed spatial inhomogeneity across brain regions and metabolites. With age, NAA decreased significantly in bilateral caudate nucleus and putamen, left pallidum, and left thalamus, tCr decreased in left putamen and bilateral pallidum, mI increased in bilateral caudate nucleus and right thalamus, and spectral linewidth increased in left putamen and right thalamus. In conclusion, normal aging of striato-thalamic metabolism in healthy human is associated with regional specific decreases of NAA and tCr and increases of mI, which may reflect the individual role of each brain structure within brain functionality.

Clinically Applicable Quantitative Magnetic Resonance Morphologic Measurements of Grey Matter Changes in the Human Brain.

(1) Purpose: Quantitative magnetic resonance imaging (qMRI) measurements can be used to sensitively estimate brain morphological alterations and may support clinical diagnosis of neurodegenerative diseases (ND). We aimed to establish a normative reference database for a clinical applicable quantitative MR morphologic measurement on neurodegenerative changes in patients; (2) Methods: Healthy subjects (HCs, n = 120) with an evenly distribution between 21 to 70 years and amyotrophic lateral sclerosis (ALS) patients (n = 11, mean age = 52.45 ± 6.80 years), as an example of ND patients, underwent magnetic resonance imaging (MRI) examinations under routine diagnostic conditions. Regional cortical thickness (rCTh) in 68 regions of interest (ROIs) and subcortical grey matter volume (SGMV) in 14 ROIs were determined from all subjects by using Computational Anatomy Toolbox. Those derived from HCs were analyzed to determine age-related differences and subsequently used as reference to estimate ALS-related alterations; (3) Results: In HCs, the rCTh (in 49/68 regions) and the SGMV (in 9/14 regions) in elderly subjects were less than those in younger subjects and exhibited negative linear correlations to age (p < 0.0007 for rCTh and p < 0.004 for SGMV). In comparison to age- and sex-matched HCs, the ALS patients revealed significant decreases of rCTh in eight ROIs, majorly located in frontal and temporal lobes; (4) Conclusion: The present study proves an overall grey matter decline with normal ageing as reported previously. The provided reference may be used for detection of grey matter alterations in neurodegenerative diseases that are not apparent in standard MR scans, indicating the potential of using qMRI as an add-on diagnostic tool in a clinical setting.

Cerebrospinal Fluid Parameters in Antisense Oligonucleotide-Treated Adult 5q-Spinal Muscular Atrophy Patients.

Approval of nusinersen, an intrathecally administered antisense oligonucleotide, for the treatment of 5q-spinal muscular atrophy (SMA) marked the beginning of a new therapeutic era in neurological diseases. Changes in routine cerebrospinal fluid (CSF) parameters under nusinersen have only recently been described in adult SMA patients. We aimed to explore these findings in a real-world setting and to identify clinical and procedure-associated features that might impact CSF parameters. Routinely collected CSF parameters (leukocyte count, lactate, total protein, CSF/serum albumin quotient (QAlbumin), oligoclonal bands) of 28 adult SMA patients were examined for up to 22 months of nusinersen treatment. Total protein and QAlbumin values significantly increased in the first 10 months, independent of the administration procedure. By month 14, no further increases were detected. Two patients developed transient pleocytosis. In two cases, positive oligoclonal bands were found in the beginning and in four patients throughout the whole observation period. No clinical signs of inflammatory central nervous system disease were apparent. Our data confirm elevated CSF total protein and QAlbumin during nusinersen treatment. These alterations may be caused by both repeated lumbar punctures and the interval between procedures rather than by the medication itself. Generally, there were no severe alterations of CSF routine parameters. These results further underline the safety of nusinersen therapy.