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Background Enzyme replacement therapy (ERT) with recombinant human alpha-glucosidase (rhGAA, alglucosidase alfa) has improved survival, motor outcomes, daily life activity and quality of life in Pompe patients. However, ERT in Pompe disease often induces formation of antibodies, which may reduce the efficacy of treatment and can lead to adverse events. In this study antibody formation and their effect on clinical outcome in patients with childhood onset Pompe disease treated with enzyme replacement therapy (ERT) with recombinant human alpha-glucosidase (rhGAA) are analyzed. Methods Enzyme-linked immunosorbent assay (ELISA) was used to determine anti-rhGAA antibody titers at predefined time points. The effect of antibodies on rhGAA activity (neutralizing effects) was measured in vitro. Clinical effects were evaluated by assessing muscle strength (MRC score) and function (QMFT-score), pulmonary function and infusion associated reactions (IARs). Results Twenty-two patients were included (age at start ERT 1.1–16.4 years, median treatment duration 12.4 years). Peak antibody titers were low ( Conclusions Ninety-one percent of childhood onset Pompe patients developed anti-rhGAA antibodies (above background level), a minority of whom had high antibody titers at repeated time points, which do not seem to interfere with clinical outcome. High antibody titers may be associated with the occurrence of IARs. Although the majority of patients does not develop high titers; antibody titers should be determined in case of clinical deterioration.

Background: Magnetic Resonance Imaging (MRI) analysis method “brain-age” paradigm could offer an intuitive prognostic metric (brain-predicted age difference: brain-PAD) for disability in Multiple Sclerosis (MS), reflecting structural brain health adjusted for aging. Equally, cellular senescence has been reported in MS using T-cell biomarker CD8+CD57+.Objective: Here we explored links between MRI-derived brain-age and blood-derived cellular senescence. We examined the value of combining brain-PAD with CD8+CD57+(ILT2+PD-1+) T-cells when predicting disability score in MS and considered whether age-related biological mechanisms drive disability.Methods: Brain-age analysis was applied to T1-weighted MRI images. Disability was assessed and peripheral blood was examined for CD8+CD57+ T-cell phenotypes. Linear regression models were used, adjusted for sex, age and normalized brain volume.Results: We included 179 mainly relapsing-remitting MS patients. A high brain-PAD was associated with high physical disability (mean brain-PAD = +6.54 [5.12–7.95]). CD8+CD57+(ILT2+PD-1+) T-cell frequency was neither associated with disability nor with brain-PAD. Physical disability was predicted by the interaction between brain-PAD and CD8+CD57+ILT2+PD-1+ T-cell frequency (AR2 = 0.196), yet without improvement compared to brain-PAD alone (AR2 = 0.206; AICc = 1.8).Conclusion: Higher frequency of CD8+CD57+ILT2+PD-1+ T-cells in the peripheral blood in patients with an older appearing brain was associated with worse disability scores, suggesting a role of these cells in the development of disability in MS patients with poorer brain health.

Microglia-induced neuroinflammation after stroke contributes to the exacerbation of post-ischemic damage but also supports neurorestorative events. Longitudinal molecular imaging of microglia-targeted therapies will support the assessment of target engagement, therapy efficacy, and deciphering the mode of action. We investigated the effects of chronic colony stimulating factor-1 receptor (CSF-1R) inhibitor-mediated microglia depletion on translocator protein (TSPO)-dependent neuroinflammation and cerebrovascular parameters using positron emission tomography (PET)/magnetic resonance (MR) imaging. Methods:N = 40 C57BL/6 mice underwent a 30 minutes transient middle cerebral artery occlusion (tMCAo) and were randomly assigned to either control group or treated with CSF-1R inhibitor (PLX5622; Plexxikon Inc.). N = 8 mice/group were used for 18F-DPA-714 (TSPO) PET imaging at days 7, 14, 21, and 30 post ischemia and behavioural tests prior to and after surgery. An extra group of n = 8 mice/group underwent MR imaging including T2-weighted (infarct), perfusion- (cerebral blood flow) and diffusion-weighted (water diffusion, cellular density) at days 1, 3, 7, 14, 21 and 30. Ex vivo analysis (immunoreactivity, gene expression) were performed to characterize the inflammatory environment. Results: We demonstrated that long-term CSF-1R inhibition transiently decreases the TSPO-PET signal within the infarct. Residual TSPO activity was partly due to potentially resistant Iba-1+ cell populations with low CSF-1R and transmembrane 119 (TMEM119) expression. The decrease in selected pro- and anti-inflammatory marker expression suggested an apparent global dampening of the neuroinflammatory response. Furthermore, the temporal changes of the MRI parameters highlighted treatment-induced effects on reperfusion and tissue homeostasis, associated with impaired motor functions at late stages. Conclusion: Longitudinal TSPO-PET/MR imaging allows the assessment of target engagement and optimization of drug efficiency. PLX5622 has promising immunomodulatory effects and the optimal therapeutic time window for its application needs to be defined.

Introduction A rapid transition from a clinical-based classification to a pathology-based classification of neurodegenerative conditions, largely promoted by the increasing availability of imaging biomarkers, is emerging. The Framework for Innovative Multi-tracer molecular Brain Imaging, funded by the EU Joint Program - Neurodegenerative Disease Research 2016 “Working Groups for Harmonisation and Alignment in Brain Imaging Methods for Neurodegeneration,” aimed at providing a roadmap for the applications of established and new molecular imaging techniques in dementia. Methods We consider current and future implications of adopting a pathology-based framework for the use and development of positron emission tomography techniques. Results This approach will enhance efforts to understand the multifactorial etiology of Alzheimer's disease and other dementias. Discussion The availability of pathology biomarkers will soon transform clinical and research practice. Crucially, a comprehensive understanding of strengths and caveats of these techniques will promote an informed use to take full advantage of these tools.

The presence of chelate and subchelate fore legs in Phymatinae (Hemiptera: Reduviidae), or ambush bugs, provides a unique opportunity to study the evolution of different types of raptorial legs in a closely related group of arthropods. Themonocorini have simple, possibly raptorial legs, Phymatini and Macrocephalini distinct subchelate fore legs, and the charismatic Carcinocorini are the only insects with a chelate fore leg apart from female dryinid Chysidoidea (Hymenoptera). Relationships between the four phymatine tribes are here analyzed in a cladistic framework thus permitting testable hypotheses on the evolution of raptorial legs. The presented analysis of phymatine tribal level relationships is based on a dataset comprising 11 species of Phymatinae and 54 non-phymatine Reduviidae and Heteroptera. The molecular data set consists of ∼3500 MAFFT aligned bases of 16S, 28S D2–D3, and 18S ribosomal genes. Parsimony and maximum likelihood analyses resulted in identical topologies for the ingroup with the relationships Themonocorini + (Phymatini + (Carcinocorini + Macrocephalini)) receiving high support values. Eleven morphological characters, eight of them derived from fore leg morphology, were optimized on the parsimony analysis. These optimizations indicate that the ancestral ambush bug had a simple raptorial leg; that size reduction of the tarsus, enlargement of the femur, curvature of the fore tibia, armature of tibia and femur with rows of tiny tubercles that allow for gripping of a prey insect, and the large process on the ventral surface of the femur arose in the common ancestor of Carcinocorini + Macrocephalini + Phymatini. The chelate leg in Carcinocorini is likely derived from a subchelate precursor similar to the one seen in recent Macrocephalini and may have evolved through elongation of the ventral, proximal portion of the fore femur and modification of the median process to form part of the digitus fixus. © The Willi Hennig Society 2010.

Immunomodulatory therapies have fueled interest in targeting microglial cells as part of the innate immune response after infection or injury. In this context, the colony-stimulating factor 1 (CSF-1) and its receptor (CSF-1R) have gained attention in various neurological conditions to deplete and reprogram the microglia/macrophages compartment. Published data in physiological conditions support the use of small-molecule inhibitors to study microglia/macrophages dynamics under inflammatory conditions and as a therapeutic strategy in pathologies where those cells support disease progression. However, preclinical and clinical data highlighted that the complexity of the spatiotemporal inflammatory response could limit their efficiency due to compensatory mechanisms, ultimately leading to therapy resistance. We review the current state-of-art in the field of CSF-1R inhibition in glioma and stroke and provide an overview of the fundamentals, ongoing research, potential developments of this promising therapeutic strategy and further application toward molecular imaging.

Studies on colony-stimulating factor 1 receptor (CSF-1R) inhibition-induced microglia depletion indicated that inhibitor withdrawal allowed the renewal of the microglia compartment via repopulation and resolved the inflammatory imbalance. Therefore, we investigated for the first time (to our knowledge) the effects of microglia repopulation on inflammation and functional outcomes in an ischemic mouse model using translocator protein (TSPO)-PET/CT and MR imaging, ex vivo characterization, and behavioral tests.

Simple Summary Patients with brain metastasis are at a severe stage of cancer, and brain surgery can prevent neurological morbidity. However, the success of brain surgery might require a patient’s physical integrity prior to the operation. In the present study, we asked whether a preoperative physical decline affects survival in patients with brain metastasis from lung cancer. In order to measure the physical condition, we used a commonly-known index—the so-called frailty index—and additionally measured the thickness of a particular masticatory muscle as muscle loss correlates to physical decline. We found that a decreased muscle thickness was accompanied by worsened survival for patients < 65 years and an increased frailty index correlated to worsened survival for patients ≥ 65 years. These results encourage to use of the frailty index and muscle thickness as easily available parameters in order to more sufficiently estimate individual treatment success in patients with metastatic lung cancer. Abstract Neurosurgical resection represents an important therapeutic pillar in patients with brain metastasis (BM). Such extended treatment modalities require preoperative assessment of patients’ physical status to estimate individual treatment success. The aim of the present study was to analyze the predictive value of frailty and sarcopenia as assessment tools for physiological integrity in patients with non-small cell lung cancer (NSCLC) who had undergone surgery for BM. Between 2013 and 2018, 141 patients were surgically treated for BM from NSCLC at the authors’ institution. The preoperative physical condition was assessed by the temporal muscle thickness (TMT) as a surrogate parameter for sarcopenia and the modified frailty index (mFI). For the ≥65 aged group, median overall survival (mOS) significantly differed between patients classified as ‘frail’ (mFI ≥ 0.27) and ‘least and moderately frail’ (mFI < 0.27) (15 months versus 11 months (p = 0.02)). Sarcopenia revealed significant differences in mOS for the

Multimodal molecular imaging allows a direct coregistration of different images, facilitating analysis of the spatial relation of various imaging parameters. Here, we further explored the relation of proliferation, as measured by [Nude mice subcutaneously inoculated with either lung cancer cells (n = 11 A549 tumors, n = 20 H1975 tumors) or colorectal cancer cells (n = 13 Colo205 tumors) were imaged with [Analyses were conducted on a total of 76 datasets, comprising a median of 2890 data points (ranging from 81 to 13,597). Scatterplots showing [A spatial relation of water diffusion, as measured by DW-MRI, and cellular proliferation, as measured by [

Zusammenfassung Anamnese Es erfolgt die Aufnahme einer 82-jährigen Patientin zur weiteren Abklärung zunehmender kognitiver Defizite und Gangunsicherheit. Diagnostik und Befunde In der durchgeführten Computertomografie des Kopfes zeigten sich die Zeichen einer fortgeschrittenen subkortikalen arteriosklerotischen Enzephalopathie (SAE). Laborchemisch fiel ein erhöhter Hämoglobinwert von 19,9 g/dl auf. Bei zusätzlicher Mutation in der JAK-2-Analyse wurde die Diagnose einer Polycythämia vera (Pv) gestellt. Nach Aderlass-Therapie zeigte sich eine Verbesserung der Kognition. Diskussion Die progredienten kognitiven Defizite sind bei vorbestehender SAE im Zusammenhang mit der neu diagnostizierten Pv zu sehen. Nach entsprechender Therapie der Pv ist auch langfristig eine Besserung der Kognition zu beobachten, sodass in diesem Fallbericht die Wichtigkeit einer Abklärung sekundärer, potenziell behandelbarer Ursachen von kognitiven Defiziten hervorgehoben wird.

Introduction Myasthenia gravis (MG) crisis has no specific reported correlation with atrial fibrillation (AF). We present a series of patients observed from a single general neurologist's outpatient and inpatient practice over a 9-year period who experienced the combination of MG crisis and AF. Case report Retrospective chart review of patients within 1 neurologist's inpatient and outpatient practice was done. Charts were selected based on the occurrence of newly diagnosed AF during MG crisis over a 9-year period. Most patients were diagnosed in the hospital and then followed as outpatients. Charts were reviewed to determine factors that may have played a role in the co-occurrence of these 2 conditions. Eight patients were identified that had co-occurring MG crisis and AF. All patients had very active MG, and were in or had recently been in MG crisis at the time their AF was discovered. Patients tended to have late-onset MG to be male, to be acetylcholinesterase receptor antibody positive, and to have improvement or remission of their AF once the MG achieved better clinical control. Conclusion New-onset AF can occur during MG crisis. The cardiac outcome improves with treatment of the underlying disease, after initial cardiac stabilization.

Activated carbon (AC) materials are porous structures generated by activation of either pyrolyzed plant or coke materials through physical or chemical means. While being widely used in industry for...

Recent studies in neurodegenerative conditions have increasingly highlighted that the same neuropathology can trigger different clinical phenotypes or, vice-versa, that similar phenotypes can be triggered by different neuropathologies. This evidence has called for the adoption of a pathology spectrum-based approach to study neurodegenerative proteinopathies. These conditions share brain deposition of abnormal protein aggregates, leading to aberrant biochemical, metabolic, functional, and structural changes. Positron emission tomography (PET) is a well-recognized and unique tool for the in vivo assessment of brain neuropathology, and novel PET techniques are emerging for the study of specific protein species. Today, key applications of PET range from early research and clinical diagnostic tools to their use in clinical trials for both participants screening and outcome evaluation. This position article critically reviews the role of distinct PET molecular tracers for different neurodegenerative proteinopathies, highlighting their strengths, weaknesses, and opportunities, with special emphasis on methodological challenges and future applications. (C) 2019 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

As a result of the aging population dementia is a growing challenge, especially in healthcare. Nevertheless, cognitive disorders are often not systematically evaluated, especially during hospital stays for other reasons; however, cognitive impairment is associated with a number of geriatric syndromes, including falls, delirium, dysphagia and lack of adherence to treatment plans. This article considers the current state of diagnosis and treatment of dementia. Non-pharmacological therapeutic approaches as well as current and future pharmacological treatment options are discussed. The drugs of choice for the symptomatic treatment of cognitive deficits in Alzheimer's disease and Parkinson-associated dementia are cholinesterase inhibitors and memantine; there is no specific pharmacological treatment for other types of dementia. Prevention and treatment of cardiovascular risk factors can potentially retard the progression of possibly all forms of dementia.

Research question: What concentration of anti-Mullerian hormone (AMH) corresponds to an antral follicle count (AFC) >15 for determination of ovarian reserve? Design: A prospective study conducted at 13 US fertility clinics in women aged 21–44 years who presented for AFC evaluation by transvaginal ultrasound. Serum samples were collected at the time of AFC evaluation (menstrual cycle day 2–4). AMH concentrations were measured by the Elecsys® AMH immunoassay; oestradiol and follicle-stimulating hormone (FSH) concentrations were also measured. The serum AMH cut-off able to detect AFC >15 with high sensitivity was determined (derivation cohort). Clinical performance of the AMH assay at the derived cut-off was evaluated (validation cohort). Receiver operating characteristic (ROC) analyses were also performed. Results: In the derivation cohort (n = 306), an optimal serum AMH cut-off value of 1.77 ng/ml was determined to correspond to AFC >15 with 89.63% sensitivity and 69.01% specificity, using the Elecsys AMH assay. In the validation cohort (n = 856), this 1.77 ng/ml cut-off could identify women with an AFC >15 with a sensitivity of 88.34% and a specificity of 68.29%; corresponding positive predictive and negative predictive values were 75.19% and 84.34%, respectively. ROC analyses demonstrated that AMH performed better than oestradiol or FSH in predicting AFC, with area under the curves of 85.7%, 57.1% and 69.7%, respectively, in the validation cohort. Conclusion: The Elecsys AMH immunoassay provides a robust and fully automated method to measure serum AMH levels. Women with AMH values below the cut-off of 1.77 ng/ml are unlikely to have AFC >15.

Zusammenfassung Anamnese und klinischer Befund Wir berichten von einem 86-jährigen Patienten, der aufgrund einer zunehmenden Schwäche des rechten Beines aufgenommen wurde. Untersuchungen und Diagnose Laborchemisch zeigten sich erhöhte Blutspiegel von Kreatinkinase und Kreatinin und im EMG konnte zusätzlich eine pseudomonotone Entladung im Sinne einer neuromuskulären Schädigung nachgewiesen werden. Da anamnestisch eine Erhöhung der Statindosis auf 80 mg täglich vor ca. 6 Monaten zu eruieren war, wurde die Diagnose einer Simvastatin-induzierten Myopathie mit Rhabdomyolyse gestellt. Therapie und Verlauf Nach Absetzen der Statin-Therapie und unter Flüssigkeitssubstitution zeigten sich sowohl die Laborwerte als auch die klinische Symptomatik deutlich rückläufig. Folgerung Bei unklarer neurologischer Symptomatik unter Statin-Therapie sollte an eine Statin-induzierte Myopathie gedacht und ggf. die Therapie beendet werden.

Background Adolescent-onset depression often results in a chronic and recurrent course, and is associated with worse outcomes relative to adult-onset depression. Targeting habitual depressive rumination, a specific known risk factor for relapse, may improve clinical outcomes for adolescents who have experienced a depressive episode. Randomized controlled trials (RCTs) thus far have demonstrated that rumination-focused cognitive behavioral therapy (RFCBT) reduces depressive symptoms and relapse rates in patients with residual depression and adolescents and young adults with elevated rumination. This was also observed in a pilot RCT of adolescents at risk for depressive relapse. Rumination can be measured at the self-report, behavioral, and neural levels- using patterns of connectivity between the Default Mode Network (DMN) and Cognitive Control Network (CCN). Disrupted connectivity is a putative important mechanism for understanding reduced rumination via RFCBT. A feasibility trial in adolescents found that reductions in connectivity between DMN and CCN regions following RFCBT were correlated with change in rumination and depressive symptoms. Method This is a phase III two-arm, two-stage, RCT of depression prevention. The trial tests whether RFCBT reduces identified risk factors for depressive relapse (rumination, patterns of neural connectivity, and depressive symptoms) in adolescents with partially or fully remitted depression and elevated rumination. In the first stage, RFCBT is compared to treatment as usual within the community. In the second stage, the comparator condition is relaxation therapy. Primary outcomes will be (a) reductions in depressive rumination, assessed using the Rumination Response Scale, and (b) reductions in resting state functional magnetic resonance imaging connectivity of DMN (posterior cingulate cortex) to CCN (inferior frontal gyrus), at 16 weeks post-randomization. Secondary outcomes include change in symptoms of depression following treatment, recurrence of depression over 12 months post-intervention period, and whether engagement with therapy homework (as a dose measure) is related to changes in the primary outcomes. Discussion RFCBT will be evaluated as a putative preventive therapy to reduce the risk of depressive relapse in adolescents, and influence the identified self-report, behavioral, and neural mechanisms of change. Understanding mechanisms that underlie change in rumination is necessary to improve and further disseminate preventive interventions. Trial registration ClinicalTrials.gov Identifier: NCT03859297, registered 01 March 2019.

One of the most important geriatric syndromes is dizziness in conjunction with gait disorder and consequent falls. There are various differential diagnoses for dizziness, one of them is benign paroxysmal positional vertigo (BPPV).A targeted diagnostic work-up and treatment of BPPV can prevent subsequent falls and a decline in the patients' quality of life, prolonged hospitalization with unnecessary examinations and medication.Prospective examination of patients with a positive medical history of BPPV.All patients treated within the Department of Geriatrics between 05/2015 and 03/2018 were included. A total of n = 5166 patients were screened (n = 2651 geriatrics; n = 2515 controls).All patients from other wards subjected to a neurological examination due to vertigo served as controls. Patients with typical hints in the medical history for a BPPV were subjected to the diagnostic Dix-Hallpike maneuver and, if positive, subsequent canalith repositioning maneuvers. The percentage of successful positional treatments was determined in both groups.N = 254 patients (4.9 %) had indications in the medical history for a BPPV. For 71 of n = 254 patients (28 %; in total 1.4 %; mean age: 78.4 ± 12.3 years) the diagnosis of BPPV was proven by a positive Dix-Hallpike maneuver. N = 39 (54.9 %) patients belong to the geriatric group (mean age 82 years) and n = 32 (45.1 %) to the control group (mean age 73.9 years). The frequency of BPPV was similar in both groups (1.3-1.5 %). In 91.9 % of patients the BPPV was localized in the posterior semicircular canal. Up to 93 % were asymptomatic after one or repeated canalith repositioning maneuvers.The BPPV should be considered as an important differential diagnosis for geriatric patients with dizziness and falls. After therapeutic repositioning maneuvers most of the patients are asymptomatic. Therefore, targeted screening and therapy ("theragnostic") of BPPV at an advanced age increases diagnostic accuracy and prevents unnecessary examinations, medications and future falls.

The real-world performance of a home telemonitoring strategy (ForeseeHome AMD Monitoring System®, Notal Vision, Inc.,Manassas VA, USA) was evaluated and compared to the device arm of the AREDS2-HOME study among patients with intermediate AMD (iAMD) who converted to neovascular AMD (nAMD). All patients with confirmed conversion to nAMD who used the home monitoring system from 10/2009 through 9/2018 were identified by Notal Vision Diagnostic Clinic’s medical records. Selected outcome variables were evaluated, including visual acuity (VA) at baseline and at conversion, and change in visual acuity (VA) from baseline to time of conversion. In total, 8991 patients performed 3,200,999 tests at a frequency of 5.6 ± 3.2 times/week. The 306 eyes that converted from iAMD to nAMD over the study period (a 2.7% annual rate) were included in the analyses. There was a median (interquartile range) change of −3.0 (0.0–(−10.0)) letters among converted eyes, 81% [95% confidence interval (72–88%)] maintained a VA ≥ 20/40 at the time of conversion, while 69% of the conversion detections were triggered by system alerts. The real-world performance of an at-home testing strategy was similar to that reported for the device arm of the AREDS2-HOME study. The home telemonitoring system can markedly increase early detection of conversion to nAMD.

Predominantly the older population is affected by a severe course of COVID-19. The mortality of hospitalized patients with COVID-19 above the age of 80 years is up to 54% in international studies. These observations indicate the necessity to highlight the geriatric perspective on this disease. The diagnostics and treatment of COVID-19 do not differ between younger and older patients but atypical symptoms should be expected more frequently in old age. Older subjects show an increased need for rehabilitation after COVID-19. Paradoxically, increasing rehabilitation demands go along with a reduced availability of geriatric rehabilitation options, the latter being a consequence of closure or downsizing of rehabilitation departments during the pandemic. In general, measures of isolation and quarantine should be diligently balanced as the health and emotional consequences of such measures may be severe in older persons. In light of the poor prognosis of older COVID-19 patients, advanced care planning becomes even more relevant. Caregivers and physicians should be encouraged to compose advanced care directives that also reflect the specific circumstances of COVID-19. Fortunately, current data suggest that the effectiveness of the vaccination with the mRNA-vaccines approved in Germany may be equally high in older compared to younger persons.Schwerwiegend verlaufende COVID-19-Erkrankungen betreffen vorwiegend die ältere Bevölkerung. Die Mortalität der hospitalisierten COVID-19-Patienten im Alter über 80 Jahre liegt international bei bis zu 54 %. Daher ist ein Blick auf die Erkrankung aus geriatrischer Perspektive erforderlich. Diagnostik und Therapie der COVID-19-Erkrankung unterscheiden sich bei den älteren Patienten nicht grundsätzlich von der bei jüngeren Patienten. Allerdings ist bei Patienten im hohen Alter gehäuft mit einer atypischen Symptomatik zu rechnen. Der Rehabilitationsbedarf nach durchgemachter Infektion ist bei älteren COVID-19-Patienten deutlich höher als bei jüngeren Patienten. Paradoxerweise steht der Notwendigkeit vermehrter Rehabilitationsleistungen jedoch ein sinkendes Angebot geriatrischer Rehabilitationsmöglichkeiten gegenüber, da viele Abteilungen entweder geschlossen oder deren Behandlungskapazitäten reduziert wurden. Generell sollten Quarantäne- und Isolationsmaßnahmen in der älteren Bevölkerung verstärkt auf ihre Verhältnismäßigkeit überprüft werden, da die gesundheitlichen und emotionalen Auswirkungen gravierend sein können. Angesichts der ungünstigen Prognose bei hochaltrigen COVID-19-Patienten kommt der Berücksichtigung des Patientenwillens eine besondere Bedeutung zu. Daher sollten Angehörige und Ärzte sich frühzeitig, d. h. möglichst bereits vor dem Auftreten einer Infektion, bemühen, diesen zu eruieren und angemessen zu dokumentieren. Erfreulicherweise lassen die bisherigen Daten hoffen, dass die Impfung mit den in Deutschland zugelassenen mRNA-Impfstoffen gegen SARS-CoV‑2 auch im hohen Alter gut wirksam ist.

Immune cells have been implicated in influencing stroke outcomes depending on their temporal dynamics, number, and spatial distribution after ischemia. Depending on their activation status, immune cells can have detrimental and beneficial properties on tissue outcome after stroke, highlighting the need to modulate inflammation towards beneficial and restorative immune responses. Novel dietary therapies may promote modulation of pro- and anti-inflammatory immune cell functions. Among the dietary interventions inspired by the Mediterranean diet, hydroxytyrosol (HT), the main phenolic component of the extra virgin olive oil (EVOO), has been suggested to have antioxidant and anti-inflammatory properties in vitro. However, immunomodulatory effects of HT have not yet been studied in vivo after stroke. The aim of this project is therefore to monitor the therapeutic effect of a HT-enriched diet in an experimental stroke model using non-invasive in vivo multimodal imaging, behavioural phenotyping and cross-correlation with ex vivo parameters. Methods: A total of N = 22 male C57BL/6 mice were fed with either a standard chow (n = 11) or a HT enriched diet (n = 11) for 35 days, following a 30 min transient middle cerebral artery occlusion (tMCAo). T2-weighted (lesion) and perfusion (cerebral blood flow)-/diffusion (cellular density)-weighted MR images were acquired at days 1, 3, 7, 14, 21 and 30 post ischemia. [18F]DPA-714 (TSPO, neuroinflammation marker) PET-CT scans were acquired at days 7, 14, 21 and 30 post ischemia. Infarct volume (mm3), cerebral blood flow (mL/100g/min), apparent diffusion coefficient (10-4·mm2/s) and percentage of injected tracer dose (%ID/mL) were assessed. Behavioural tests (grip test, rotarod, open field, pole test) were performed prior and after ischemia to access therapy effects on sensorimotor functions. Ex vivo analyses (IHC, IF, WB) were performed to quantify TSPO expression, immune cells including microglia/macrophages (Iba-1, F4/80), astrocytes (GFAP) and peripheral markers in serum such as thiobarbituric acid reactive substances (TBARS) and nitric oxide (NO) 35 days post ischemia. Additionally, gene expression of pro- and anti-inflammatory markers were assessed by rt-qPCR, including tspo, cd163, arg1, tnf and Il-1β. Results: No treatment effect was observed on temporal [18F]DPA-714 uptake within the ischemic and contralateral region (two-way RM ANOVA, p = 0.71). Quantification of the percentage of TSPO+ area by immunoreactivity indicated a slight 2-fold increase in TSPO expression within the infarct region in HT-fed mice at day 35 post ischemia (p = 0.011) correlating with a 2-3 fold increase in Iba-1+ cell population expressing CD163 as anti-inflammatory marker (R2 = 0.80). Most of the GFAP+ cells were TSPO-. Only few F4/80+ cells were observed at day 35 post ischemia in both groups. No significant treatment effect was observed on global ADC and CBF within the infarct and the contralateral region over time. Behavioural tests indicated improved strength of the forepaws at day 14 post ischemia (p = 0.031). Conclusion: An HT-enriched diet significantly increased the number of Iba-1+ microglia/macrophages in the post-ischemic area, inducing higher expression of anti-inflammatory markers while no clear-cut effect was observed. Also, HT did not affect recovery of the cerebrovascular parameters, including ADC and CBF. Altogether, our data indicated that a prolonged dietary intervention with HT, as a single component of the Mediterranean diet, induces molecular changes that may improve stroke outcomes. Therefore, we support the use of the Mediterranean diet as a multicomponent therapy approach after stroke.

Eurasian beaver, Castor fiber has been restored to England’s natural fauna following a trial reintroduction located in the country’s southwestern region. Beavers characteristically generate profound and frequently beneficial shifts to river dynamics, nutrient cycling, biodiversity, and human cultural experience, but can also be associated with unwanted human interactions, impacts and costs. Consequently, an important objective of the trial design was to ensure conservation leadership, monitoring and mitigation for problems such as burrowing, damming and flooding, and damage to valued trees. To understand how these developments are perceived and accepted, implicated key stakeholder mental models were elicited and explored, using fuzzy cognitive map techniques. Analysis showed broad alignment of ecological understanding between stakeholders. Social perspectives showed marked divergence, a focus of concern as social conflict can undermine otherwise ecologically viable conservation benefits. To investigate perceived effectiveness of trial conservation measures, stakeholder models with and without conservation actions were experimentally compared under dynamic analysis. Overall, the findings indicate that actions taken are sustaining beaver acceptance and limiting persecution. Of stakeholder groups examined, farming appeared most susceptible to model divergence, but also strongly protected by mitigation. This is important as reconciling mental model differences is considered a necessary element in building socio-ecological system resilience. These findings highlight mental model analysis as a valuable aid to assessment of social dimensions of conservation policies. Further, mental modelling could help to focus how farm payment reform in the U.K. and similar economies might be used to support leadership and mitigation designed to improve human-beaver ecosystem resilience.

Simple Summary Meningiomas are most commonly benign intracranial tumors, and surgical resection represents the treatment modality of choice. However, especially for patients of higher age and with increasing comorbidities, brain surgery might be accompanied by the need for postoperative prolonged intensive care, which might impair intended operative benefit. In the present study, we therefore analyzed prolonged mechanical ventilation (PMV) as an indicator variable for such intensive care treatment with regard to potential effects on mortality after meningioma resection in patients aged 70 years and older. We found that patients with postoperative PMV exhibited a profoundly increased probability to die within 1 year after surgery. Based on these findings, we identified risk factors for postoperative PMV occurrence and developed an easy-to-use score which allows us to estimate the risk of PMV occurrence preliminary to the surgical resection. We believe that this score might help to more sufficiently guide patients in the course of risk–benefit assessment and preoperative counseling. Abstract Indication for surgical treatment in patients with intracranial meningioma must include both clinical aspects and an individual risk–benefit stratification, especially in geriatric patients. Prolonged mechanical ventilation (PMV) has not been investigated for its potential effects in patients with meningioma. We therefore analyzed the impact of PMV on mortality in geriatric patients who had undergone meningioma resection. Between 2009 and 2019, 261 patients aged ≥ 70 years were surgically treated for intracranial meningioma at our institution. PMV was defined as postoperative invasive ventilation of >7 days. Postoperative PMV was present in 17 of 261 geriatric meningioma patients (7%). Twenty-five geriatric patients (10%) died within 1 year after surgery. A scoring system (“ACKT”) based on the variables of age, preoperative C-reactive protein (CRP) value, Karnofsky performance scale and tumor size supports prediction of postoperative PMV (sensitivity 73%, specificity 84%). PMV is significantly associated with increased mortality after surgical treatment of meningiomas in geriatric patients. Furthermore, we suggest a novel score (“ACKT”) to preoperatively estimate the risk of PMV occurrence, which might help to guide future risk–benefit assessment and patient counseling in the geriatric meningioma population.

Gliomas are highly dynamic and heterogeneous tumours of the central nervous system (CNS). They constitute the most common neoplasm of the CNS and the second most common cause of death from intracranial disease after stroke. The advances in detailing the genetic profile of paediatric and adult gliomas along with the progress in MRI and PET multimodal molecular imaging technologies have greatly improved prognostic stratification of patients with glioma and informed on treatment decisions. Amino acid PET has already gained broad clinical application in the study of gliomas. PET imaging targeting the translocator protein (TSPO) has recently been applied to decipher the heterogeneity and dynamics of the tumour microenvironment (TME) and its various cellular components especially in view of targeted immune therapies with the goal to delineate pro- and anti-glioma immune cell modulation. The current review provides a comprehensive overview on the historical developments of TSPO PET for gliomas and summarizes the most relevant experimental and clinical data with regard to the assessment and quantification of various cellular components with the TME of gliomas by in vivo TSPO PET imaging.

A tightly regulated innate immune response to trypanosome infections is critical to strike a balance between parasite control and inflammation-associated pathology. In the present study, we make use of the recently established Trypanosoma carassii infection model in larval zebrafish to study the early response of macrophages and neutrophils to trypanosome infections in vivo. We consistently identified high- and low-infected individuals and were able to simultaneously characterize their differential innate response. Not only did macrophage and neutrophil number and distribution differ between the two groups, but also macrophage morphology and activation state. Exclusive to high-infected zebrafish, was the appearance of macrophages rich in lipid droplets, confirmed to be foamy macrophages and characterized by a strong pro-inflammatory profile. Altogether, we provide an in vivo characterization of the differential response of macrophage and neutrophil to trypanosome infection and identify foamy macrophages as potentially associated with an exacerbated immune response and susceptibility to the infection. To our knowledge this is the first report of the occurrence of foamy macrophages during an extracellular trypanosome infection.

A 82-years old woman was admitted with a progressive cognitive decline for further investigations and treatment.In the computed tomography of the brain findings of subcortical artherosclerotic encephalopathy (SAE) were present. Laboratory findings revealed elevated hemoglobin-levels (19.9 g/dl). In further investigations we found a mutation in JAK-2 as diagnostic sign for polycythemia vera (Pv). After specific treatment of the Pv cognition improved significantly.In this case report we were able to relate the progressive cognitive impairment in the context of newly diagnosed Pv in conjunction with pre-existing SAE. After Pv-directed therapy cognition improved. This case report underlines the importance of a good diagnostic work-up of patients with cognitive impairment to rule out secondary and possible treatable causes.Es erfolgt die Aufnahme einer 82-jährigen Patientin zur weiteren Abklärung zunehmender kognitiver Defizite und Gangunsicherheit.In der durchgeführten Computertomografie des Kopfes zeigten sich die Zeichen einer fortgeschrittenen subkortikalen arteriosklerotischen Enzephalopathie (SAE). Laborchemisch fiel ein erhöhter Hämoglobinwert von 19,9 g/dl auf. Bei zusätzlicher Mutation in der JAK-2-Analyse wurde die Diagnose einer Polycythämia vera (Pv) gestellt. Nach Aderlass-Therapie zeigte sich eine Verbesserung der Kognition.Die progredienten kognitiven Defizite sind bei vorbestehender SAE im Zusammenhang mit der neu diagnostizierten Pv zu sehen. Nach entsprechender Therapie der Pv ist auch langfristig eine Besserung der Kognition zu beobachten, sodass in diesem Fallbericht die Wichtigkeit einer Abklärung sekundärer, potenziell behandelbarer Ursachen von kognitiven Defiziten hervorgehoben wird.

Background Antibodies to the aquaporin-4 (AQP4) water channel in neuromyelitis optica spectrum disorder (NMOSD) are reported to trigger the complement cascade, which is implicated in astrocyte damage and subsequent neuronal injury. The PREVENT study demonstrated that the terminal complement inhibitor eculizumab reduces adjudicated relapse risk in patients with anti-AQP4 immunoglobulin G-positive (AQP4+) NMOSD. The objective of this analysis was to evaluate the efficacy of eculizumab in reducing relapse risk and its safety in AQP4+ NMOSD across clinically relevant subgroups in PREVENT. Methods In the randomized, double-blind, time-to-event, phase 3 PREVENT trial, 143 adults received eculizumab (maintenance dose, 1200 mg/2 weeks) or placebo (2:1), with stable-dose concomitant immunosuppressive therapy (IST) permitted (except rituximab and mitoxantrone). Post hoc analyses of relapses and adverse events were performed for prespecified and post hoc subgroups based on concomitant IST and prior rituximab use, demographic and disease characteristics, and autoimmune comorbidity. Results The significant reduction in relapse risk observed for eculizumab versus placebo in the overall PREVENT population was consistently maintained across subgroups based on concomitant IST and previous rituximab use, age, sex, region, race, time since clinical onset of NMOSD, historical annualized relapse rate, baseline Expanded Disability Status Scale score, and history of another autoimmune disorder. The serious infection rate was lower with eculizumab than placebo regardless of rituximab use in the previous year, concomitant IST use, or history of another autoimmune disorder. Conclusion Across a wide range of clinically relevant AQP4+ NMOSD patient subgroups in PREVENT, eculizumab therapy was consistently effective versus placebo in reducing relapse risk, with no apparent increase in serious infection rate. Trial registration NCT01892345 (ClinicalTrials.gov).

Metachromatic leukodystrophy (MLD) is an autosomal recessively inherited sulfatide storage disease caused by deficient activity of the lysosomal enzyme arylsulfatase A (ASA). Genetic analysis of the ARSA gene is important in MLD diagnosis and screening of family members. In addition, more information on genotype prevalence will help interpreting MLD population differences between countries. In this study, we identified 31 different ARSA variants in the patient cohort (n = 67) of the Dutch expertise center for MLD. The most frequently found variant, c.1283C > T, p.(Pro428Leu), was present in 43 (64%) patients and resulted in a high prevalence of the juvenile MLD type (58%) in The Netherlands. Furthermore, we observed in five out of six patients with a non-Caucasian ethnic background previously unreported pathogenic ARSA variants. In total, we report ten novel variants including four missense, two nonsense, and two frameshift variants and one in-frame indel, which were all predicted to be disease causing in silico. In addition, one silent variant was found, c.1200C > T, that most likely resulted in erroneous exonic splicing, including partial skipping of exon 7. The c.1200C > T variant was inherited in cis with the pseudodeficiency allele c.1055A > G, p.(Asn352Ser) + ∗96A > G. With this study we provide a genetic base of the unique MLD phenotype distribution in The Netherlands. In addition, our study demonstrated the importance of genetic analysis in MLD diagnosis and the increased likelihood of unreported, pathogenic ARSA variants in patients with non-Caucasian ethnic backgrounds. Electronic supplementary material The online version of this article (10.1007/s10048-020-00621-6) contains supplementary material, which is available to authorized users.

Inflammation is a highly dynamic and complex adaptive process to preserve and restore tissue homeostasis in neurological disorders and often serves as a prognostic marker for disease outcome. The underlying cellular and factorial heterogeneity represents an opportunity in the development of disease-modifying therapies. Molecular imaging of neuroinflammation (NI) may support the characterization of key aspects of the dynamic interplay of various inducers, sensors, transducers, and effectors of the multifactorial inflammatory response in vivo in animal models and patients. The characterization of the NI response by molecular imaging will (i) support early diagnosis and disease follow-up, (ii) guide (stereotactic) biopsy sampling, (iii) highlight the dynamic changes during disease pathogenesis in a noninvasive manner, (iv) help monitoring existing therapies, (v) support the development of novel NI-modifying therapies, and (vi) aid stratification of patients, according to their individual NI profile. This book chapter will review the basic principles of NI, recent developments and applications of novel molecular imaging targets, key considerations for the selection and development of imaging targets, as well as examples of successful clinical translation of NI imaging.