Search

Metachromatic leukodystrophy is a lethal metabolic leukodystrophy, with emerging treatments for early disease stages. Biomarkers to measure disease activity are required for clinical assessment and treatment follow-up. This retrospective study compared neurofilament light chain and glial fibrillary acidic protein (GFAP) levels in CSF (n = 11) and blood (n = 92) samples of 40 patients with metachromatic leukodystrophy (aged 0–42 years) with 38 neurologically healthy children (aged 0–17 years) and 38 healthy adults (aged 18–45 years), and analysed the associations between these levels with clinical phenotype and disease evolution in untreated and transplanted patients. Metachromatic leukodystrophy subtype was determined based on the (expected) age of symptom onset. Disease activity was assessed by measuring gross motor function deterioration and brain MRI. Longitudinal analyses with measurements up to 23 years after diagnosis were performed using linear mixed models. CSF and blood neurofilament light chain and GFAP levels in paediatric controls were negatively associated with age (all P < 0.001). Blood neurofilament light chain level at diagnosis (median, interquartile range; picograms per millilitre) was significantly increased in both presymptomatic (14.7, 10.6–56.7) and symptomatic patients (136, 40.8–445) compared to controls (5.6, 4.5–7.1), and highest among patients with late-infantile (456, 201–854) or early-juvenile metachromatic leukodystrophy (291.0, 104–445) and those ineligible for treatment based on best practice (291, 57.4–472). GFAP level (median, interquartile range; picogram per millilitre) was only increased in symptomatic patients (591, 224–1150) compared to controls (119, 78.2–338) and not significantly associated with treatment eligibility (P = 0.093). Higher blood neurofilament light chain and GFAP levels at diagnosis were associated with rapid disease progression in late-infantile (P = 0.006 and P = 0.051, respectively) and early-juvenile patients (P = 0.048 and P = 0.039, respectively). Finally, blood neurofilament light chain and GFAP levels decreased during follow-up in untreated and transplanted patients but remained elevated compared with controls. Only neurofilament light chain levels were associated with MRI deterioration (P < 0.001). This study indicates that both proteins may be considered as non-invasive biomarkers for clinical phenotype and disease stage at clinical assessment, and that neurofilament light chain might enable neurologists to make better informed treatment decisions. In addition, neurofilament light chain holds promise assessing treatment response. Importantly, both biomarkers require paediatric reference values, given that their levels first decrease before increasing with advancing age.

In a Dutch non-consanguineous patient having mitochondrial encephalomyopathy with complex I and complex IV deficiency, whole exome sequencing revealed two compound heterozygous variants in SLIRP. SLIRP gene encodes a stem-loop RNA-binding protein that regulates mitochondrial RNA expression and oxidative phosphorylation (OXPHOS). A frameshift and a deep-intronic splicing variant reduced the amount of functional wild-type SLIRP RNA to 5%. Consequently, in patient fibroblasts, MT-ND1, MT-ND6, and MT-CO1 expression was reduced. Lentiviral transduction of wild-type SLIRP cDNA in patient fibroblasts increased MT-ND1, MT-ND6, and MT-CO1 expression (2.5–7.2-fold), whereas mutant cDNAs did not. A fourfold decrease of citrate synthase versus total protein ratio in patient fibroblasts indicated that the resulting reduced mitochondrial mass caused the OXPHOS deficiency. Transduction with wild-type SLIRP cDNA led to a 2.4-fold increase of this ratio and partly restored OXPHOS activity. This confirmed causality of the SLIRP variants. In conclusion, we report SLIRP variants as a novel cause of mitochondrial encephalomyopathy with OXPHOS deficiency.

Recently, new approaches to wildlife management are being developed, such as coexistence management and convivial conservation. These approaches aim to shift management practices from mitigating human–wildlife conflicts towards cohabitation and explore mutual benefits. To align empirical research to these new approaches, we argue for the relevance of positive psychology theory to inspire and structure research into the benefits of human–wildlife interactions. Positive psychology suggests three pathways through which human–wildlife interactions may lead to happiness and well-being: pleasure, engagement, and meaning. Applying these pathways to human–wildlife research may (i) structure existing research into the benefits of human–wildlife interactions, (ii) disclose unidentified benefits of human–wildlife interactions, and (iii) unravel mechanisms which make experiencing and protecting wildlife worthwhile and rewarding. Also, we suggest a potential feedback loop between wildlife experiences, happiness and well-being, and pro-environmental behaviours. More in-depth research into these mechanisms may improve our understanding of attitudes towards conservation of wildlife and its habitat and may suggest strategies to strengthen stewardship actions and public support for conservation strategies. Together, these strands of research could initiate research into what could be called a “Positive Ecology”.

Rationale: The heterogeneous nature of gliomas makes the development and application of novel treatments challenging. In particular, infiltrating myeloid cells play a role in tumor progression and therapy resistance. Hence, a detailed understanding of the dynamic interplay of tumor cells and immune cells in vivo is necessary. To investigate the complex interaction between tumor progression and therapy-induced changes in the myeloid immune component of the tumor microenvironment, we used a combination of [18F]FET (amino acid metabolism) and [18F]DPA-714 (TSPO, GAMMs, tumor cells, astrocytes, endothelial cells) PET/MRI together with immune-phenotyping. The aim of the study was to monitor temozolomide (TMZ) treatment response and therapy-induced changes in the inflammatory tumor microenvironment (TME). Methods: Eighteen NMRInu/nu mice orthotopically implanted with Gli36dEGFR cells underwent MRI and PET/CT scans before and after treatment with TMZ or DMSO (vehicle). Tumor-to-background (striatum) uptake ratios were calculated and areas of unique tracer uptake (FET vs. DPA) were determined using an atlas-based volumetric approach. Results: TMZ therapy significantly modified the spatial distribution and uptake of both tracers. [18F]FET uptake was significantly reduced after therapy (-53 ± 84%) accompanied by a significant decrease of tumor volume (-17 ± 6%). In contrast, a significant increase (61 ± 33%) of [18F]DPA-714 uptake was detected by TSPO imaging in specific areas of the tumor. Immunohistochemistry (IHC) validated the reduction in tumor volumes and further revealed the presence of reactive TSPO-expressing glioma-associated microglia/macrophages (GAMMs) in the TME. Conclusion: We confirm the efficiency of [18F]FET-PET for monitoring TMZ-treatment response and demonstrate that in vivo TSPO-PET performed with [18F]DPA-714 can be used to identify specific reactive areas of myeloid cell infiltration in the TME.

The introduction of gas warfare in World War One was impactful, as it both expanded the breadth of warfare and fueled the invention of techniques required to treat these new injuries. Gas injuries were responsible for 91,000 of 1.3 million deaths in World War One. Gassed soldiers had wounds which the world had never seen. They presented in large scale to medical tents and base hospitals across Europe. As gas casualties poured in, doctors and nurses had to treat these conditions in the best way they knew. Gas warfare changed how war was performed and how casualties of this attack were treated. The techniques learned from treating the multitudes of men with gas burns led to advances in the field of burn care, which have helped to improve mortality and reduce morbidity in hospitals across the world.

To evaluate medication-related risks in older patients with cancer and their association with severe toxicity during antineoplastic therapy.This is a secondary analysis of two prospective, single-center observational studies which included patients ≥ 70 years with cancer. The patients' medication lists were investigated regarding possible risks: polymedication (defined as the use of ≥ 5 drugs), potentially inappropriate medication (PIM), and relevant potential drug-drug interactions (rPDDI). The risks were analyzed before and after start of cancer therapy. Severe toxicity during antineoplastic therapy was captured from medical records according to the Common Terminology Criteria for Adverse Events (CTCAE). The association between grade ≥ 3 toxicity and medication risks was evaluated by univariate as well as multivariate regression adjusted by ECOG and age.The study cohort comprised 136 patients (50% female, mean age 77 years, 42% hematological malignancies). Before the start of cancer therapy, patients took on average 5 drugs as long-term medication and 52% of patients were exposed to polymedication. More than half of patients used at least one PIM. Approximately one third of patients exhibited rPDDI. The prevalence of medication risks increased after start of cancer therapy. rPDDI were significantly associated with severe overall toxicity (OR, 5.07; p = 0.036; 95% Confidence Interval (CI) 1.11-23.14; toxicity in patients with rPDDI 94.1% (32/34) vs 75.9% (60/79) in patients without rPDDI) and hematological toxicity (OR, 3.95; p = 0.010; 95% CI 1.38-11.29; hematological toxicity in patients with rPDDI 85.3% (29/34) vs 59.5% (47/79) in patients without rPDDI). In the multivariate analysis adjusted by ECOG and age, only the association for rPDDI with hematological toxicity remained statistically significant (OR, 4.51; p = 0.007; 95% CI 1.52-13.38). These findings should be further investigated in larger studies.Medication risks are common in older patients with cancer and might be associated with toxicity. This raises the need for tailored interventions to ensure medication safety in this patient cohort.

In the following case report, we describe a patient with acute renal failure due to an urinary congestion level II-III under BCG-(Bacillus Calmette-Guérin)-therapy because of bladder cancer. Cystoscopy revealed the diagnosis of BCG-induced intramural narrowing of distal ureters bilaterally. After receiving a double-J-catheter the renal function returned to normal. Although postrenal failure is relatively rare (5 %), also seldom causes such as medication-induced (e. g. BCG) ureter stenosis has to be included into the differential diagnosis. Der folgende Case Report berichtet über die Aufnahme eines Patienten mit einem akut auf chronischen Nierenversagen unter BCG-(Bacillus-Calmette-Guérin)-Erhaltungstherapie bei bekanntem Blasenkarzinom mit sonografisch dargestelltem Harnstau II.–III. Grades ohne Restharn. Die zystoskopisch nachweisbare beidseitige intramurale Engstelle kann im Rahmen der BCG-Therapie gedeutet werden. Es folgte die Anlage einer Doppel-J-Schiene, worunter sich die Nierenretentions-Parameter schnell besserten. Ein postrenales Nierenversagen ist mit 5 % eher selten, wobei in der differenzialdiagnostischen Überlegung neben anderen Ursachen auch eine medikamentös-induzierte Ursache (z. B. BCG) einzubeziehen ist.

Geriatric medicine is a rapidly evolving field that addresses diagnostic, therapeutic and care aspects of older adults. Some disabilities and disorders affecting cognition (e.g. dementia), motor function (e.g. stroke, Parkinson’s disease, neuropathies), mood (e.g. depression), behavior (e.g. delirium) and chronic pain disorders are particularly frequent in old subjects. As knowledge about these age-associated conditions and disabilities is steadily increasing, the integral implementation of neurogeriatric knowledge in geriatric medicine and specific neurogeriatric research is essential to develop the field. This article discusses how neurological know-how could be integrated in academic geriatric medicine to improve care of neurogeriatric patients, to foster neurogeriatric research and training concepts and to provide innovative care concepts for geriatric patients with predominant neurological conditions and disabilities.

The sigma 1 receptor (S1R) is widely expressed in the CNS and is mainly located on the endoplasmic reticulum. The S1R is involved in the regulation of many neurotransmission systems and, indirectly, in neurodegenerative diseases. The S1R may therefore represent an interesting neuronal biomarker in neurodegenerative diseases such as Parkinson's (PD) or Alzheimer's diseases (AD). Here we present the characterisation of the S1R-specific 18F-labelled tracer 18F-IAM6067 in two animal models and in human brain tissue. Methods: Wistar rats were used for PET-CT imaging (60 min dynamic acquisition) and metabolite analysis (1, 2, 5, 10, 20, 60 min post-injection). To verify in vivo selectivity, haloperidol, BD1047 (S1R ligand), CM398 (S2R ligand) and SB206553 (5HT2B/C antagonist) were administrated for pre-saturation studies. Excitotoxic lesions induced by intra-striatal injection of AMPA were also imaged by 18F-IAM6067 PET-CT to test the sensitivity of the methods in a well-established model of neuronal loss. Tracer brain uptake was also verified by autoradiography in rats and in a mouse model of PD (intrastriatal 6-hydroxydopamine (6-OHDA) unilateral lesion). Finally, human cortical binding was investigated by autoradiography in three groups of subjects (control subjects with Braak ≤2, and AD patients, Braak >2 & ≤4 and Braak >4 stages). Results: We demonstrate that despite rapid peripheral metabolism of 18F-IAM6067, radiolabelled metabolites were hardly detected in brain samples. Brain uptake of 18F-IAM6067 showed differences in S1R anatomical distribution, namely from high to low uptake: pons-raphe, thalamus medio-dorsal, substantia nigra, hypothalamus, cerebellum, cortical areas and striatum. Pre-saturation studies showed 79-90% blockade of the binding in all areas of the brain indicated above except with the 5HT2B/C antagonist SB206553 and S2R ligand CM398 which induced no significant blockade, indicating good specificity of 18F-IAM6067 for S1Rs. No difference between ipsi- and contralateral sides of the brain in the mouse model of PD was detected. AMPA lesion induced a significant 69% decrease in 18F-IAM6067 uptake in the globus pallidus matching the neuronal loss as measured by NeuN, but only a trend to decrease (-16%) in the caudate putamen despite a significant 91% decrease in neuronal count. Moreover, no difference in the human cortical binding was shown between AD groups and controls. Conclusion: This work shows that 18F-IAM6067 is a specific and selective S1R radiotracer. The absence or small changes in S1R detected here in animal models and human tissue warrants further investigations and suggests that S1R might not be the anticipated ideal biomarker for neuronal loss in neurodegenerative diseases such as AD and PD.

To evaluate long-term visual acuity (VA) and performance of a monitoring strategy with a self-operated artificial-intelligence-enabled home monitoring system in conjunction with standard care for early detection of neovascular age-related macular degeneration (nAMD).Retrospective review.Patients with dry-age-related macular degeneration from 5 referral clinics.Clinical data of patients monitored with ForeseeHome (FSH) device from August 2010 to July 2020 were reviewed.Visual acuity at baseline, VA at diagnosis of nAMD for eyes that converted while monitored, and VA from the final study follow-up, weekly frequency of use, duration of monitoring, modality of conversion diagnosis (system alert vs. detection by other standard care means), and duration and number of treatments since conversion to final study follow-up were collected.We reviewed 3334 eyes of 2123 patients with a mean (standard deviation [SD]) age of 74(8) years, monitored for a mean (SD) duration of 3.1 (2.4) years, with a total of 1 706 433 tests in 10 474 eye-monitoring years. The mean (SD) weekly use per patient was 5.2 (3.4), and it was persistent over the usage period. Two hundred eighty-five eyes converted while monitored at an annual rate of 2.72% and were treated with a mean (SD) 17.3 (16.5) injections over a mean (SD) 2.7 (2.0) years, with 6.4 (3.1) injections per year for eyes treated for1 year. The median VAs at baseline and at final follow-up for eyes that did not convert were 20/27 and 20/34 with a median change of 0.0 letters. The median VAs at baseline, conversion, and final follow-up for eyes that converted during the monitoring period were 20/30, 20/39, and 20/32 with a median change from baseline to conversion, baseline to recent, and conversion to recent of -4, -4, and 0 letters, respectively. Fifty-two percent of conversions detected had a system alert before conversion. Forty-eight percent of patients were detected by symptoms or routine visit. Patients experienced a non-nAMD alert on average every 4.6 years. At conversion and at final follow-up, the proportion (95% CI) of eyes that maintained ≥ 20/40 was 84% (78% to 88%) and 82% (76% to 86%), respectively.Patients in the FSH monitoring program showed excellent long-term VA years after conversion to nAMD.

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.

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.

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 [

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.

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.

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.

Background Neuronal ceroid lipofuscinosis type 2 (CLN2 disease) is a rare rapidly progressive neurodegenerative disorder, resulting in early death. Intracerebroventricular enzyme replacement therapy (ERT) with cerliponase alfa is now available and has shown to delay disease progression in symptomatic patients. It is yet unknown if cerliponase alfa can prevent disease onset in presymptomatic patients. Results We evaluated the effect of 2 years of intracerebroventricular ERT in two siblings with CLN2 disease, one symptomatic (age 47 months) and one presymptomatic (age 23 months) at treatment start, using the CLN2 Clinical Rating Scale (CLN2 CRS), Gross Motor Function Measure-66 (GMFM-66) for motor function, Bayley Scales of Infant and Toddler Development, 3rd Edition, Dutch (BSID-III-NL) for neurocognitive development, brain MRI, and visual evoked potentials (VEP), electroretinogram (ERG) and retinoscopy for visual function. On the CLN2 CRS patient 1 showed a decline from 3 to 2 in the combined motor and language score due to regression in language use (CLN2 CRS total score after 2 years of treatment: 8), whereas a decline of 2 or more points in the combined motor and language score would be expected without treatment. Patient 2 retained the maximum score of 3 in all 4 subdomains (CLN2 CRS total score after 2 years of treatment: 12). The GMFM-66 total score declined from 46 to 39 in patient 1 and showed an age-appropriate increase from 66 to 84 in patient 2. Cognitive-developmental age decreased from 24 to 11 months in patient 1, whereas an increase in cognitive-developmental age from 21 to 39 months was seen in patient 2. Cerebral and cerebellar atrophy observed on MRI in patient 1 at age 42 months (before treatment) was not observed in patient 2 at age 48 months (after 2 years of treatment). Conclusion We show that cerliponase alfa is able to delay the onset of symptoms when treatment is started in a presymptomatic stage of CLN2 disease. Our results advocate the start of treatment at an early age before symptom onset, but should be confirmed in a larger cohort study.

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.

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 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.

Object Increasing age is a known negative prognostic factor for glioblastoma. However, a multifactorial approach is necessary to achieve optimal neuro-oncological treatment. It remains unclear to what extent frailty, comorbidity burden, and obesity might exert influence on survival in geriatric glioblastoma patients. We have therefore reviewed our institutional database to assess the prognostic value of these factors in elderly glioblastoma patients. Methods Between 2012 and 2018, patients aged ≥ 65 years with newly diagnosed glioblastoma were included in this retrospective analysis. Patients frailty was analyzed using the modified frailty index (mFI), while patients comorbidity burden was assessed according to the Charlson comorbidity index (CCI). Body mass index (BMI) was used as categorized variable. Results A total of 110 geriatric patients with newly diagnosed glioblastoma were identified. Geriatric patients categorized as least-frail achieved a median overall survival (mOS) of 17 months, whereas most frail patients achieved a mOS of 8 months (p = 0.003). Patients with a CCI > 2 had a lower mOS of 6 months compared to patients with a lower comorbidity burden (12 months; p = 0.03). Multivariate analysis identified “subtotal resection” (p = 0.02), “unmethylated MGMT promoter status” (p = 0.03), “BMI 2 0.31). Conclusions The present study concludes that both increased frailty and comorbidity burden are significantly associated with poor OS in geriatric patients with glioblastoma. Further, the present series suggests an obesity paradox in geriatric glioblastoma patients.

Neurological disorders can occur before the diagnosis of a malignoma is set. These disorders are induced by a misguided immune response with antibodies against intracellular or cell surface antigens. One of the most common paraneoplastic diseases is the subacute degeneration of the cerebellum. In most of the cases antibodies against Anti Hu, CRMP5/CV2, Amphiphysin and Ma/Ta are found and small cell bronchial carcinoma, breast cancer and lymphoma are diagnosed. We report about a 67 years old man with cerebellar symptoms and a weight loss of 10 kg who was treated in our clinic. After our diagnostic work up we found a non small cell cancer and diagnosed a subacute degeneration of the cerebellum as a paraneoplastic disorder. We found a high positive titer for Anti-Tr3 antibodies while the rest of the paraneoplastic antibodies described as typically associated with the subacute degeneration of the cerebellum were negative. The Anti-Tr3 antibodies are usually found in patients with Hodgkin and less often Non-Hodgkin disease. After initiation of a tumor specific therapy and intravenous immunoglobulin therapy the cerebellar symptoms decreased. In future follow up examinations we will see if the anti-Tr3 antibodies were associated with the non small cell bronchial carcinoma or if a lymphoma will occur in our patient.

Developmental and/or epileptic encephalopathies (DEEs) are a group of devastating genetic disorders, resulting in early-onset, therapy-resistant seizures and developmental delay. Here we report on 22 individuals from 15 families presenting with a severe form of intractable epilepsy, severe developmental delay, progressive microcephaly, visual disturbance and similar minor dysmorphisms. Whole exome sequencing identified a recurrent, homozygous variant (chr2:64083454A > G) in the essential UDP-glucose pyrophosphorylase (UGP2) gene in all probands. This rare variant results in a tolerable Met12Val missense change of the longer UGP2 protein isoform but causes a disruption of the start codon of the shorter isoform, which is predominant in brain. We show that the absence of the shorter isoform leads to a reduction of functional UGP2 enzyme in neural stem cells, leading to altered glycogen metabolism, upregulated unfolded protein response and premature neuronal differentiation, as modeled during pluripotent stem cell differentiation in vitro. In contrast, the complete lack of all UGP2 isoforms leads to differentiation defects in multiple lineages in human cells. Reduced expression of Ugp2a/Ugp2b in vivo in zebrafish mimics visual disturbance and mutant animals show a behavioral phenotype. Our study identifies a recurrent start codon mutation in UGP2 as a cause of a novel autosomal recessive DEE syndrome. Importantly, it also shows that isoform-specific start-loss mutations causing expression loss of a tissue-relevant isoform of an essential protein can cause a genetic disease, even when an organism-wide protein absence is incompatible with life. We provide additional examples where a similar disease mechanism applies. Electronic supplementary material The online version of this article (10.1007/s00401-019-02109-6) contains supplementary material, which is available to authorized users.

The tumour microenvironment (TME) surrounding tumour cells is a highly dynamic and heterogeneous composition of immune cells, fibroblasts, precursor cells, endothelial cells, signalling molecules and extracellular matrix (ECM) components. Due to the heterogeneity and the constant crosstalk between the TME and the tumour cells, the components of the TME are important prognostic parameters in cancer and determine the response to novel immunotherapies. To improve the characterization of the TME, novel non-invasive imaging paradigms targeting the complexity of the TME are urgently needed.The characterization of the TME by molecular imaging will (1) support early diagnosis and disease follow-up, (2) guide (stereotactic) biopsy sampling, (3) highlight the dynamic changes during disease pathogenesis in a non-invasive manner, (4) help monitor existing therapies, (5) support the development of novel TME-targeting therapies and (6) aid stratification of patients, according to the cellular composition of their tumours in correlation to their therapy response.This chapter will summarize the most recent developments and applications of molecular imaging paradigms beyond FDG for the characterization of the dynamic molecular and cellular changes in the TME.

Background Tumor-associated microglia and macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) are potent immunosuppressors in the glioma tumor microenvironment (TME). Their infiltration is associated with tumor grade, progression, and therapy resistance. Specific tools for image-guided analysis of spatiotemporal changes in the immunosuppressive myeloid tumor compartments are missing. We aimed (i) to evaluate the role of fluorodeoxyglucose (18F)DPA-714* (translocator protein [TSPO]) PET-MRI in the assessment of the immunosuppressive TME in glioma patients, and (ii) to cross-correlate imaging findings with in-depth immunophenotyping. Methods To characterize the glioma TME, a mixed collective of 9 glioma patients underwent [18F]DPA-714-PET-MRI in addition to [18F]fluoro-ethyl-tyrosine (FET)-PET-MRI. Image-guided biopsy samples were immunophenotyped by multiparametric flow cytometry and immunohistochemistry. In vitro autoradiography was performed for image validation and assessment of tracer binding specificity. Results We found a strong relationship (r = 0.84, P = 0.009) between the [18F]DPA-714 uptake and the number and activation level of glioma-associated myeloid cells (GAMs). TSPO expression was mainly restricted to human leukocyte antigen D related–positive (HLA-DR+) activated GAMs, particularly to tumor-infiltrating HLA-DR+ MDSCs and TAMs. [18F]DPA-714–positive tissue volumes exceeded [18F]FET-positive volumes and showed a differential spatial distribution. Conclusion [18F]DPA-714-PET may be used to non-invasively image the glioma-associated immunosuppressive TME in vivo. This imaging paradigm may also help to characterize the heterogeneity of the glioma TME with respect to the degree of myeloid cell infiltration at various disease stages. [18F]DPA-714 may also facilitate the development of new image-guided therapies targeting the myeloid-derived TME.

The aim of this systematic review is to describe the epidemiology of chordoma and to provide a clear overview of clinical prognostic factors predicting progression-free and overall survival. Four databases of medical literature were searched. Separate searches were performed for each of the two objectives. Reference and citation tracking was performed. Papers were processed by two independent reviewers according to a protocol that included risk of bias analysis. Disagreement was resolved by discussion. Pooled analyses were planned if homogeneity of data would allow. Incidence—incidence rates ranged between 0.18 and 0.84 per million persons per year and varied between countries and presumably between races. On average patients were diagnosed in their late fifties and gender data indicate clear male predominance. Two of the largest studies (n = 400 and n = 544) reported different anatomical distributions: one reporting the skull base and sacrococcygeal area affected in 32% and 29% of cases, whereas the other reporting that they were affected in 26% and 45% of cases, respectively. Statistically significant adverse prognostic factors predicting progression-free and overall survival include female sex, older age, bigger tumour size, increasing extent of tumour invasion, non-total resection, presence of metastasis, local recurrence, and dedifferentiated histological subtype. Incidence rate and anatomical distribution vary between countries and presumably between races. Most chordomas arise in the skull base and sacrococcygeal spine, and the tumour shows clear male predominance. Multiple adverse prognostic factors predicting progression-free and overall survival were identified in subgroups of patients. These slides can be retrieved under Electronic Supplementary Material.

Microglia are potential targets for therapeutic intervention in neurological and neurodegenerative diseases affecting the central nervous system. In order to assess the efficacy of therapies aimed to reduce the tissue damaging activities of microglia and/or to promote the protective potential of these cells, suitable pre-clinical and clinical tools for the in vivo analysis of microglia activities and dynamics are required. The aim of this work was to identify new translational markers of the anti-inflammatory / protective state of microglia for the development of novel PET tracers. Methods: New translational markers of the anti-inflammatory/protective activation state of microglia were selected by bioinformatic approaches and were in vitro and ex vivo validated by qPCR and immunohistochemistry in rodent and human samples. Once a viable marker was identified, a novel PET tracer was developed. This tracer was subsequently confirmed by autoradiography experiments in murine and human brain tissues. Results: Here we provide evidence that P2RY12 expression increases in murine and human microglia following exposure to anti-inflammatory stimuli, and that its expression is modulated in the reparative phase of experimental and clinical stroke. We then synthesized a novel carbon-11 labeled tracer targeting P2RY12, showing increased binding in brain sections of mice treated with IL4, and low binding to brain sections of a murine stroke model and of a stroke patient. Conclusion: This study provides new translational targets for PET tracers for the anti-inflammatory/protective activation state of microglia and shows the potential of a rationale-based approach. It therefore paves the way for the development of novel non-invasive methodologies aimed to monitor the success of therapeutic approaches in various neurological diseases.

Background Major Depressive Disorder (MDD) is a prevalent, disruptive illness. A majority of those with MDD are at high risk for recurrence and increased risk for morbidity and mortality. This study examined whether multimodal baseline (and retest) Cognitive Control performance and neuroimaging markers (task activation and neural connectivity between key brain nodes) could differentiate between those with and without future recurrence of a major depressive (MD) episode within one year. We hypothesized that performance and neuroimaging measures of Cognitive Control would identify markers that differ between these two groups. Methods A prospective cohort study of young adults (ages 18–23) with history (h) of early-onset MDD (N = 60), now remitted, and healthy young adults (N = 49). Baseline Cognitive Control measures of performance, task fMRI and resting state connectivity (and reliability retest 4–12 weeks later) were used to compare those with future recurrence of MDD (N = 21) relative to those without future recurrence of MDD (N = 34 with resilience). The measures tested were (1) Parametric Go/No-Go (PGNG) performance, and task activation for (2) PGNG Correct Rejections, (3) PGNG Commission errors, and (4 & 5), resting state connectivity analyses of Cognitive Control Network to and from subgenual anterior cingulate. Results Relative to other groups at baseline, the group with MDD Recurrence had less bilateral middle frontal gyrus activation during commission errors. MDD Recurrence exhibited greater connectivity of right middle frontal gyrus to subgenual anterior cingulate (SGAC). SGAC connectivity was also elevated in this group to numerous regions in the Cognitive Control Network. Moderate to strong ICCs were present from test to retest, and highest for rs-fMRI markers. There were modest, significant correlations between task, connectivity and behavioral markers that distinguished between groups. Conclusion Markers of Cognitive Control function could identify those with early course MD who are at risk for depression recurrence. Those at high risk for recurrence would benefit from maintenance or preventative treatments. Future studies could test and validate these markers as potential predictors, accounting for sample selection and bias in feature detection., Graphical abstract Unlabelled Image, Highlights • Tools are needed to increase identification of MDD recurrence • Cognitive control behavior and depression symptoms have been predictive of recurrence in prior studies, but with low accuracy • In remitted Major Depressive Disorder, those who will go on to have future depressive episodes differed in cognitive control activation and connectivity • Symptoms, performance, task activation, and seed-based connectivity can contribute to identification of risk for recurrence

Maternal rumination is a cognitive-affective trait that could influence offspring's ability to respond flexibly to positive and negative events, depending on the quality of maternal problem-solving behaviors with which rumination co-occurs. As reward circuitry is sensitive to stressors and related to risk for depression, reward circuitry is an appropriate candidate mechanism for how maternal characteristics influence offspring. We evaluated the independent and combined effect of maternal rumination and disengagement on adolescent neural response to reward win and loss. Participants were 122 boys and their mothers from low-income, urban backgrounds followed prospectively in a longitudinal study. The combination of high maternal rumination at child age 6 and high maternal disengagement during problem-solving at child age 10–12 was associated with lower anterior cingulate response to winning reward at age 20, but unrelated to neural response to losing reward. Lower anterior cingulate response to winning reward was associated with fewer anxiety symptoms during late adulthood. Findings suggest that maternal rumination occurring within the context of maternal disengagement during challenging experiences may be related to offspring blunted engagement during positive events. Helping highly ruminative mothers to restructure repetitive negative thoughts and to develop context-appropriate problem-solving behaviors may be important for promoting offspring affective development.

Objectives To compare the CARG (Cancer and Aging Research Group) and CRASH (Chemotherapy Risk Assessment Scale for High-Age Patients) score regarding the predictive performance for severe toxicity in older patients with cancer. Methods We recruited patients ≥70 years and applied the CARG and CRASH score before the start of systemic cancer treatment. The CARG predicts severe overall toxicity; the CRASH additionally predicts hematologic and nonhematologic toxicity. We captured ≥ grade 3 toxicity according to Common Terminology Criteria for Adverse Events (CTCAE) from medical records. Predictive performance was assessed using logistic regression and the area under the receiver operating characteristic curve (ROC-AUC). Results The study cohort comprised 120 patients (50% female, mean age 77.2 years, 57% solid tumors). The median of the CARG (range 0–23) and the combined CRASH (range 0–12) were 9 and 8, respectively. 81% of patients experienced toxicity; 67% showed hematologic toxicity. The predictive performance of the CARG and the combined CRASH was similar for overall toxicity (CARG: Odds ratio per unit increase (OR) 1.266, P = .015; ROC-AUC 0.681, P = .010; combined CRASH: OR 1.337, P = .029; ROC-AUC 0.650, P = .032). For hematologic toxicity, the hematologic CRASH was a significant predictor and showed numerically a higher ROC-AUC than the CARG which was not statistically different (CARG: OR 1.048, P = .462; ROC-AUC 0.564, P = .271; hematologic CRASH: OR 1.602, P = .007; ROC-AUC 0.665, P = .005). Conclusion Both scores exhibited similar predictive performance for toxicity in older patients with cancer.

Purpose Primary angiitis of the central nervous system (PACNS) is a heterogeneous, rare, and poorly understood inflammatory disease. We aimed at non-invasive imaging of activated microglia/macrophages in patients with PACNS by PET-MRI targeting the translocator protein (TSPO) with [18F]DPA-714 to potentially assist differential diagnosis, therapy monitoring, and biopsy planning. Methods In total, nine patients with ischemic stroke and diagnosed or suspected PACNS underwent [18F]DPA-714-PET-MRI. Dynamic PET scanning was performed for 60 min after injection of 233 ± 19 MBq [18F]DPA-714, and MRI was simultaneously acquired. Results In two PACNS patients, [18F]DPA-714 uptake patterns exceeded MRI correlates of infarction, whereas uptake was confined to the infarct in four patients where initial suspicion of PACNS could not be confirmed. About three patients with PACNS or cerebral predominant lymphocytic vasculitis showed no or only faintly increased uptake. Short-term [18F]DPA-714-PET follow-up in a patient with PACNS showed reduced lesional [18F]DPA-714 uptake after anti-inflammatory treatment. Biopsy in the same patient pinpointed the source of tracer uptake to TSPO-expressing immune cells. Conclusions [18F]DPA-714-PET imaging may facilitate the diagnosis and treatment monitoring of PACNS. Further studies are needed to fully understand the potential of TSPO-PET in deciphering the heterogeneity of the disease. Electronic supplementary material The online version of this article (10.1007/s00259-019-04662-4) contains supplementary material, which is available to authorized users.

BACKGROUND: Glioblastoma (GBM) is the most devastating brain tumor. Despite the use of multimodal treatments, most patients relapse, often due to the highly invasive nature of gliomas. However, the detection of glioma infiltration remains challenging. The aim of this study was to assess advanced PET and MRI techniques for visualizing biological activity and infiltration of the tumor. METHODS: Using multimodality imaging, we investigated [(18)F]DPA-714, a radiotracer targeting the 18 kDa translocator protein (TSPO), [(18)F]FET PET, non-Gaussian diffusion MRI (apparent diffusion coefficient, kurtosis), and the S-index, a composite diffusion metric, to detect tumor infiltration in a human invasive glioma model. In vivo imaging findings were confirmed by autoradiography and immunofluorescence. RESULTS: Increased tumor-to-contralateral [(18)F]DPA-714 uptake ratios (1.49 ± 0.11) were found starting 7 weeks after glioma cell implantation. TSPO-PET allowed visualization of glioma infiltration into the contralateral hemisphere 2 weeks earlier compared with the clinically relevant biomarker for biological glioma activity [(18)F]FET. Diffusion-weighted imaging (DWI), in particular kurtosis, was more sensitive than standard T2-weighted MRI to detect differences between the glioma-bearing and the contralateral hemisphere at 5 weeks. Immunofluorescence data reflect in vivo findings. Interestingly, labeling for tumoral and stromal TSPO indicates a predominant expression of TSPO by tumor cells. CONCLUSION: These results suggest that advanced PET and MRI methods, such as [(18)F]DPA-714 and DWI, may be superior to standard imaging methods to visualize glioma growth and infiltration at an early stage.

BACKGROUND: Decompression surgery for lumbar spinal stenosis (LSS) is the most common spinal procedure in the elderly. To avoid persisting low back pain, adding arthrodesis has been recommended, especially if there is a coexisting degenerative spondylolisthesis. However, this strategy remains controversial, resulting in practice-based variation.PURPOSE: To evaluate in a pragmatic study if surgical selection criteria and variation in use of arthrodesis in three Scandinavian countries can be linked to variation in treatment effectiveness.STUDY DESIGN: An observational study based on a combined cohort from the national spine registries of Norway, Sweden, and Denmark.PATIENT SAMPLE: Patients aged 50 and higher operated 2011-2013 for LSS were included.OUTCOME MEASURES: Patient-reported outcome measures (PROMs) Oswestry disability index (ODI) (primary outcome), numeric rating scale (NRS) for leg pain and back pain, and health-related quality of life (EQ-5D). Analysis included case-mix adjustment. In addition, we report differences in hospital stay.METHODS: Analyses of baseline data were done by analysis of variance (ANOVA), Chi-square, or logistic regression tests. The comparisons of the mean changes of PROMs at one-year follow-up between the countries were done by ANOVA (crude) and analyses of covariance (ANCOVA, case mix adjustment). There are no conflicts of interest. Funding was received from the Danish Society of Spinal Surgery ($5,925), the Northern Norway Regional Health Authority ($5,925) and from Swedish Association of Local Authorities and Regions ($11,885). The sponsor had no role in the acquisition of data, analysis, or preparation of the manuscript.RESULTS: Out of 14,223 included patients, 10,890 (77%) responded at one-year follow-up. Apart from fewer smokers in Sweden and higher comorbidity rate in Norway, baseline characteristics were similar. The rate of additional fusion surgery (patients without, with spondylolisthesis) was: Norway 11% (4%, 47%), Sweden 21% (9%, 56%) and Denmark 28% (15%, 88%). At one-year follow-up the mean improvement for ODI (95%CI) was: Norway 18 (17 to 18), Sweden 17 (17 to 18), and Denmark 18 (17 to 19). Patients operated with arthrodesis had prolonged hospital stay.CONCLUSIONS: Real life data from three national spine registers showed similar indications for decompression surgery, but significant differences in the use of concomitant arthrodesis in Scandinavia. Additional arthrodesis was not associated with better treatment effectiveness.

We present a 86-year-old patient who suffered from progressive weakness in his right leg. Due to a hypercholesterinemia he had received Simvastatin for a few years. Because of higher cholesterine levels the dosis had been increased from 40 to 80 mg 6 months ago.We saw elevated levels of creatinine kinase and creatinine. In the EMG, a neuromuscular impairment was detected. In context with the medical history we could make the diagnosis of a statin-induced myopathy with rhabdomyolysis.After stopping the medication with statin and under liquid substitution, creatinine kinase and creatinine levels dropped. After therapy the weakness of the leg was totally recurrent.In case of unclear neurological symptoms and under therapy with statins, a myopathy should be considered.Wir berichten von einem 86-jährigen Patienten, der aufgrund einer zunehmenden Schwäche des rechten Beines aufgenommen wurde.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.Nach Absetzen der Statin-Therapie und unter Flüssigkeitssubstitution zeigten sich sowohl die Laborwerte als auch die klinische Symptomatik deutlich rückläufig.Bei unklarer neurologischer Symptomatik unter Statin-Therapie sollte an eine Statin-induzierte Myopathie gedacht und ggf. die Therapie beendet werden.

BackgroundRecent meta-analyses of resting-state networks in major depressive disorder (MDD) implicate network disruptions underlying cognitive and affective features of illness. Heterogeneity of findings to date may stem from the relative lack of data parsing clinical features of MDD such as phase of illness and the burden of multiple episodes.MethodResting-state functional magnetic resonance imaging data were collected from 17 active MDD and 34 remitted MDD patients, and 26 healthy controls (HCs) across two sites. Participants were medication-free and further subdivided into those with single v. multiple episodes to examine disease burden. Seed-based connectivity using the posterior cingulate cortex (PCC) seed to probe the default mode network as well as the amygdala and subgenual anterior cingulate cortex (sgACC) seeds to probe the salience network (SN) were conducted.ResultsYoung adults with remitted MDD demonstrated hyperconnectivity of the left PCC to the left inferior frontal gyrus and of the left sgACC to the right ventromedial prefrontal cortex (PFC) and left hippocampus compared with HCs. Episode-independent effects were observed between the left PCC and the right dorsolateral PFC, as well as between the left amygdala and right insula and caudate, whereas the burden of multiple episodes was associated with hypoconnectivity of the left PCC to multiple cognitive control regions as well as hypoconnectivity of the amygdala to large portions of the SN.ConclusionsThis is the first study of a homogeneous sample of unmedicated young adults with a history of adolescent-onset MDD illustrating brain-based episodic features of illness.

OBJECT Delayed ischemic neurological deficits (DINDs) and cerebral vasospasm (CVS) are responsible fora poor outcome in patients with aneurysmal subarachnoid hemorrhage (SAH), most likely because of a decreased availability of nitric oxide (NO) in the cerebral microcirculation. In this study, the authors examined the effects of treatment with the NO donor molsidomine with regard to decreasing the incidence of spasm-related delayed brain infarctions and improving clinical outcome in patients with SAH. METHODS Seventy-four patients with spontaneous aneurysmal SAH were included in this post hoc analysis. Twenty-nine patients with SAH and proven CVS received molsidomine in addition to oral or intravenous nimodipine. Control groups consisted of 25 SAH patients with proven vasospasm and 20 SAH patients without. These patients received nimodipine therapy alone. Cranial computed tomography (CCT) before and after treatment was analyzed for CVS-related infarcts. A modified National Institutes of Health Stroke Scale (mNIHSS) and the modified Rankin Scale (mRS) were used to assess outcomes at a 3-month clinical follow-up. RESULTS Four of the 29 (13.8%) patients receiving molsidomine plus nimodipine and 22 of the 45 (48%) patients receiving nimodipine therapy alone developed vasospasm-associated brain infarcts (p < 0.01). Follow-up revealed a median mNIHSS score of 3.0 and a median mRS score of 2.5 in the molsidomine group compared with scores of 11.5 and 5.0, respectively, in the nimodipine group with CVS (p < 0.001). One patient in the molsidomine treatment group died, and 12 patients in the standard care group died (p < 0.01). CONCLUSIONS In this post hoc analysis, patients with CVS who were treated with intravenous molsidomine had a significant improvement in clinical outcome and less cerebral infarction. Molsidomine offers a promising therapeutic option in patients with severe SAH and CVS and should be assessed in a prospective study.

Early-onset depression is associated with increased lifespan chronicity, suicidality, and the functional burdens associated with recurrent episodes. Reduction of these negative long-term outcomes requires an understanding of what interventions reduce vulnerabilities or ameliorate their associated neural patterns. Rumination-Focused Cognitive Behavior Therapy (RFCBT), an evidence-based treatment which directly targets a well-known risk for depressive relapse (i.e., ruminative habit), has shown preliminary success for reducing relapse rates among adolescents and adults in remission from Major Depressive Disorder (rMDD). In the current pilot study, clinical outcomes and neuroimaging predictors are explored over two years following a randomized controlled trial of eight weeks of RFCBT (n = 17) or Assessment Only (AO; n = 16) to prevent depressive relapse among adolescents. Baseline neural activation during a rumination induction task, neural change during treatment, and treatment group are examined as predictors of relapse. Regions selected were based upon hyperactivation patterns in rMDD compared to healthy adolescents, and occurred largely in default mode, somatomotor, visual and salience network regions. Twenty-five adolescents successfully completed quality fMRI scans at Baseline and after eight weeks of RFCBT or AO. RFCBT-treated youth maintained lower depression scores over the two-year period, relapsed at slower and less frequent rates, and were hospitalized less often for suicidality than AO. Although both groups reported lower ruminative tendencies after one year, at two-year follow-up, RFCBT maintained reductions whereas AO reported a return of ruminative tendencies. Adolescents who demonstrated higher activation at Baseline in default mode and limbic regions during rumination induction reported reduced depressive symptoms over the follow-up period. These data offer preliminary evidence that targeting rumination can stave off depressive relapse among vulnerable adolescents, and that such targeted treatment may aid a compensation process for disease-related brain functioning reducing risk to further depressive episodes. Clinical trials registration NCT01905267, https://clinicaltrials.gov/ct2/show/NCT01905267

Only small amounts of data are available on the prescription frequency of physical therapies (PT) for patients with rheumatoid arthritis (RA).The aim of the study was to evaluate prescription frequencies of PT considering functional status and sociodemographic factors.A total of 98,963 adults diagnosed with RA in 2013 were identified in claims data from the BARMER health insurance. A questionnaire was sent to a representative sample of 6193 people requesting information on the disease status. Of these 2535 persons were included who agreed to the linking of the questionnaire and claims data and who confirmed a diagnosis of RA. From the routine claims data the prescription of PT and occupational therapy as well as the medical discipline of the prescribing physician were analyzed. Multivariable logistic regression was conducted to determine which variables (age, sex, M05/M06 diagnosis, residential area, income, functional status and rheumatological care) were associated with the use of PT.In 2015 a total of 47% of the study population received PT (35% physiotherapy, 15% thermotherapy, 15% manual therapy, 2% electrotherapy and 6% massage) and 3% occupational therapy. Of the PT prescriptions 37% were issued by general practitioners, 27% by orthopedists and 18% by rheumatologists. Women and persons living in the eastern states of Germany and patients with high functional impairment were prescribed PT more often. Income, educational status, seropositivity and rheumatological care did not have any influence on the frequency of prescription of PT.There are deficits in the outpatient prescription of PT but without indications of an undersupply of population groups due to low socioeconomic status. In contrast to the prescription of disease-modifying antirheumatic drug (DMARD) treatment, PT is predominantly prescribed by general practitioners.

What concentration of anti-Müllerian hormone (AMH) corresponds to an antral follicle count (AFC)15 for determination of ovarian reserve?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 ElecsysIn the derivation cohort (n = 306), an optimal serum AMH cut-off value of 1.77 ng/ml was determined to correspond to AFC15 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 AFC15 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.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 AFC15.

For the selection of treatment in patients with spinal bone metastases (SBM), survival estimation plays a crucial role to avoid over- and under-treatment. To aid clinicians in this difficult task, several prediction models have been developed, consisting of many different risk factors. The aim of this systematic review was to identify prognostic factors that are associated with survival in patients with SBM to support development of predictive models. A systematic review was performed with focus on prognostic factors associated with survival in patients with SBM. Two reviewers independently selected studies for inclusion and assessed the risk of bias. A level of evidence synthesis was performed for each prognostic factor. Inter-observer agreement for the risk of bias assessment was determined by the kappa-statistic. After screening, 142 full-text articles were obtained, of which 22 met the eligibility criteria. A total of 43 different prognostic factors were investigated in the included studies, of which 17 were relevant to pre-treatment survival estimation. The prognostic factors most frequently associated with survival were the primary tumor and the performance status. The prognostic factors most frequently not associated with survival were age, gender, number and location of the SBM and the presence of a pathologic fracture. Prognostication for patients with SBM should be based on an accurate primary tumor classification, combined with a performance score. The benefit of adding other prognostic factors is doubtful.

Background The placement of intervertebral cages in anterior cervical discectomy (ACDF) supposedly maintains foraminal height. The most commonly reported cage-related complication is subsidence, although it is unknown whether a correlation between subsidence and clinical outcome exists. Aim To assess the incidence and relevance of subsidence. Methods Literature searches were performed in PubMed, MEDLINE, Embase, Web of Science, COCHRANE, and CENTRAL. The inclusion criteria were as follows: ≥ 20 patients, ADCF with cage, subsidence assessed, and primary data. Risk of bias was assessed using adjusted Cochrane checklists. Results Seventy-one studies, comprising 4784 patients, were included. Subsidence was generally defined as ≥ 3-mm loss of height comparing postoperative intervertebral heights with heights at last follow-up. Mean incidence of subsidence was 21% (range 0–83%). Of all patients, 46% of patients received polyether-ether-ketone (PEEK) cages, 31% received titanium cages, 18% received cage-screw-combinations, and 5% received polymethyl-methacrylate (PMMA) cages. Patients treated with cage-screw-combinations had significantly less subsidence than patients treated with PEEK, titanium, or PMMA cages (15.1% vs. 23.5% vs. 24.9% vs. 30.2%; p

Background Three well-established intrinsic connectivity networks (ICNs) involved in cognitive-affective processing include the cognitive control network (CCN), default mode network (DMN), and salience and emotional network (SEN). Despite recent advances in understanding developmental changes in these ICNs, the majority of research has focused on single seeds or networks in isolation with limited age ranges. Additionally, although internalizing psychopathologies (IPs), such as anxiety and depression, are often characterized by maladaptive cognitive-affective processing styles, it is not clear how IP history influences age-related changes in brain networks. Method The current study aimed to characterize the normative development of the CCN, DMN, and SEN across a large age-span (7-29 year olds) of typically developing (TD) individuals (n = 97). We also explore how age may impact differences in network connectivity between TD individuals and patients with IPs (n = 136). Results Among TD individuals, DMN and CCN connectivity strengthened with age, whereas connectivity between the SEN and ventromedial prefrontal cortex weakened across development. When exploring group (IP vs. TD) differences, the IP group was characterized by greater connectivity between the CCN and cerebellum and between the SEN and caudate from childhood to early adulthood, relative to TD individuals. In addition, patients with IPs, versus TD individuals, exhibited reduced connectivity between the SEN and medial frontal gyrus from adolescence to adulthood. Conclusions The current findings shed light on differential age-related changes in brain network patterns among psychiatrically free, TD individuals and those with internalizing disorders, and may provide plausible targets for novel mechanism-based treatments that differ based on developmental stage.

Background: Longitudinal research is critical for understanding the biological mechanisms underlying the development of depression. Researchers recruit high-risk cohorts to understand how risk is transmitted from one generation to the next. Biological measurements have been incorporated into these longitudinal high-risk (LHR) studies in order to illuminate mechanistic pathways. Methods: To frame our review, we first present heritability estimates along the gene-by-environment continuum as a foundation. We then offer a Biomarkers of Intergenerational Risk for Depression (BIRD) model to describe the multiple hits individuals at risk receive and to allow for greater focus on the interactive effects of markers. BIRD allows for the known multifinality of pathways towards depression and considers the context (i.e., environment) in which these mechanisms emerge. Next, we review the extant LHR cohort studies that have assessed central nervous system (electroencephalography (EEG), neuroimaging), endocrine (hypothalamic–pituitary–adrenal axis (HPA)/cortisol), autonomic (startle, heart rate), genetic, sleep, and birth characteristics. Results: Results to date, in conjunction with the proposed model, point towards several pathways of discovery in understanding mechanisms, providing clear direction for future research examining potential endophenotypes. Limitations: Our review is based on relatively narrow inclusion and exclusion criteria. As such, many interesting studies were excluded, but this weakness is offset by strengths such as the increased reliability of findings. Conclusions: Blanket prevention programs are inefficient and plagued by low effect sizes due to low rates of actual conversion to disorder. The inclusion of biomarkers of risk may lead to enhanced program efficiency by targeting those at greatest risk.

Healthcare-associated infections are an important cause of inpatient morbidity and mortality (1). Infections with multidrug-resistant (MDR) gram-negative bacteria, especially carbapenem-resistant organisms, are of particular concern since their treatment is complicated by the paucity of active and reliable antibiotics and the limited availability of rapid and accurate diagnostics (2). In an era of organ shortages, transplant recipients, by nature of their underlying condition and anticipated clinical course, are at increased risk for infection with MDR organisms (3, 4). Given the impact of antimicrobial resistance in transplant recipients, defining fundamental strategies to prevent and manage infections will be critical for the advancement of transplantation. Here, we describe a fatal case of endocarditis and disseminated carbapenem-resistant Acinetobacter baumannii (CRAb) infection in a simultaneous pancreas-kidney transplant recipient. Our goal is to highlight the unappreciated virulence of A. baumannii and difficulties in recognizing and treating infections caused by CRAb after organ transplantation.

BACKGROUND CONTEXT: Percutaneous laser disc decompression (PLDD) is a minimally invasive treatment for lumbar disc herniation, with Food and Drug Administration approval since 1991. However, no randomized trial comparing PLDD to conventional treatment has been performed. PURPOSE: In this trial, we assessed the effectiveness of a strategy of PLDD as compared with conventional surgery. STUDY DESIGN/SETTING: This randomized prospective trial with a noninferiority design was carried out in two academic and six teaching hospitals in the Netherlands according to an intent-to-treat protocol with full institutional review board approval. PATIENT SAMPLE: One hundred fifteen eligible surgical candidates, with sciatica from a disc herniation smaller than one-third of the spinal canal, were included. OUTCOME MEASURES: The main outcome measures for this trial were the Roland-Morris Disability Questionnaire for sciatica, visual analog scores for back and leg pain, and the patient's report of perceived recovery. METHODS: Patients were randomly allocated to PLDD (n=57) or conventional surgery (n=58). Blinding was impossible because of the nature of the interventions. This study was funded by the Healthcare Insurance Board of the Netherlands. RESULTS: The primary outcome, Roland-Morris Disability Questionnaire, showed noninferiority of PLDD at 8 (-0.1; [95% confidence interval (CI), -2.3 to 2.1]) and 52 weeks (-1.1; 95% CI, -3.4 to 1.1) compared with conventional surgery. There was, however, a higher speed of recovery in favor of conventional surgery (hazard ratio, 0.64 [95% CI, 0.42-0.97]). The number of reoperations was significantly less in the conventional surgery group (38% vs. 16%). Overall, a strategy of PLDD, with delayed surgery if needed, resulted in noninferior outcomes at 1 year. CONCLUSIONS: At 1 year, a strategy of PLDD, followed by surgery if needed, resulted in noninferior outcomes compared with surgery. (C) 2015 Elsevier Inc. All rights reserved.