Showing papers by "Gereon R. Fink published in 2022"

Gender gap in deep brain stimulation for Parkinson’s disease

Abstract: Previous studies have shown less access to deep brain stimulation (DBS) for Parkinson's disease (PD) in women compared to men raising concerns about a potential gender gap resulting from nonclinical factors or gender differences in clinical efficacy for postoperative quality of life (QoL), motor, and nonmotor symptoms (NMS) outcomes. This was a cross-sectional and a longitudinal, prospective, observational, controlled, quasi-experimental, international multicenter study. A total sample size of 505 consisted of 316 consecutively referred patients for DBS indication evaluation at the University Hospital Cologne (01/2015-09/2020) and 189 consecutively treated patients at DBS centers in the University Hospitals Cologne and Marburg, Salford's Royal Hospital Manchester, and King's College Hospital London. In the cross-sectional cohort, we examined gender proportions at referral, indication evaluations, and DBS surgery. In the longitudinal cohort, clinical assessments at preoperative baseline and 6-month follow-up after surgery included the PD Questionnaire-8, NMSScale, Scales for Outcomes in PD-motor scale, and levodopa-equivalent daily dose. Propensity score matching resulted in a pseudo-randomized sub-cohort balancing baseline demographic and clinical characteristics between women with PD and male controls. 316 patients were referred for DBS. 219 indication evaluations were positive (women n = 102, respectively n = 82). Women with PD were disproportionally underrepresented in referrals compared to the general PD population (relative risk [RR], 0.72; 95%CI, 0.56-0.91; P = 0.002), but more likely to be approved for DBS than men (RR, 1.17; 95%CI, 1.03-1.34; P = 0.029). Nonetheless, their total relative risk of undergoing DBS treatment was 0.74 (95%CI, 0.48-1.12) compared to men with PD. At baseline, women had longer disease duration and worse dyskinesia. Exploring QoL domains, women reported worse mobility and bodily discomfort. At follow-up, all main outcomes improved equally in both genders. Our study provides evidence of a gender gap in DBS for PD. Women and men with PD have distinct preoperative nonmotor and motor profiles. We advocate that more focus should be directed toward the implementation of gender equity as both genders benefit from DBS with equal clinical efficacy. This study provides Class II evidence of beneficial effects of DBS in women with PD compared to male controls.

Use of advanced neuroimaging and artificial intelligence in meningiomas

Abstract: Anatomical cross‐sectional imaging methods such as contrast‐enhanced MRI and CT are the standard for the delineation, treatment planning, and follow‐up of patients with meningioma. Besides, advanced neuroimaging is increasingly used to non‐invasively provide detailed insights into the molecular and metabolic features of meningiomas. These techniques are usually based on MRI, e.g., perfusion‐weighted imaging, diffusion‐weighted imaging, MR spectroscopy, and positron emission tomography. Furthermore, artificial intelligence methods such as radiomics offer the potential to extract quantitative imaging features from routinely acquired anatomical MRI and CT scans and advanced imaging techniques. This allows the linking of imaging phenotypes to meningioma characteristics, e.g., the molecular‐genetic profile. Here, we review several diagnostic applications and future directions of these advanced neuroimaging techniques, including radiomics in preclinical models and patients with meningioma.

Gender gap in deep brain stimulation for Parkinson’s disease

Abstract: Previous studies have shown less access to deep brain stimulation (DBS) for Parkinson's disease (PD) in women compared to men raising concerns about a potential gender gap resulting from nonclinical factors or gender differences in clinical efficacy for postoperative quality of life (QoL), motor, and nonmotor symptoms (NMS) outcomes. This was a cross-sectional and a longitudinal, prospective, observational, controlled, quasi-experimental, international multicenter study. A total sample size of 505 consisted of 316 consecutively referred patients for DBS indication evaluation at the University Hospital Cologne (01/2015-09/2020) and 189 consecutively treated patients at DBS centers in the University Hospitals Cologne and Marburg, Salford's Royal Hospital Manchester, and King's College Hospital London. In the cross-sectional cohort, we examined gender proportions at referral, indication evaluations, and DBS surgery. In the longitudinal cohort, clinical assessments at preoperative baseline and 6-month follow-up after surgery included the PD Questionnaire-8, NMSScale, Scales for Outcomes in PD-motor scale, and levodopa-equivalent daily dose. Propensity score matching resulted in a pseudo-randomized sub-cohort balancing baseline demographic and clinical characteristics between women with PD and male controls. 316 patients were referred for DBS. 219 indication evaluations were positive (women n = 102, respectively n = 82). Women with PD were disproportionally underrepresented in referrals compared to the general PD population (relative risk [RR], 0.72; 95%CI, 0.56-0.91; P = 0.002), but more likely to be approved for DBS than men (RR, 1.17; 95%CI, 1.03-1.34; P = 0.029). Nonetheless, their total relative risk of undergoing DBS treatment was 0.74 (95%CI, 0.48-1.12) compared to men with PD. At baseline, women had longer disease duration and worse dyskinesia. Exploring QoL domains, women reported worse mobility and bodily discomfort. At follow-up, all main outcomes improved equally in both genders. Our study provides evidence of a gender gap in DBS for PD. Women and men with PD have distinct preoperative nonmotor and motor profiles. We advocate that more focus should be directed toward the implementation of gender equity as both genders benefit from DBS with equal clinical efficacy. This study provides Class II evidence of beneficial effects of DBS in women with PD compared to male controls.

IGNITE Status Epilepticus Survey: A Nationwide Interrogation about the Current Management of Status Epilepticus in Germany

Abstract: We aimed to evaluate the current management of status epilepticus (SE) in intensive care units (ICUs) in Germany, depending on the different hospital levels of care and the ICU specialty. We performed a nationwide web-based anonymized survey, including all German ICUs registered with the German Society for Neurointensive and Emergency Care (Deutsche Gesellschaft für Neurointensiv- und Notfallmedizin; DGNI). The response rate was 83/232 (36%). Continuous EEG monitoring (cEEG) was available in 86% of ICUs. Regular written cEEG reports were obtained in only 50%. Drug management was homogeneous with a general consensus regarding substance order: benzodiazepines—anticonvulsants—sedatives. Thereunder first choice substances were lorazepam (90%), levetiracetam (91%), and propofol (73%). Data suggest that network structures for super-refractory SE are not permeable, as 75% did not transfer SE patients. Our survey provides “real world data” concerning the current management of SE in Germany. Uniform standards in the implementation of cEEG could help further improve the overall quality. Initial therapy management is standardized. For super-refractory SE, a concentration of highly specialized centers establishing network structures analogous to neurovascular diseases seems desirable to apply rescue therapies with low evidence carefully, ideally collecting data on this rare condition in registries and clinical trials.

Brain Morphometry Associated With Response to Levodopa and Deep Brain Stimulation in Parkinson Disease.

Abstract: Whether treatment response in patients with Parkinson disease depends on brain atrophy is insufficiently understood. The goal of this study is to identify specific atrophy patterns associated with response to dopaminergic therapy and deep brain stimulation.In this study, we analyzed the association of gray matter brain atrophy patterns, as identified by voxel-based morphometry, with acute response to levodopa (N = 118) and subthalamic nucleus deep brain stimulation (N = 39). Motor status was measured as a change in points on the Unified Parkinson's Disease Rating Scale III score. Baseline values were obtained before surgery, after cessation of dopaminergic medication for at least 12 hours; response to medication was assessed after administration of a standardized dose of levodopa. Response to deep brain stimulation was measured three months after surgery in the clinical condition after withdrawal of dopaminergic medication.Although frontoparietal brain gray matter loss was associated with subpar response to deep brain stimulation, there was no significant link between brain atrophy and response to levodopa.We conclude that response to deep brain stimulation relies on gray matter integrity; hence, gray matter loss may present a risk factor for poor response to deep brain stimulation and may be considered when making decision regarding clinical practice.

Multidomain cognitive impairment in non-hospitalized patients with the post-COVID-19 syndrome: results from a prospective monocentric cohort

Abstract: Abstract Background A fraction of patients with asymptomatic to mild/moderate acute COVID-19 disease report cognitive deficits as part of the post-COVID-19 syndrome. This study aimed to assess the neuropsychological profile of these patients. Methods Assessment at baseline (three months or more following acute COVID-19) of a monocentric prospective cohort of patients with post-COVID-19 syndrome. Multidomain neuropsychological tests were performed, and questionnaires on depression, anxiety, fatigue, sleep, and general health status were administered. Results Of the 58 patients screened, six were excluded due to possible alternative causes of cognitive impairment (major depression, neurodegenerative disease). Of the remaining 52 individuals, only one had a below-threshold screening result on Mini-Mental State Examination, and 13 scored below the cut-off on Montreal Cognitive Assessment. Extended neuropsychological testing revealed a neurocognitive disorder (NCD) in 31 (59.6%) participants with minor NCD in the majority of cases ( n = 26). In patients with NCD, the cognitive domains learning/memory and executive functions were impaired in 60.7%, complex attention in 51.6%, language in 35.5%, and perceptual-motor function in 29.0%. Cognitive profiles were associated with daytime sleepiness but not with depression, anxiety, sleep quality, total general health status, or fatigue. Conclusion Neurocognitive impairment can be confirmed in around 60% of individuals with self-reported deficits as part of post-COVID-19 syndrome following a mild acute COVID-19 disease course. Notably, screening tests cannot reliably detect this dysfunction. Standard psychiatric assessments showed no association with cognitive profiles. Longitudinal studies are needed to further evaluate the course of neurocognitive deficits and clarify pathophysiology.

Efficacy and tolerability of regorafenib in pretreated patients with progressive CNS grade 3 or 4 gliomas

Abstract: Abstract Background The phase 2 REGOMA trial suggested an encouraging overall survival benefit in glioblastoma patients at first relapse treated with the multikinase inhibitor regorafenib. Here, we evaluated the efficacy and side effects of regorafenib in a real-life setting. Methods From 2018 to 2021, 30 patients with progressive WHO CNS grade 3 or 4 gliomas treated with regorafenib (160 mg/day; first 3 weeks of each 4-week cycle) with individual dose adjustment depending on toxicity were retrospectively identified. Side effects were evaluated according to the Common Terminology Criteria for Adverse Events (version 5.0). MRI was obtained at baseline and after every second cycle. Tumor progression was assessed according to RANO criteria. After regorafenib initiation, the median PFS and OS were calculated. Results The median number of treatment lines before regorafenib was 2 (range 1–4). Most patients (73%) had two or more pretreatment lines. At first relapse, 27% of patients received regorafenib. A total of 94 regorafenib cycles were administered (median 2 cycles; range 1–9 cycles). Grade 3 and 4 side effects were observed in 47% and 7% of patients, respectively, and were not significantly increased in patients with two or more pretreatments (P > 0.05). The most frequent grade 3 or 4 side effects were laboratory abnormalities (62%). PFS was 2.6 months (range 0.8–8.2 months), and the OS was 6.2 months (range 0.9–24 months). Conclusions In patients with progressive WHO grade 3 or 4 gliomas, predominantly with two pretreatment lines or more, regorafenib seems to be effective despite considerable grade 3 or 4 side effects.

Combined TMS-fMRI Reveals Behavior-Dependent Network Effects of Right Temporoparietal Junction Neurostimulation in an Attentional Belief Updating Task.

Abstract: Updating beliefs after unexpected events is fundamental for an optimal adaptation to the environment. Previous findings suggested a causal involvement of the right temporoparietal junction (rTPJ) in belief updating in an attention task. We combined offline continuous theta-burst stimulation (cTBS) over rTPJ with functional magnetic resonance imaging (fMRI) to investigate local and remote stimulation effects within the attention and salience networks. In a sham-controlled, within-subject crossover design, 25 participants performed an attentional cueing task during fMRI with true or false information about cue predictability. By estimating learning rates from response times, we characterized participants' belief updating. Model-derived cue predictability entered the fMRI analysis as a parametric regressor to identify the neural correlates of updating. rTPJ-cTBS effects showed high interindividual variability. The expected learning rate reduction with false cue predictability information by cTBS was only observed in participants showing higher updating in false than in true blocks after sham. cTBS modulated the neural signatures of belief updating, both in rTPJ and in nodes of the attention and salience networks. The interindividual variability of the behavioral cTBS effect was related to differential activity and rTPJ connectivity of the right anterior insula. These results demonstrate a crucial interaction between ventral attention and salience networks for belief updating.

Two Decades of Brain Tumour Imaging with O-(2-[18F]fluoroethyl)-L-tyrosine PET: The Forschungszentrum Jülich Experience

Abstract: Simple Summary PET using radiolabelled amino acids has become an essential tool for diagnosing brain tumours in addition to MRI. O-(2-[18F]fluoroethyl)-L-tyrosine (FET) is one of the most successful tracers in the field. We analysed our database of 6534 FET PET examinations regarding the diagnostic needs and preferences of the referring physicians for FET PET in the clinical decision-making process. The demand for FET PET increased considerably in the last decade, especially for differentiating tumour progress from treatment-related changes in gliomas. Accordingly, referring physicians rated the diagnostics of recurrent glioma and recurrent brain metastases as the most relevant indication for FET PET. The analysis and survey results confirm the high relevance of FET PET in the clinical diagnosis of brain tumours and support the need for approval for routine use. Abstract O-(2-[18F]fluoroethyl)-L-tyrosine (FET) is a widely used amino acid tracer for positron emission tomography (PET) imaging of brain tumours. This retrospective study and survey aimed to analyse our extensive database regarding the development of FET PET investigations, indications, and the referring physicians’ rating concerning the role of FET PET in the clinical decision-making process. Between 2006 and 2019, we performed 6534 FET PET scans on 3928 different patients against a backdrop of growing demand for FET PET. In 2019, indications for the use of FET PET were as follows: suspected recurrent glioma (46%), unclear brain lesions (20%), treatment monitoring (19%), and suspected recurrent brain metastasis (13%). The referring physicians were neurosurgeons (60%), neurologists (19%), radiation oncologists (11%), general oncologists (3%), and other physicians (7%). Most patients travelled 50 to 75 km, but 9% travelled more than 200 km. The role of FET PET in decision-making in clinical practice was evaluated by a questionnaire consisting of 30 questions, which was filled out by 23 referring physicians with long experience in FET PET. Fifty to seventy per cent rated FET PET as being important for different aspects of the assessment of newly diagnosed gliomas, including differential diagnosis, delineation of tumour extent for biopsy guidance, and treatment planning such as surgery or radiotherapy, 95% for the diagnosis of recurrent glioma, and 68% for the diagnosis of recurrent brain metastases. Approximately 50% of the referring physicians rated FET PET as necessary for treatment monitoring in patients with glioma or brain metastases. All referring physicians stated that the availability of FET PET is essential and that it should be approved for routine use. Although the present analysis is limited by the fact that only physicians who frequently referred patients for FET PET participated in the survey, the results confirm the high relevance of FET PET in the clinical diagnosis of brain tumours and support the need for its approval for routine use.

Recovered grasping performance after stroke depends on interhemispheric frontoparietal connectivity

Abstract: Abstract Activity changes in the ipsi- and contralesional parietal cortex and abnormal interhemispheric connectivity between these regions are commonly observed after stroke, however, their significance for motor recovery remains poorly understood. We here assessed the contribution of ipsilesional and contralesional anterior intraparietal cortex (aIPS) for hand motor function in 18 recovered chronic stroke patients and 18 healthy control subjects using a multimodal assessment consisting of resting-state functional MRI, motor task functional MRI, online-repetitive transcranial magnetic stimulation (rTMS) interference, and 3D movement kinematics. Effects were compared against two control stimulation sites, i.e. contralesional M1 and a sham stimulation condition. We found that patients with good motor outcome compared to patients with more substantial residual deficits featured increased resting-state connectivity between ipsilesional aIPS and contralesional aIPS as well as between ipsilesional aIPS and dorsal premotor cortex. Moreover, interhemispheric connectivity between ipsilesional M1 and contralesional M1 as well as ipsilesional aIPS and contralesional M1 correlated with better motor performance across tasks. TMS interference at individual aIPS and M1 coordinates led to differential effects depending on the motor task that was tested, i.e. index finger-tapping, rapid pointing movements, or a reach-grasp-lift task. Interfering with contralesional aIPS deteriorated the accuracy of grasping, especially in patients featuring higher connectivity between ipsi- and contralesional aIPS. In contrast, interference with the contralesional M1 led to impaired grasping speed in patients featuring higher connectivity between bilateral M1. These findings suggest differential roles of contralesional M1 and aIPS for distinct aspects of recovered hand motor function, depending on the reorganization of interhemispheric connectivity.

Association of Intraventricular Fibrinolysis With Clinical Outcomes in Intracerebral Hemorrhage: An Individual Participant Data Meta-Analysis

Abstract: Background: In patients with intracerebral hemorrhage (ICH), the presence of intraventricular hemorrhage constitutes a promising therapeutic target. Intraventricular fibrinolysis (IVF) reduces mortality, yet impact on functional disability remains unclear. Thus, we aimed to determine the influence of IVF on functional outcomes. Methods: This individual participant data meta-analysis pooled 1501 patients from 2 randomized trials and 7 observational studies enrolled during 2004 to 2015. We compared IVF versus standard of care (including placebo) in patients treated with external ventricular drainage due to acute hydrocephalus caused by ICH with intraventricular hemorrhage. The primary outcome was functional disability evaluated by the modified Rankin Scale (mRS; range: 0–6, lower scores indicating less disability) at 6 months, dichotomized into mRS score: 0 to 3 versus mRS: 4 to 6. Secondary outcomes included ordinal-shift analysis, all-cause mortality, and intracranial adverse events. Confounding and bias were adjusted by random effects and doubly robust models to calculate odds ratios and absolute treatment effects (ATE). Results: Comparing treatment of 596 with IVF to 905 with standard of care resulted in an ATE to achieve the primary outcome of 9.3% (95% CI, 4.4–14.1). IVF treatment showed a significant shift towards improved outcome across the entire range of mRS estimates, common odds ratio, 1.75 (95% CI, 1.39–2.17), reduced mortality, odds ratio, 0.47 (95% CI, 0.35–0.64), without increased adverse events, absolute difference, 1.0% (95% CI, −2.7 to 4.8). Exploratory analyses provided that early IVF treatment (≤48 hours) after symptom onset was associated with an ATE, 15.2% (95% CI, 8.6–21.8) to achieve the primary outcome. Conclusions: As compared to standard of care, the administration of IVF in patients with acute hydrocephalus caused by intracerebral and intraventricular hemorrhage was significantly associated with improved functional outcome at 6 months. The treatment effect was linked to an early time window <48 hours, specifying a target population for future trials.

Communication, Coordination, and Security for People with Multiple Sclerosis (COCOS-MS): a randomised phase II clinical trial protocol

Abstract: Introduction Patients with multiple sclerosis (MS) have complex needs that range from organising one’s everyday life to measures of disease-specific therapy monitoring to palliative care. Patients with MS are likely to depend on multiple healthcare providers and various authorities, which are often difficult to coordinate. Thus, they will probably benefit from comprehensive cross-sectoral coordination of services provided by care and case management (CCM). Though studies have shown that case management improves quality of life (QoL), functional status and reduces service use, such benefits have not yet been investigated in severely affected patients with MS. In this explorative phase ll clinical trial, we evaluated a CCM with long-term, cross-sectoral and outreaching services and, in addition, considered the unit of care (patients and caregivers). Methods and analysis Eighty patients with MS and their caregivers will be randomly assigned to either the control (standard care) or the intervention group (standard care plus CCM (for 12 months)). Regular data assessments will be done at baseline and then at 3-month intervals. As primary outcome, we will evaluate patients’ QoL. Secondary outcomes are patients’ treatment-related risk perception, palliative care needs, anxiety/depression, use of healthcare services, caregivers’ burden and QoL, meeting patients’ and caregivers’ needs, and evaluating the CCM intervention. We will also evaluate CCM through individual interviews and focus groups. The sample size calculation is based on a standardised effect of 0.5, and one baseline and four follow-up assessments (with correlation 0.5). Linear mixed models for repeated measures will be applied to analyse changes in quantitative outcomes over time. Multiple imputation approaches are taken to assess the robustness of the results. The explorative approach (phase ll clinical trial) with embedded qualitative research will allow for the development of a final design for a confirmative phase lll trial. Ethics and dissemination The trial will be conducted under the Declaration of Helsinki and has been approved by the Ethics Commission of Cologne University’s Faculty of Medicine. Trial results will be published in an open-access scientific journal and presented at conferences. Trial registration number German Register for Clinical Studies (DRKS) (DRKS00022771).

Antibody Response after COVID‐19 Vaccination in Intravenous Immunoglobulin‐Treated Immune Neuropathies

Abstract: This study assessed the prevalence of anti‐SARS‐CoV‐2 antibodies in therapeutic immunoglobulin and their impact on serological response to COVID‐19 mRNA vaccine in patients with intravenous immunoglobulin (IVIg)‐treated chronic immune neuropathies.

Age and Anterior Basal Forebrain Volume Predict the Cholinergic Deficit in Patients with Mild Cognitive Impairment due to Alzheimer's Disease.

Abstract: BACKGROUND Early and severe neuronal loss in the cholinergic basal forebrain is observed in Alzheimer's disease (AD). To date, cholinomimetics play a central role in the symptomatic treatment of AD dementia. Although basic research indicates that a cholinergic deficit is present in AD before dementia, the efficacy of cholinomimetics in mild cognitive impairment (MCI) remains controversial. Predictors of cholinergic impairment could guide individualized therapy. OBJECTIVE To investigate if the extent of the cholinergic deficit, measured using positron emission tomography (PET) and the tracer 11C-N-methyl-4-piperidyl acetate (MP4A), could be predicted from the volume of cholinergic basal forebrain nuclei in non-demented AD patients. METHODS Seventeen patients with a high likelihood of MCI due to AD and 18 age-matched cognitively healthy adults underwent MRI-scanning. Basal forebrain volume was assessed using voxel-based morphometry and a cytoarchitectonic atlas of cholinergic nuclei. Cortical acetylcholinesterase (AChE) activity was measured using MP4A-PET. RESULTS Cortical AChE activity and nucleus basalis of Meynert (Ch4 area) volume were significantly decreased in MCI. The extent of the cholinergic deficit varied considerably across patients. Greater volumes of anterior basal forebrain nuclei (Ch1/2 area) and younger age (Spearman's rho (17) = -0.596, 95% -CI [-0.905, -0.119] and 0.593, 95% -CI [0.092, 0.863])) were associated with a greater cholinergic deficit. CONCLUSION Data suggest that less atrophy of the Ch1/2 area and younger age are associated with a more significant cholinergic deficit in MCI due to AD. Further investigations are warranted to determine if the individual response to cholinomimetics can be inferred from these measures.

Clinical applications and prospects of PET imaging in patients with IDH-mutant gliomas

Abstract: PET imaging using radiolabeled amino acids in addition to MRI has become a valuable diagnostic tool in the clinical management of patients with brain tumors. This review provides a comprehensive overview of PET studies in glioma patients with a mutation in the isocitrate dehydrogenase gene (IDH). A considerable fraction of these tumors typically show no contrast enhancement on MRI, especially when classified as grade 2 according to the World Health Organization classification of Central Nervous System tumors. Major diagnostic challenges in this situation are differential diagnosis, target definition for diagnostic biopsies, delineation of glioma extent for treatment planning, differentiation of treatment-related changes from tumor progression, and the evaluation of response to alkylating agents. The main focus of this review is the role of amino acid PET in this setting. Furthermore, in light of clinical trials using IDH inhibitors targeting the mutated IDH enzyme for treating patients with IDH-mutant gliomas, we also aim to give an outlook on PET probes specifically targeting the IDH mutation, which appear potentially helpful for response assessment.

The role of corticospinal and extrapyramidal pathways in motor impairment after stroke

Abstract: Anisotropy of descending motor pathways has repeatedly been linked to the severity of motor impairment following stroke-related damage to the corticospinal tract (CST). Despite promising findings consistently tying anisotropy of the ipsilesional CST to motor outcome, anisotropy is not yet utilized as a biomarker for motor recovery in clinical practice as a conclusive understanding of degenerative processes in the ipsilesional CST and compensatory roles of other descending motor pathways is hindered by methodological constraints such as estimating anisotropy in voxels with multiple fiber directions, sampling biases, and confounds due to aging-related atrophy. The present study addressed these issues by combining diffusion spectrum imaging (DSI) with a novel compartmentwise analysis approach differentiating voxels with one dominant fiber direction (one-directional voxels) from voxels with multiple fiber directions. Compartmentwise anisotropy for bihemispheric CST and extrapyramidal tracts was compared between chronic stroke patients (N=25), age-matched controls (N=22), and young controls (N=24) and its associations with motor performance of the upper and lower limbs were assessed. Our results provide direct evidence for Wallerian degenration along the entire length of the ipsilesional CST reflected by decreased anisotropy in descending fibers compared to age-matched controls, while aging-related atrophy was observed more ubiquitously across compartments. Anisotropy of descending ipsilesional CST voxels showed a highly robust correlation with various aspects of upper and lower limb motor impairment, highlighting the behavioral relevance of Wallerian degeneration. Moreover, anisotropy measures of two-directional voxels within bihemispheric rubrospinal and reticulospinal tracts were linked to lower limb deficits, while anisotropy of two-directional contralesional rubrospinal voxels explained gross motor performance of the affected hand. Of note, the relevant extrapyramidal structures contained fibers crossing the midline, fibers potentially mitigating output from brain stem nuclei, and fibers transferring signals between the extrapyramidal system and the cerebellum. Thus, specific parts of extrapyramidal pathways seem to compensate for impaired gross arm and leg movements incurred through stroke-related CST lesions, while fine motor control of the paretic hand critically relies on ipsilesional CST integrity. Importantly, our findings suggest that the extrapyramidal system may serve as a compensatory structural reserve independent of post-stroke reorganization of extrapyramidal tracts. In summary, compartment-specific anisotropy of ipsilesional CST and extrapyramidal tracts explained distinct aspects of motor impairment, with both systems representing different pathophysiological mechanisms contributing to motor control post-stroke. Considering both systems in concert may help develop diffusion imaging biomarkers for specific motor functions after stroke.

Cost Effectiveness of 18F-FET PET for Early Treatment Response Assessment in Glioma Patients After Adjuvant Temozolomide Chemotherapy

Abstract: Visual Abstract In light of increasing health-care costs, higher medical expenses should be justified socioeconomically. Therefore, we calculated the effectiveness and cost effectiveness of PET using the radiolabeled amino acid O-(2-18F-fluoroethyl)-l-tyrosine (18F-FET) compared with conventional MRI for early identification of responders to adjuvant temozolomide chemotherapy. A recently published study in isocitrate dehydrogenase wild-type glioma patients suggested that 18F-FET PET parameter changes predicted a significantly longer survival already after 2 cycles whereas MRI changes were not significant. Methods: To determine the effectiveness and cost effectiveness of serial 18F-FET PET imaging, we analyzed published clinical data and calculated the associated costs from the perspective of the German Statutory Health Insurance system. Based on a decision-tree model, the effectiveness of 18F-FET PET and MRI was calculated—that is, the probability to correctly identify a responder as defined by an overall survival of at least 15 mo. To determine the cost effectiveness, the incremental cost effectiveness ratio (ICER) was calculated—that is, the cost for each additionally identified responder by 18F-FET PET who would have remained undetected by MRI. The robustness of the results was tested by deterministic and probabilistic Monte Carlo sensitivity analyses. Results: Compared with MRI, 18F-FET PET increased the rate of correctly identified responders to chemotherapy by 26%; thus, 4 patients needed to be examined by 18F-FET PET to identify 1 additional responder. Considering the respective costs for serial 18F-FET PET and MRI, the ICER resulted in €4,396.83 for each additional correctly identified responder by 18F-FET PET. Sensitivity analyses confirmed the robustness of the results. Conclusion: In contrast to conventional MRI, the model suggests that 18F-FET PET is cost-effective in terms of ICER values. Considering the high cost of temozolomide, the integration of 18F-FET PET has the potential to avoid premature chemotherapy discontinuation at reasonable cost.

Structural Connectivity of Subthalamic Nucleus Stimulation for Improving Freezing of Gait.

Abstract: BACKGROUND Freezing of gait (FOG) is among the most common and disabling symptoms of Parkinson's disease (PD). Studies show that deep brain stimulation (DBS) of the subthalamic nucleus (STN) can reduce FOG severity. However, there is uncertainty about pathways that need to be modulated to improve FOG. OBJECTIVE To investigate whether STN-DBS effectively reduces FOG postoperatively and whether structural connectivity of the stimulated tissue explains variance of outcomes. METHODS We investigated 47 patients with PD and preoperative FOG. Freezing prevalence and severity was primarily assessed using the Freezing of Gait Questionnaire (FOG-Q). In a subset of 18 patients, provoked FOG during a standardized walking course was assessed. Using a publicly available model of basal-ganglia pathways we determined stimulation-dependent connectivity associated with postoperative changes in FOG. A region-of-interest analysis to a priori defined mesencephalic regions was performed using a disease-specific normative connectome. RESULTS Freezing of gait significantly improved six months postoperatively, marked by reduced frequency and duration of freezing episodes. Optimal stimulation volumes for improving FOG structurally connected to motor areas, the prefrontal cortex and to the globus pallidus. Stimulation of the lenticular fasciculus was associated with worsening of FOG. This connectivity profile was robust in a leave-one-out cross-validation. Subcortically, stimulation of fibers crossing the pedunculopontine nucleus and the substantia nigra correlated with postoperative improvement. CONCLUSION STN-DBS can alleviate FOG severity by modulating specific pathways structurally connected to prefrontal and motor cortices. More differentiated FOG assessments may allow to differentiate pathways for specific FOG subtypes in the future.

Glia from the central and peripheral nervous system are differentially affected by paclitaxel chemotherapy via modulating their neuroinflammatory and neuroregenerative properties

Abstract: Glia are critical players in defining synaptic contacts and maintaining neuronal homeostasis. Both astrocytes as glia of the central nervous system (CNS), as well as satellite glial cells (SGC) as glia of the peripheral nervous system (PNS), intimately interact with microglia, especially under pathological conditions when glia regulate degenerative as well as regenerative processes. The chemotherapeutic agent paclitaxel evokes peripheral neuropathy and cognitive deficits; however, the mechanisms underlying these diverse clinical side effects are unclear. We aimed to elucidate the direct effects of paclitaxel on the function of astrocytes, microglia, and SGCs, and their glia-glia and neuronal-glia interactions. After intravenous application, paclitaxel was present in the dorsal root ganglia of the PNS and the CNS of rodents. In vitro, SGC enhanced the expression of pro-inflammatory factors and reduced the expression of neurotrophic factor NT-3 upon exposure to paclitaxel, resulting in predominantly neurotoxic effects. Likewise, paclitaxel induced a switch towards a pro-inflammatory phenotype in microglia, exerting neurotoxicity. In contrast, astrocytes expressed neuroprotective markers and increasingly expressed S100A10 after paclitaxel exposure. Astrocytes, and to a lesser extent SGCs, had regulatory effects on microglia independent of paclitaxel exposure. Data suggest that paclitaxel differentially modulates glia cells regarding their (neuro-) inflammatory and (neuro-) regenerative properties and also affects their interaction. By elucidating those processes, our data contribute to the understanding of the mechanistic pathways of paclitaxel-induced side effects in CNS and PNS. Graphical Abstract Main Points: Paclitaxel differentially modulates inflammatory and regenerative properties of glial cells; Paclitaxel affects glia-glia and glia-neuron interactions; Paclitaxel induces pro-inflammatory effects in microglia and satellite glial cells and anti-inflammatory effects in astrocytes.

Alterations in white matter fiber density associated with structural MRI and metabolic PET lesions following multimodal therapy in glioma patients

Abstract: Background In glioma patients, multimodality therapy and recurrent tumor can lead to structural brain tissue damage characterized by pathologic findings in MR and PET imaging. However, little is known about the impact of different types of damage on the fiber architecture of the affected white matter. Patients and methods This study included 121 pretreated patients (median age, 52 years; ECOG performance score, 0 in 48%, 1-2 in 51%) with histomolecularly characterized glioma (WHO grade IV glioblastoma, n=81; WHO grade III anaplastic astrocytoma, n=28; WHO grade III anaplastic oligodendroglioma, n=12), who had a resection, radiotherapy, alkylating chemotherapy, or combinations thereof. After a median follow-up time of 14 months (range, 1-214 months), anatomic MR and O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET images were acquired on a 3T hybrid PET/MR scanner. Post-therapeutic findings comprised resection cavities, regions with contrast enhancement or increased FET uptake and T2/FLAIR hyperintensities. Local fiber density was determined from high angular-resolution diffusion-weighted imaging and advanced tractography methods. A cohort of 121 healthy subjects selected from the 1000BRAINS study matched for age, gender and education served as a control group. Results Lesion types differed in both affected tissue volumes and relative fiber densities compared to control values (resection cavities: median volume 20.9 mL, fiber density 16% of controls; contrast-enhanced lesions: 7.9 mL, 43%; FET uptake areas: 30.3 mL, 49%; T2/FLAIR hyperintensities: 53.4 mL, 57%, p<0.001). In T2/FLAIR-hyperintense lesions caused by peritumoral edema due to recurrent glioma (n=27), relative fiber density was as low as in lesions associated with radiation-induced gliosis (n=13, 48% vs. 53%, p=0.17). In regions with pathologically increased FET uptake, local fiber density was inversely related (p=0.005) to the extent of uptake. Total fiber loss associated with contrast-enhanced lesions (p=0.006) and T2/FLAIR hyperintense lesions (p=0.013) had a significant impact on overall ECOG score. Conclusions These results suggest that apart from resection cavities, reduction in local fiber density is greatest in contrast-enhancing recurrent tumors, but total fiber loss induced by edema or gliosis has an equal detrimental effect on the patients’ performance status due to the larger volume affected.

Single-center experience of induction therapy in non-systemic vasculitic neuropathy

Abstract: Abstract Background No controlled studies for non-systemic vasculitic neuropathy treatment exist (NSVN). We compared the treatment response to induction therapy commonly used in clinical practice in NSVN. Methods In this retrospective single-center study, 43 patients with biopsy-proven NSVN were analyzed. Patients were subdivided into groups depending on their initial treatment. Relapse rates, changes of motor and sensory symptoms, adverse events, predictors of relapses, and second-line treatment were compared. Results Initial treatment regimens were corticosteroid monotherapy, cyclophosphamide monotherapy, pulsed corticosteroid therapy, and combination therapy. Discontinuation due to adverse events occurred in 6 of 43 patients. Clinical data did not differ between treatment groups. Within 12 months, 24.3% of patients relapsed. The median time to relapse was 4 (1.5, 6) months. No relapse occurred in the combination therapy group. However, there was no statistically significant difference in relapse-free survival between treatment groups ( p = 0.58). Neither clinical data nor biopsy analysis predicted relapses sufficiently. As a second-line treatment, cyclophosphamide as mono- or combination therapy was used (7 of 9 patients) most frequently. One patient was treated with methotrexate, and one with IVIG. Conclusions Induction therapy used in clinical practice is effective and mainly well-tolerated in NSVN. Our data do not support an overall advantage of cyclophosphamide over corticosteroid monotherapy. Controlled trials comparing the effectiveness of induction and maintenance therapy in NSVN are warranted.

MRI correlates of motoneuron loss in SMA

Abstract: Magnetic resonance imaging (MRI) is currently explored as supplemental tool to monitor disease progression and treatment response in various neuromuscular disorders. We here assessed the utility of a multi-parametric magnetic resonance imaging (MRI) protocol including quantitative water T2 mapping, Dixon-based proton density fat fraction (PDFF) estimation and diffusion tensor imaging (DTI) to detect loss of spinal motor neurons and subsequent muscle damage in adult SMA patients.Sixteen SMA patients and 13 age-matched controls were enrolled in this prospective, longitudinal study. All participants underwent MRI imaging including measurements of Dixon-based PDFF and DTI of the sciatic nerve. SMA patients furthermore underwent measurements of muscle water T2 (T2w) of the biceps femoris muscle (BFM) and quadriceps femoris muscle (QFM). Ten participants returned for a second scan six months later. MRI parameter were correlated with clinical data. All patients were on nusinersen treatment.There were significantly higher intramuscular fat fractions in the BFM and QFM of SMA patients compared to healthy controls at baseline and after 6 months. Furthermore, T2 values significantly correlated positively with intramuscular fat fractions. The Hammersmith functional motor scale significantly correlated with the QFM's intramuscular fat fractions. DTI scans of the sciatic nerve were not significantly different between the two groups.This study demonstrates that, water T2 mapping and Dixon-based PDFF estimation may distinguish between adult SMA patients and controls, due to massive intramuscular fat accumulation in SMA. More extensive long-term studies are warranted to further evaluate these two modalities as surrogate markers in SMA patients during treatment.

Results of a Randomized Clinical Trial of Speech After Early Neurostimulation in Parkinson's Disease

Abstract: The EARLYSTIM trial demonstrated for Parkinson's disease patients with early motor complications that deep brain stimulation of the subthalamic nucleus (STN‐DBS) and best medical treatment (BMT) was superior to BMT alone.

Neuropsychological Evidence for a Motor Working Memory Subsystem Related to Apraxia

Abstract: Abstract Recent evidence in healthy participants suggests that a motor subcomponent of working memory (mWM) may exist. We investigated whether this mWM is impaired in patients with a motor-dominant left hemisphere (LH) stroke and apraxia. Furthermore, we hypothesized that a deficient mWM contributes to deficits in motor cognition, that is, apraxia, in LH stroke. The study included 52 patients with LH stroke and 25 age-matched controls. Patients were classified into LH stroke patients with and without apraxia based on deficits in gesture imitation and object use. All participants were examined using the block span test (visuospatial WM), the digit span test (verbal WM), and a novel mWM task. In the latter, participants were presented with static pictures depicting three different actions: actions with objects, meaningless actions, and meaningful actions. In the mWM task, LH stroke patients with apraxia performed worse than age-matched controls. Notably, LH stroke patients with apraxia showed more pronounced mWM deficits than those without apraxia. These results remained significant even after controlling for visuospatial and verbal WM deficits. Regression analyses revealed that LH stroke patients' mWM deficits predicted deficits in imitation. Data provide neuropsychological evidence for a motor subsystem of WM and suggest that deficits in mWM contribute to the severity of apraxia in LH stroke patients.

The manifestation of affective symptoms in multiple sclerosis and discussion of the currently available diagnostic assessment tools

Abstract: In addition to physical and cognitive symptoms, patients with multiple sclerosis (MS) have an increased risk of experiencing mental health problems.This narrative review provides an overview of the appearance and epidemiology of affective symptoms in MS such as depression, anxiety, bipolar disorder, euphoria, and pseudobulbar affect. Furthermore, the association between affective symptoms and quality of life and the currently used diagnostic instruments for assessing these symptoms are considered whereby relevant studies published between 2009 and 2021 were included in the review.Patients with mild and moderate disability more frequently reported severe problems with depression and anxiety than severe mobility problems. Apart from the occurrence of depression, little is known about the association of other affective symptoms such as anxiety, bipolar disorder, euphoria, and pseudobulbar affect and subsyndromal symptoms, which fail to meet the diagnostic criteria but are nevertheless a significant source of distress. Although there are a few recommendations in the research to perform routine screenings for diagnosable affective disorders, a standardized diagnostic procedure to assess subsyndromal symptoms is still lacking. As the applied measurements are diverse and show low accuracy to detect these symptoms, patients who experience affective symptoms are less likely to be identified.In addition to the consideration of definite psychiatric diagnoses, there is an unmet need for a common definition and assessment of disease-related affective symptoms in MS. Future studies should focus on the improvement and standardization of a common diagnostic procedure for subsyndromal affective symptoms in MS to enable integrated and optimal care for patients.

Transcranial-Direct-Current-Stimulation Accelerates Motor Recovery After Cortical Infarction in Mice: The Interplay of Structural Cellular Responses and Functional Recovery

Abstract: Background Transcranial direct current stimulation (tDCS) promotes recovery after stroke in humans. The underlying mechanisms, however, remain to be elucidated. Animal models suggest tDCS effects on neuroinflammation, stem cell proliferation, neurogenesis, and neural plasticity. Objective In a longitudinal study, we employed tDCS in the subacute and chronic phase after experimental focal cerebral ischemia in mice to explore the relationship between functional recovery and cellular processes. Methods Mice received photothrombosis in the right motor cortex, verified by Magnetic Resonance Imaging. A composite neuroscore quantified subsequent functional deficits. Mice received tDCS daily: either 5 sessions from day 5 to 9, or 10 sessions with days 12 to 16 in addition. TDCS with anodal or cathodal polarity was compared to sham stimulation. Further imaging to assess proliferation and neuroinflammation was performed by immunohistochemistry at different time points and Positron Emission Tomography at the end of the observation time of 3 weeks. Results Cathodal tDCS at 198 kC/m2 (220 A/m2) between days 5 and 9 accelerated functional recovery, increased neurogenesis, decreased microglial activation, and mitigated CD16/32-expression associated with M1-phenotype. Anodal tDCS exerted similar effects on neurogenesis and microglial polarization but not on recovery of function or microglial activation. TDCS on days 12 to 16 after stroke did not induce any further effects, suggesting that the therapeutic time window was closed by then. Conclusion Overall, data suggest that non-invasive neuromodulation by tDCS impacts neurogenesis and microglial activation as critical cellular processes influencing functional recovery during the early phase of regeneration from focal cerebral ischemia.