Neurologische Klinik und Poliklinik
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Neurodegeneration by α-synuclein-specific T cells in AAV-A53T-α-synuclein Parkinson’s disease mice
(2022)
Background
Antigen-specific neuroinflammation and neurodegeneration are characteristic for neuroimmunological diseases. In Parkinson’s disease (PD) pathogenesis, α-synuclein is a known culprit. Evidence for α-synuclein-specific T cell responses was recently obtained in PD. Still, a causative link between these α-synuclein responses and dopaminergic neurodegeneration had been lacking. We thus addressed the functional relevance of α-synuclein-specific immune responses in PD in a mouse model.
Methods
We utilized a mouse model of PD in which an Adeno-associated Vector 1/2 serotype (AAV1/2) expressing human mutated A53T-α-Synuclein was stereotactically injected into the substantia nigra (SN) of either wildtype C57BL/6 or Recombination-activating gene 1 (RAG1)\(^{-/-}\) mice. Brain, spleen, and lymph node tissues from different time points following injection were then analyzed via FACS, cytokine bead assay, immunohistochemistry and RNA-sequencing to determine the role of T cells and inflammation in this model. Bone marrow transfer from either CD4\(^{+}\)/CD8\(^{-}\), CD4\(^{-}\)/CD8\(^{+}\), or CD4\(^{+}\)/CD8\(^{+}\) (JHD\(^{-/-}\)) mice into the RAG-1\(^{-/-}\) mice was also employed. In addition to the in vivo studies, a newly developed A53T-α-synuclein-expressing neuronal cell culture/immune cell assay was utilized.
Results
AAV-based overexpression of pathogenic human A53T-α-synuclein in dopaminergic neurons of the SN stimulated T cell infiltration. RNA-sequencing of immune cells from PD mouse brains confirmed a pro-inflammatory gene profile. T cell responses were directed against A53T-α-synuclein-peptides in the vicinity of position 53 (68–78) and surrounding the pathogenically relevant S129 (120–134). T cells were required for α-synuclein-induced neurodegeneration in vivo and in vitro, while B cell deficiency did not protect from dopaminergic neurodegeneration.
Conclusions
Using T cell and/or B cell deficient mice and a newly developed A53T-α-synuclein-expressing neuronal cell culture/immune cell assay, we confirmed in vivo and in vitro that pathogenic α-synuclein peptide-specific T cell responses can cause dopaminergic neurodegeneration and thereby contribute to PD-like pathology.
Neurodegeneration plays an essential role in Parkinson’s disease (PD). Several crucial neuronal pro-and antidegeneration markers were described to be altered in disease models accompanied by neurodegeneration. In the AAV1/2-A53T-aSyn PD rat model progressive time-dependent motor impairment and neurodegeneration in the nigrostriatal tract starting from 2 weeks after PD model induction could be found. Downregulation of Nrf2 in SN and nigrostriatal axon localization, a trend of Tau downregulation in SN and upregulation in axon localization in the AAV1/2-A53T-aSyn PD rat model were observed, indicating potential therapeutic value of these two molecular targets in PD. No alterations of SARM1 and NMNAT2 could be detected, indicating little relevance of these two molecules with our AAV1/2-A53T-aSyn rat model.
Background
Ischemic stroke immediately evokes a strong neuro-inflammatory response within the vascular compartment, which contributes to primary infarct development under vessel occlusion as well as further infarct growth despite recanalization, referred to as ischemia/reperfusion injury. Later, in the subacute phase of stroke (beyond day 1 after recanalization), further inflammatory processes within the brain parenchyma follow. Whether this second wave of parenchymal inflammation contributes to an additional/secondary increase in infarct volumes and bears the potential to be pharmacologically targeted remains elusive. We addressed the role of the NLR-family pyrin domain-containing protein 3 (NLRP3) inflammasome in the subacute phase of ischemic stroke.
Methods
Focal cerebral ischemia was induced in C57Bl/6 mice by a 30-min transient middle cerebral artery occlusion (tMCAO). Animals were treated with the NLRP3 inhibitor MCC950 therapeutically 24 h after or prophylactically before tMCAO. Stroke outcome, including infarct size and functional deficits as well as the local inflammatory response, was assessed on day 7 after tMCAO.
Results
Infarct sizes on day 7 after tMCAO decreased about 35% after delayed and about 60% after prophylactic NLRP3 inhibition compared to vehicle. Functionally, pharmacological inhibition of NLRP3 mitigated the local inflammatory response in the ischemic brain as indicated by reduction of infiltrating immune cells and reactive astrogliosis.
Conclusions
Our results demonstrate that the NLRP3 inflammasome continues to drive neuroinflammation within the subacute stroke phase. NLRP3 inflammasome inhibition leads to a better long-term outcome—even when administered with a delay of 1 day after stroke induction, indicating ongoing inflammation-driven infarct progression. These findings may pave the way for eagerly awaited delayed treatment options in ischemic stroke.
There is no approved drug for fibromyalgia syndrome (FMS) in Europe. In the German S3 guideline, amitriptyline, duloxetine, and pregabalin are recommended for temporary use. The aim of this study was to cross-sectionally investigate the current practice of medication in FMS patients in Germany. We systematically interviewed 156 patients with FMS, while they were participating in a larger study. The patients had been stratified into subgroups with and without a decrease in intraepidermal nerve fiber density. The drugs most commonly used to treat FMS pain were nonsteroidal anti-inflammatory drugs (NSAIDs) (41.0% of all patients), metamizole (22.4%), and amitriptyline (12.8%). The most frequent analgesic treatment regimen was “on demand” (53.9%), during pain attacks, while 35.1% of the drugs were administered daily and the remaining in other regimens. Median pain relief as self-rated by the patients on a numerical rating scale (0–10) was 2 points for NSAIDS, 2 for metamizole, and 1 for amitriptyline. Drugs that were discontinued due to lack of efficacy rather than side effects were acetaminophen, flupirtine, and selective serotonin reuptake inhibitors. Reduction in pain severity was best achieved by NSAIDs and metamizole. Our hypothesis that a decrease in intraepidermal nerve fiber density might represent a neuropathic subtype of FMS, which would be associated with better effectiveness of drugs targeting neuropathic pain, could not be confirmed in this cohort. Many FMS patients take “on-demand” medication that is not in line with current guidelines. More randomized clinical trials are needed to assess drug effects in FMS subgroups.
CNS imaging characteristics in fibromyalgia patients with and without peripheral nerve involvement
(2022)
We tested the hypothesis that reduced skin innervation in fibromyalgia syndrome is associated with specific CNS changes. This prospective case–control study included 43 women diagnosed with fibromyalgia syndrome and 40 healthy controls. We further compared the fibromyalgia subgroups with reduced (n = 21) and normal (n = 22) skin innervation. Brains were analysed for cortical volume, for white matter integrity, and for functional connectivity. Compared to controls, cortical thickness was decreased in regions of the frontal, temporal and parietal cortex in the fibromyalgia group as a whole, and decreased in the bilateral pericalcarine cortices in the fibromyalgia subgroup with reduced skin innervation. Diffusion tensor imaging revealed a significant increase in fractional anisotropy in the corona radiata, the corpus callosum, cingulum and fornix in patients with fibromyalgia compared to healthy controls and decreased FA in parts of the internal capsule and thalamic radiation in the subgroup with reduced skin innervation. Using resting-state fMRI, the fibromyalgia group as a whole showed functional hypoconnectivity between the right midfrontal gyrus and the posterior cerebellum and the right crus cerebellum, respectively. The subgroup with reduced skin innervation showed hyperconnectivity between the inferior frontal gyrus, the angular gyrus and the posterior parietal gyrus. Our results suggest that the subgroup of fibromyalgia patients with pronounced pathology in the peripheral nervous system shows alterations in morphology, structural and functional connectivity also at the level of the encephalon. We propose considering these subgroups when conducting clinical trials.
Diabetes Mellitus Is a Possible Risk Factor for Nodo-paranodopathy With Antiparanodal Autoantibodies
(2022)
Background and Objectives
Nodo-paranodopathies are peripheral neuropathies with dysfunction of the node of Ranvier. Affected patients who are seropositive for antibodies against adhesion molecules like contactin-1 and neurofascin show distinct clinical features and a disruption of the paranodal complex. An axoglial dysjunction is also a characteristic finding of diabetic neuropathy. Here, we aim to investigate a possible association of antibody-mediated nodo-paranodopathy and diabetes mellitus (DM).
Methods
We retrospectively analyzed clinical data of 227 patients with chronic inflammatory demyelinating polyradiculoneuropathy and Guillain-Barré syndrome from multiple centers in Germany who had undergone diagnostic testing for antiparanodal antibodies targeting neurofascin-155, pan-neurofascin, contactin-1–associated protein 1, and contactin-1. To study possible direct pathogenic effects of antiparanodal antibodies, we performed immunofluorescence binding assays on human pancreatic tissue sections.
Results The frequency of DM was 33.3% in seropositive patients and thus higher compared with seronegative patients (14.1%, OR = 3.04, 95% CI = 1.31–6.80). The relative risk of DM in seropositive patients was 3.4-fold higher compared with the general German population. Seropositive patients with DM most frequently harbored anti–contactin-1 antibodies and had higher antibody titers than seropositive patients without DM. The diagnosis of DM preceded the onset of neuropathy in seropositive patients. No immunoreactivity of antiparanodal antibodies against pancreatic tissue was detected.
Discussion
We report an association of nodo-paranodopathy and DM. Our results suggest that DM may be a potential risk factor for predisposing to developing nodo-paranodopathy and argue against DM being induced by the autoantibodies. Our findings set the basis for further research investigating underlying immunopathogenetic connections.
Background:
Methylphenidate (MPH) is the first-line pharmacological treatment of attention-deficit/hyperactivity disorder (ADHD). MPH binds to the dopamine (DA) transporter (DAT), which has high density in the striatum. Assessments of the striatal dopamine transporter by single positron emission computed tomography (SPECT) in childhood and adolescent patients are rare but can provide insight on how the effects of MPH affect DAT availability. The aim of our within-subject study was to investigate the effect of MPH on DAT availability and how responsivity to MPH in DAT availability is linked to clinical symptoms and cognitive functioning.
Methods
Thirteen adolescent male patients (9–16 years) with a diagnosis of ADHD according to the DSM-IV and long-term stimulant medication (for at least 6 months) with MPH were assessed twice within 7 days using SPECT after application of I-123-β-CIT to examine DAT binding potential (DAT BP). SPECT measures took place in an on- and off-MPH status balanced for order across participants. A virtual reality continuous performance test was performed at each time point. Further clinical symptoms were assessed for baseline off-MPH.
Results
On-MPH status was associated with a highly significant change (−29.9%) of striatal DAT BP as compared to off-MPH (t = −4.12, p = 0.002). A more pronounced change in striatal DAT BP was associated with higher off-MPH attentional and externalizing symptom ratings (Pearson r = 0.68, p = 0.01). Striatal DAT BP off-MPH, but not on-MPH, was associated with higher symptom ratings (Pearson r = 0.56, p = 0.04).
Conclusion
Our findings corroborate previous reports from mainly adult samples that MPH changes striatal DAT BP availability and suggest higher off-MPH DAT BP, likely reflecting low baseline DA levels, as a marker of symptom severity.
Objective: Gait adaptation to environmental challenges is fundamental for independent and safe community ambulation. The possibility of precisely studying gait modulation using standardized protocols of gait analysis closely resembling everyday life scenarios is still an unmet need.
Methods: We have developed a fully-immersive virtual reality (VR) environment where subjects have to adjust their walking pattern to avoid collision with a virtual agent (VA) crossing their gait trajectory. We collected kinematic data of 12 healthy young subjects walking in real world (RW) and in the VR environment, both with (VR/A+) and without (VR/A-) the VA perturbation. The VR environment closely resembled the RW scenario of the gait laboratory. To ensure standardization of the obstacle presentation the starting time speed and trajectory of the VA were defined using the kinematics of the participant as detected online during each walking trial.
Results: We did not observe kinematic differences between walking in RW and VR/A-, suggesting that our VR environment per se might not induce significant changes in the locomotor pattern. When facing the VA all subjects consistently reduced stride length and velocity while increasing stride duration. Trunk inclination and mediolateral trajectory deviation also facilitated avoidance of the obstacle.
Conclusions: This proof-of-concept study shows that our VR/A+ paradigm effectively induced a timely gait modulation in a standardized immersive and realistic scenario. This protocol could be a powerful research tool to study gait modulation and its derangements in relation to aging and clinical conditions.
Parkinson’s Disease (PD) constitutes a major healthcare burden in Europe. Accounting for aging alone, ~700,000 PD cases are predicted by 2040. This represents an approximately 56% increase in the PD population between 2005 and 2040, with a consequent rise in annual disease‐related medical costs. Gait and balance disorders are a major problem for patients with PD and their caregivers, mainly because to their correlation with falls. Falls occur as a result of a complex interaction of risk factors. Among them, Freezing of Gait (FoG) is a peculiar gait derangement characterized by a sudden and episodic inability to produce effective stepping, causing falls, mobility restrictions, poor quality of life, and increased morbidity and mortality. Between 50–70% of PD patients have FoG and/or falls after a disease duration of 10 years, only partially and inconsistently improved by dopaminergic treatment and Deep Brain Stimulation (DBS). Treatment-induced worsening has been also observed under certain conditions. Effective treatments for gait disturbances in PD are lacking, probably because of the still poor understanding of the supraspinal locomotor network.
In my thesis, I wanted to expand our knowledge of the supraspinal locomotor network and in particular the contribution of the basal ganglia to the control of locomotion. I believe this is a key step towards new preventive and personalized therapies for postural and gait problems in patients with PD and related disorders. In addition to patients with PD, my studies also included people affected by Progressive Supranuclear Palsy (PSP). PSP is a rare primary progressive parkinsonism characterized at a very early disease stage by poor balance control and frequent backwards falls, thus providing an in vivo model of dysfunctional locomotor control.
I focused my attention on one of the most common motor transitions in daily living, the initiation of gait (GI). GI is an interesting motor task and a relevant paradigm to address balance and gait impairments in patients with movement disorders, as it is associated with FoG and high risk of falls. It combines a preparatory (i.e., the Anticipatory Postural Adjustments [APA]) and execution phase (the stepping) and allows the study of movement scaling and timing as an expression of muscular synergies, which follow precise and online feedback information processing and integration into established feedforward patterns of motor control.
By applying a multimodal approach that combines biomechanical assessments and neuroimaging investigations, my work unveiled the fundamental contribution of striatal dopamine to GI in patients with PD. Results in patients with PSP further supported the fundamental role of the striatum in GI execution, revealing correlations between the metabolic intake of the left caudate nucleus with diverse GI measurements. This study also unveiled the interplay of additional brain areas in the motor control of GI, namely the Thalamus, the Supplementary Motor Area (SMA), and the Cingulate cortex. Involvement of cortical areas was also suggested by the analysis of GI in patients with PD and FoG. Indeed, I found major alterations in the preparatory phase of GI in these patients, possibly resulting from FoG-related deficits of the SMA. Alterations of the weight shifting preceding the stepping phase were also particularly important in PD patients with FoG, thus suggesting specific difficulties in the integration of somatosensory information at a cortical level. Of note, all patients with PD showed preserved movement timing of GI, possibly suggesting preserved and compensatory activity of the cerebellum. Postural abnormalities (i.e., increased trunk and thigh flexion) showed no relationship with GI, ruling out an adaptation of the motor pattern to the altered postural condition. In a group of PD patients implanted with DBS, I further explored the pathophysiological functioning of the locomotor network by analysing the timely activity of the Subthalamic Nucleus (STN) during static and dynamic balance control (i.e., standing and walking). For this study, I used novel DBS devices capable of delivering stimulation and simultaneously recording Local Field Potentials (LFP) of the implanted nucleus months and years after surgery. I showed a gait-related frequency shift in the STN activity of PD patients, possibly conveying cortical (feedforward) and cerebellar (feedback) information to mesencephalic locomotor areas. Based on this result, I identified for each patient a Maximally Informative Frequency (MIF) whose power changes can reliably classify standing and walking conditions. The MIF is a promising input signal for new DBS devices that can monitor LFP power modulations to timely adjust the stimulation delivery based on the ongoing motor task (e.g., gait) performed by the patient (adaptive DBS).
Altogether my achievements allowed to define the role of different cortical and subcortical brain areas in locomotor control, paving the way for a better understanding of the pathophysiological dynamics of the supraspinal locomotor network and the development of tailored therapies for gait disturbances and falls prevention in PD and related disorders.
Fabry Disease (FD) is a genetic lysosomal storage disorder based on mutations in the gene encoding α-Galactosidase A (α-GalA) leading to accumulation of globotriaosylceramide (Gb3). Missense mutations induce an amino acid exchange (AAE) in the α-GalA. Pain is a predominant symptom in FD and the pathophysiology is unclear. Skin punch biopsies were obtained from 40 adult FD patients and ten healthy controls and dermal fibroblast cultures were generated for cell culture experiments to investigate Gb3 load, gene and protein expression patterns and ion channel activity. The 3D-structure of α-GalA was downloaded into Pymol Graphics System and the AAE was depicted and located in order to investigate the correlation between the AAE location type in the α-GalA and the clinical FD phenotype.
FD dermal fibroblasts showed high Gb3 load depending on treatment interval and expressed Kca1.1 channels. Activity was reduced in FD cells at baseline, but increased over-proportionately upon Gb3-cleavage by enzyme replacement therapy. Gene and protein expression of Kca1.1 was increased in FD cells. FD dermal fibroblasts showed higher gene expression of Notch1 and several cytokines. Further, it was shown that three different AAE location types can be differentiated: mutations in the active site (‘active site’), those buried in the core of α-GalA (‘buried’) and those at another location, mostly on the protein surface (‘other’). FD patients carrying active site or buried mutations showed a severe clinical phenotype with multi-organ manifestation and early disease onset. Patients with other mutations were less severely affected with oligo-organ manifestation sparing the nervous system and later disease onset.
These results show that dermal fibroblasts may be involved in FD-associated pain and that stratification of FD patients carrying missense mutations by AAE location type may be an advantageous parameter that can help in the management of FD patients.
Regional iron accumulation and α‐synuclein (α‐syn) spreading pathology within the central nervous system are common pathological findings in Parkinson's disease (PD). Whereas iron is known to bind to α‐syn, facilitating its aggregation and regulating α‐syn expression, it remains unclear if and how iron also modulates α‐syn spreading. To elucidate the influence of iron on the propagation of α‐syn pathology, we investigated α‐syn spreading after stereotactic injection of α‐syn preformed fibrils (PFFs) into the striatum of mouse brains after neonatal brain iron enrichment. C57Bl/6J mouse pups received oral gavage with 60, 120, or 240 mg/kg carbonyl iron or vehicle between postnatal days 10 and 17. At 12 weeks of age, intrastriatal injections of 5‐µg PFFs were performed to induce seeding of α‐syn aggregates. At 90 days post‐injection, PFFs‐injected mice displayed long‐term memory deficits, without affection of motor behavior. Interestingly, quantification of α‐syn phosphorylated at S129 showed reduced α‐syn pathology and attenuated spreading to connectome‐specific brain regions after brain iron enrichment. Furthermore, PFFs injection caused intrastriatal microglia accumulation, which was alleviated by iron in a dose‐dependent way. In primary cortical neurons in a microfluidic chamber model in vitro, iron application did not alter trans‐synaptic α‐syn propagation, possibly indicating an involvement of non‐neuronal cells in this process. Our study suggests that α‐syn PFFs may induce cognitive deficits in mice independent of iron. However, a redistribution of α‐syn aggregate pathology and reduction of striatal microglia accumulation in the mouse brain may be mediated via iron‐induced alterations of the brain connectome.
Introduction: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) profoundly impacts hemostasis and microvasculature. In the light of the dilemma between thromboembolic and hemorrhagic complications, in the present paper, we systematically investigate the prevalence, mortality, radiological subtypes, and clinical characteristics of intracranial hemorrhage (ICH) in coronavirus disease (COVID-19) patients. Methods: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we performed a systematic review of the literature by screening the PubMed database and included patients diagnosed with COVID-19 and concomitant ICH. We performed a pooled analysis, including a prospectively collected cohort of critically ill COVID-19 patients with ICH, as part of the PANDEMIC registry (Pooled Analysis of Neurologic Disorders Manifesting in Intensive Care of COVID-19). Results: Our literature review revealed a total of 217 citations. After the selection process, 79 studies and a total of 477 patients were included. The median age was 58.8 years. A total of 23.3% of patients experienced the critical stage of COVID-19, 62.7% of patients were on anticoagulation and 27.5% of the patients received ECMO. The prevalence of ICH was at 0.85% and the mortality at 52.18%, respectively. Conclusion: ICH in COVID-19 patients is rare, but it has a very poor prognosis. Different subtypes of ICH seen in COVID-19, support the assumption of heterogeneous and multifaceted pathomechanisms contributing to ICH in COVID-19. Further clinical and pathophysiological investigations are warranted to resolve the conflict between thromboembolic and hemorrhagic complications in the future.
Immune-mediated polyneuropathies like chronic inflammatory demyelinating polyradiculoneuropathy or Guillain-Barré syndrome are rare diseases of the peripheral nervous system. A subgroup of patients harbors autoantibodies against nodal or paranodal antigens, associated with a distinct phenotype and treatment response. In a part of patients with pathologic paranodal or nodal immunoreactivity the autoantigens remain difficult or impossible to determine owing to limitations of the used detection approach - usually ELISAs (enzyme-linked-immunosorbent-assays) - and incomplete knowledge of the possible autoantigens. Due to their high-throughput, low sample consumption and high sensitivity as well as the possibility to display many putative nodal and paranodal autoantigens simultaneously, peptide microarray-based approaches are prime candidates for the discovery of novel autoantigens, point-of-care diagnostics and, in addition, monitoring of pathologic autoimmune response. Current applications of peptide microarrays are however limited by high false-positive rates and the associated need for detailed follow-up studies and validation. Here, robust peptide microarray-based detection of antibodies and the efficient validation of binding signals by on-chip neutralization is demonstrated. First, autoantigens were displayed as overlapping peptide libraries in microarray format. Copies of the biochips were used for the fine mapping of antibody epitopes. Next, binding signals were validated by antibody neutralization in solution. Since neutralizing peptides are obtained in the process of microarray fabrications, neither throughput nor costs are significantly altered. Similar in-situ validation approaches could contribute to future autoantibody characterization and detection methods as well as to therapeutic research. Areas of application could be expanded to any autoimmune-mediated neurological disease as a long-term vision.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that causes progressive autonomy loss and need for care. This does not only affect patients themselves, but also the patients’ informal caregivers (CGs) in their health, personal and professional lives. The big efforts of this multi-center study were not only to evaluate the caregivers' burden and to identify its predictors, but it also should provide a specific understanding of the needs of ALS patients' CGs and fill the gap of knowledge on their personal and work lives. Using standardized questionnaires, primary data from patients and their main informal CGs (n = 249) were collected. Patients' functional status and disease severity were evaluated using the Barthel Index, the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) and the King’s Stages for ALS. The caregivers' burden was recorded by the Zarit Burden Interview (ZBI). Comorbid anxiety and depression of caregivers were assessed by the Hospital Anxiety and Depression Scale. Additionally, the EuroQol Five Dimension Five Level Scale evaluated their health-related quality of life. The caregivers' burden was high (mean ZBI = 26/88, 0 = no burden, ≥24 = highly burdened) and correlated with patients' functional status (r\(_p\) = −0.555, p < 0.001, n = 242). It was influenced by the CGs' own mental health issues due to caregiving (+11.36, 95% CI [6.84; 15.87], p < 0.001), patients' wheelchair dependency (+9.30, 95% CI [5.94; 12.66], p < 0.001) and was interrelated with the CGs' depression (r\(_p\) = 0.627, p < 0.001, n = 234), anxiety (r\(_p\) = 0.550, p < 0.001, n = 234), and poorer physical condition (r\(_p\) = −0.362, p < 0.001, n = 237). Moreover, female CGs showed symptoms of anxiety more often, which also correlated with the patients' impairment in daily routine (r\(_s\) = −0.280, p < 0.001, n = 169). As increasing disease severity, along with decreasing autonomy, was the main predictor of caregiver burden and showed to create relevant (negative) implications on CGs' lives, patient care and supportive therapies should address this issue. Moreover, in order to preserve the mental and physical health of the CGs, new concepts of care have to focus on both, on not only patients but also their CGs and gender-associated specific issues. As caregiving in ALS also significantly influences the socioeconomic status by restrictions in CGs' work lives and income, and the main reported needs being lack of psychological support and a high bureaucracy, the situation of CGs needs more attention. Apart from their own multi-disciplinary medical and psychological care, more support in care and patient management issues is required.
Improving quality of life (QoL) is central to amyotrophic lateral sclerosis (ALS) treatment. This Germany-wide, multicenter cross-sectional study analyses the impact of different symptom-specific treatments and ALS variants on QoL. Health-related QoL (HRQoL) in 325 ALS patients was assessed using the Amyotrophic Lateral Sclerosis Assessment Questionnaire 5 (ALSAQ-5) and EuroQol Five Dimension Five Level Scale (EQ-5D-5L), together with disease severity (captured by the revised ALS Functional Rating Scale (ALSFRS-R)) and the current care and therapies used by our cohort. At inclusion, the mean ALSAQ-5 total score was 56.93 (max. 100, best = 0) with a better QoL associated with a less severe disease status (β = −1.96 per increase of one point in the ALSFRS-R score, p < 0.001). “Limb-onset” ALS (lALS) was associated with a better QoL than “bulbar-onset” ALS (bALS) (mean ALSAQ-5 total score 55.46 versus 60.99, p = 0.040). Moreover, with the ALSFRS-R as a covariate, using a mobility aid (β = −7.60, p = 0.001), being tracheostomized (β = −14.80, p = 0.004) and using non-invasive ventilation (β = −5.71, p = 0.030) were associated with an improved QoL, compared to those at the same disease stage who did not use these aids. In contrast, antidepressant intake (β = 5.95, p = 0.007), and increasing age (β = 0.18, p = 0.023) were predictors of worse QoL. Our results showed that the ALSAQ-5 was better-suited for ALS patients than the EQ-5D-5L. Further, the early and symptom-specific clinical management and supply of assistive devices can significantly improve the individual HRQoL of ALS patients. Appropriate QoL questionnaires are needed to monitor the impact of treatment to provide the best possible and individualized care.
Experimental evidence has emerged that local platelet activation contributes to inflammation and infarct formation in acute ischemic stroke (AIS) which awaits confirmation in human studies. We conducted a prospective observational study on 258 consecutive patients undergoing mechanical thrombectomy (MT) due to large-vessel-occlusion stroke of the anterior circulation (08/2018-05/2020). Intraprocedural microcatheter aspiration of 1 ml of local (occlusion condition) and systemic arterial blood samples (self-control) was performed according to a prespecified protocol. The samples were analyzed for differential leukocyte counts, platelet counts, and plasma levels of the platelet-derived neutrophil-activating chemokine C-X-C-motif ligand (CXCL) 4 (PF-4), the neutrophil attractant CXCL7 (NAP-2), and myeloperoxidase (MPO). The clinical-biological relevance of these variables was corroborated by specific associations with molecular-cellular, structural-radiological, hemodynamic, and clinical-functional parameters. Seventy consecutive patients fulfilling all predefined criteria entered analysis. Mean local CXCL4 (+ 39%: 571 vs 410 ng/ml, P = .0095) and CXCL7 (+ 9%: 693 vs 636 ng/ml, P = .013) concentrations were higher compared with self-controls. Local platelet counts were lower (- 10%: 347,582 vs 383,284/µl, P = .0052), whereas neutrophil counts were elevated (+ 10%: 6022 vs 5485/µl, P = 0.0027). Correlation analyses revealed associations between local platelet and neutrophil counts (r = 0.27, P = .034), and between CXCL7 and MPO (r = 0.24, P = .048). Local CXCL4 was associated with the angiographic degree of reperfusion following recanalization (r = - 0.2523, P = .0479). Functional outcome at discharge correlated with local MPO concentrations (r = 0.3832, P = .0014) and platelet counts (r = 0.288, P = .0181). This study provides human evidence of cerebral platelet activation and platelet-neutrophil interactions during AIS and points to the relevance of per-ischemic thrombo-inflammatory mechanisms to impaired reperfusion and worse functional outcome following recanalization.
Relevance of Religiosity for Coping Strategies and Disability in Patients with Fibromyalgia Syndrome
(2022)
Coping strategies are essential for the outcome of chronic pain. This study evaluated religiosity in a cohort of patients with fibromyalgia syndrome (FMS), its effect on pain and other symptoms, on coping and FMS-related disability. A total of 102 FMS patients were recruited who filled in questionnaires, a subgroup of 42 patients participated in a face-to-face interview, and data were evaluated by correlation and regression analyses. Few patients were traditionally religious, but the majority believed in a higher existence and described their spirituality as "transcendence conviction". The coping strategy "praying-hoping" and the ASP dimension "religious orientation" (r = 0.5, P < 0.05) showed a significant relationship independent of the grade of religiosity (P < 0.05). A high grade of belief in a higher existence was negatively associated with the choice of ignoring as coping strategy (r = - 0.4, P < 0.05). Mood and affect-related variables had the highest impact on disability (b = 0.5, P < 0.05). In this cohort, the grade of religiosity played a role in the choice of coping strategies, but had no effects on health and mood outcome.
Aims
We aimed to analyze prevalence and predictors of NOAC off-label under-dosing in AF patients before and after the index stroke.
Methods
The post hoc analysis included 1080 patients of the investigator-initiated, multicenter prospective Berlin Atrial Fibrillation Registry, designed to analyze medical stroke prevention in AF patients after acute ischemic stroke.
Results
At stroke onset, an off-label daily dose was prescribed in 61 (25.5%) of 239 NOAC patients with known AF and CHA2DS2-VASc score ≥ 1, of which 52 (21.8%) patients were under-dosed. Under-dosing was associated with age ≥ 80 years in patients on rivaroxaban [OR 2.90, 95% CI 1.05-7.9, P = 0.04; n = 29] or apixaban [OR 3.24, 95% CI 1.04-10.1, P = 0.04; n = 22]. At hospital discharge after the index stroke, NOAC off-label dose on admission was continued in 30 (49.2%) of 61 patients. Overall, 79 (13.7%) of 708 patients prescribed a NOAC at hospital discharge received an off-label dose, of whom 75 (10.6%) patients were under-dosed. Rivaroxaban under-dosing at discharge was associated with age ≥ 80 years [OR 3.49, 95% CI 1.24-9.84, P = 0.02; n = 19]; apixaban under-dosing with body weight ≤ 60 kg [OR 0.06, 95% CI 0.01-0.47, P < 0.01; n = 56], CHA2DS2-VASc score [OR per point 1.47, 95% CI 1.08-2.00, P = 0.01], and HAS-BLED score [OR per point 1.91, 95% CI 1.28-2.84, P < 0.01].
Conclusion
At stroke onset, off-label dosing was present in one out of four, and under-dosing in one out of five NOAC patients. Under-dosing of rivaroxaban or apixaban was related to old age. In-hospital treatment after stroke reduced off-label NOAC dosing, but one out of ten NOAC patients was under-dosed at discharge.
This expert opinion paper on cardiac imaging after acute ischemic stroke or transient ischemic attack (TIA) includes a statement of the "Heart and Brain" consortium of the German Cardiac Society and the German Stroke Society. The Stroke Unit-Commission of the German Stroke Society and the German Atrial Fibrillation NETwork (AFNET) endorsed this paper. Cardiac imaging is a key component of etiological work-up after stroke. Enhanced echocardiographic tools, constantly improving cardiac computer tomography (CT) as well as cardiac magnetic resonance imaging (MRI) offer comprehensive non- or less-invasive cardiac evaluation at the expense of increased costs and/or radiation exposure. Certain imaging findings usually lead to a change in medical secondary stroke prevention or may influence medical treatment. However, there is no proof from a randomized controlled trial (RCT) that the choice of the imaging method influences the prognosis of stroke patients. Summarizing present knowledge, the German Heart and Brain consortium proposes an interdisciplinary, staged standard diagnostic scheme for the detection of risk factors of cardio-embolic stroke. This expert opinion paper aims to give practical advice to physicians who are involved in stroke care. In line with the nature of an expert opinion paper, labeling of classes of recommendations is not provided, since many statements are based on expert opinion, reported case series, and clinical experience.
Background: Multimodal rehabilitation improves fatigue and mobility in persons with multiple sclerosis (PwMS). Effects are transient and may be conserved by internet-based physical activity promotion programs. Objective: Evaluate the effects of internet-based physical activity and exercise promotion on fatigue, quality of life, and gait in PwMS after inpatient rehabilitation. Methods: PwMS (Expanded Disability Status Scale (EDSS) ≤ 6.0, fatigue: Würzburg Fatigue Inventory for Multiple Sclerosis (WEIMuS) ≥ 32) were randomized into an intervention group (IG) or a control group (CG). After rehabilitation, IG received 3 months of internet-based physical activity promotion, while CG received no intervention. Primary outcome: self-reported fatigue (WEIMuS). Secondary outcomes: quality of life (Multiple Sclerosis Impact Scale 29, MSIS-29), gait (2min/10m walking test, Tinetti score). Measurements: beginning (T0) and end (T1) of inpatient rehabilitation, 3 (T2) and 6 (T3) months afterwards. Results: 64 of 84 PwMS were analyzed (IG: 34, CG: 30). After rehabilitation, fatigue decreased in both groups. At T2 and T3, fatigue increased again in CG but was improved in IG (p < 0.001). MSIS-29 improved in both groups at T1 but remained improved at T2 and T3 only in IG. Gait improvements were more pronounced in IG at T2. Conclusions: The study provides Class II evidence that the effects of rehabilitation on fatigue, quality of life, and gait can be maintained for 3–6 months with an internet-based physical activity and exercise promotion program.