TY - JOUR A1 - Erbacher, Christoph A1 - Vaknine, Shani A1 - Moshitzky, Gilli A1 - Lobentanzer, Sebastian A1 - Eisenberg, Lina A1 - Evdokimov, Dimitar A1 - Sommer, Claudia A1 - Greenberg, David S. A1 - Soreq, Hermona A1 - Üçeyler, Nurcan T1 - Distinct CholinomiR blood cell signature as a potential modulator of the cholinergic system in women with fibromyalgia syndrome JF - Cells N2 - Fibromyalgia syndrome (FMS) is a heterogeneous chronic pain syndrome characterized by musculoskeletal pain and other key co-morbidities including fatigue and a depressed mood. FMS involves altered functioning of the central and peripheral nervous system (CNS, PNS) and immune system, but the specific molecular pathophysiology remains unclear. Anti-cholinergic treatment is effective in FMS patient subgroups, and cholinergic signaling is a strong modulator of CNS and PNS immune processes. Therefore, we used whole blood small RNA-sequencing of female FMS patients and healthy controls to profile microRNA regulators of cholinergic transcripts (CholinomiRs). We compared microRNA profiles with those from Parkinson's disease (PD) patients with pain as disease controls. We validated the sequencing results with quantitative real-time PCR (qRT-PCR) and identified cholinergic targets. Further, we measured serum cholinesterase activity in FMS patients and healthy controls. Small RNA-sequencing revealed FMS-specific changes in 19 CholinomiRs compared to healthy controls and PD patients. qRT-PCR validated miR-182-5p upregulation, distinguishing FMS patients from healthy controls. mRNA targets of CholinomiRs bone morphogenic protein receptor 2 and interleukin 6 signal transducer were downregulated. Serum acetylcholinesterase levels and cholinesterase activity in FMS patients were unchanged. Our findings identified an FMS-specific CholinomiR signature in whole blood, modulating immune-related gene expression. KW - fibromyalgia syndrome KW - cholinergic system KW - CholinomiRs KW - microRNA KW - miR-182-5p KW - Parkinson's disease Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-270686 SN - 2073-4409 VL - 11 IS - 8 ER - TY - JOUR A1 - Grotemeyer, Alexander A1 - McFleder, Rhonda Leah A1 - Wu, Jingjing A1 - Wischhusen, Jörg A1 - Ip, Chi Wang T1 - Neuroinflammation in Parkinson’s disease – putative pathomechanisms and targets for disease-modification JF - Frontiers in Immunology N2 - Parkinson’s disease (PD) is a progressive and debilitating chronic disease that affects more than six million people worldwide, with rising prevalence. The hallmarks of PD are motor deficits, the spreading of pathological α-synuclein clusters in the central nervous system, and neuroinflammatory processes. PD is treated symptomatically, as no causally-acting drug or procedure has been successfully established for clinical use. Various pathways contributing to dopaminergic neuron loss in PD have been investigated and described to interact with the innate and adaptive immune system. We discuss the possible contribution of interconnected pathways related to the immune response, focusing on the pathophysiology and neurodegeneration of PD. In addition, we provide an overview of clinical trials targeting neuroinflammation in PD. KW - Parkinson’s disease KW - neuroinflammation KW - T cells KW - microglia KW - neurodegeneration KW - animal models KW - inflammatory cascades Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-274665 SN - 1664-3224 VL - 13 ER - TY - JOUR A1 - Appeltshauser, Luise A1 - Messinger, Julia A1 - Starz, Katharina A1 - Heinrich, David A1 - Brunder, Anna-Michelle A1 - Stengel, Helena A1 - Fiebig, Bianca A1 - Ayzenberg, Ilya A1 - Birklein, Frank A1 - Dresel, Christian A1 - Dorst, Johannes A1 - Dvorak, Florian A1 - Grimm, Alexander A1 - Joerk, Alexander A1 - Leypoldt, Frank A1 - Mäurer, Mathias A1 - Merl, Patrick A1 - Michels, Sebastian A1 - Pitarokoili, Kalliopi A1 - Rosenfeldt, Mathias A1 - Sperfeld, Anne-Dorte A1 - Weihrauch, Marc A1 - Welte, Gabriel Simon A1 - Sommer, Claudia A1 - Doppler, Kathrin T1 - Diabetes Mellitus Is a Possible Risk Factor for Nodo-paranodopathy With Antiparanodal Autoantibodies JF - Neurology: Neuroimmunology & Neuroinflammation N2 - 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. KW - Diabetes mellitus KW - Nodo-parandopathy KW - Antiparanodal Autoantibodies Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300551 VL - 9 IS - 3 ER - TY - JOUR A1 - Traub, Jan A1 - Otto, Markus A1 - Sell, Roxane A1 - Homola, György A. A1 - Steinacker, Petra A1 - Oeckl, Patrick A1 - Morbach, Caroline A1 - Frantz, Stefan A1 - Pham, Mirko A1 - Störk, Stefan A1 - Stoll, Guido A1 - Frey, Anna T1 - Serum glial fibrillary acidic protein indicates memory impairment in patients with chronic heart failure JF - ESC Heart Failure N2 - Aims Cognitive dysfunction occurs frequently in patients with heart failure (HF), but early detection remains challenging. Serum glial fibrillary acidic protein (GFAP) is an emerging biomarker of cognitive decline in disorders of primary neurodegeneration such as Alzheimer's disease. We evaluated the utility of serum GFAP as a biomarker for cognitive dysfunction and structural brain damage in patients with stable chronic HF. Methods and results Using bead-based single molecule immunoassays, we quantified serum levels of GFAP in patients with HF participating in the prospective Cognition.Matters-HF study. Participants were extensively phenotyped, including cognitive testing of five separate domains and magnetic resonance imaging (MRI) of the brain. Univariable and multivariable models, also accounting for multiple testing, were run. One hundred and forty-six chronic HF patients with a mean age of 63.8 ± 10.8 years were included (15.1% women). Serum GFAP levels (median 246 pg/mL, quartiles 165, 384 pg/mL; range 66 to 1512 pg/mL) did not differ between sexes. In the multivariable adjusted model, independent predictors of GFAP levels were age (T = 5.5; P < 0.001), smoking (T = 3.2; P = 0.002), estimated glomerular filtration rate (T = −4.7; P < 0.001), alanine aminotransferase (T = −2.1; P = 0.036), and the left atrial end-systolic volume index (T = 3.4; P = 0.004). NT-proBNP but not serum GFAP explained global cerebral atrophy beyond ageing. However, serum GFAP levels were associated with the cognitive domain visual/verbal memory (T = −3.0; P = 0.003) along with focal hippocampal atrophy (T = 2.3; P = 0.025). Conclusions Serum GFAP levels are affected by age, smoking, and surrogates of the severity of HF. The association of GFAP with memory dysfunction suggests that astroglial pathologies, which evade detection by conventional MRI, may contribute to memory loss beyond ageing in patients with chronic HF. KW - Glial fibrillary acidic protein KW - GFAP KW - Chronic heart failure KW - Cognitive decline KW - Memory dysfunction KW - Brain atrophy Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-312736 VL - 9 IS - 4 ER - TY - JOUR A1 - Bieber, Michael A1 - Schuhmann, Michael K. A1 - Bellut, Maximilian A1 - Stegner, David A1 - Heinze, Katrin G. A1 - Pham, Mirko A1 - Nieswandt, Bernhard A1 - Stoll, Guido T1 - Blockade of platelet glycoprotein Ibα augments neuroprotection in Orai2-deficient mice during middle cerebral artery occlusion JF - International Journal of Molecular Sciences N2 - During ischemic stroke, infarct growth before recanalization diminishes functional outcome. Hence, adjunct treatment options to protect the ischemic penumbra before recanalization are eagerly awaited. In experimental stroke targeting two different pathways conferred protection from penumbral tissue loss: (1) enhancement of hypoxic tolerance of neurons by deletion of the calcium channel subunit Orai2 and (2) blocking of detrimental lymphocyte–platelet responses. However, until now, no preclinical stroke study has assessed the potential of combining neuroprotective with anti-thrombo-inflammatory interventions to augment therapeutic effects. We induced focal cerebral ischemia in Orai2-deficient (Orai2\(^{-/-}\)) mice by middle cerebral artery occlusion (MCAO). Animals were treated with anti-glycoprotein Ib alpha (GPIbα) Fab fragments (p0p/B Fab) blocking GPIbα–von Willebrand factor (vWF) interactions. Rat immunoglobulin G (IgG) Fab was used as the control treatment. The extent of infarct growth before recanalization was assessed at 4 h after MCAO. Moreover, infarct volumes were determined 6 h after recanalization (occlusion time: 4 h). Orai2 deficiency significantly halted cerebral infarct progression under occlusion. Inhibition of platelet GPIbα further reduced primary infarct growth in Orai2\(^{-/-}\) mice. During ischemia–reperfusion, upon recanalization, mice were likewise protected. All in all, we show that neuroprotection in Orai2\(^{-/-}\) mice can be augmented by targeting thrombo-inflammation. This supports the clinical development of combined neuroprotective/anti-platelet strategies in hyper-acute stroke. KW - ischemic penumbra KW - Orai2 KW - glycoprotein receptor Ibα KW - ischemic stroke KW - thrombo-inflammation KW - middle cerebral artery occlusion Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-286038 SN - 1422-0067 VL - 23 IS - 16 ER - TY - JOUR A1 - Traub, Jan A1 - Grondey, Katja A1 - Gassenmaier, Tobias A1 - Schmitt, Dominik A1 - Fette, Georg A1 - Frantz, Stefan A1 - Boivin-Jahns, Valérie A1 - Jahns, Roland A1 - Störk, Stefan A1 - Stoll, Guido A1 - Reiter, Theresa A1 - Hofmann, Ulrich A1 - Weber, Martin S. A1 - Frey, Anna T1 - Sustained increase in serum glial fibrillary acidic protein after first ST-elevation myocardial infarction JF - International Journal of Molecular Sciences N2 - Acute ischemic cardiac injury predisposes one to cognitive impairment, dementia, and depression. Pathophysiologically, recent positron emission tomography data suggest astroglial activation after experimental myocardial infarction (MI). We analyzed peripheral surrogate markers of glial (and neuronal) damage serially within 12 months after the first ST-elevation MI (STEMI). Serum levels of glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) were quantified using ultra-sensitive molecular immunoassays. Sufficient biomaterial was available from 45 STEMI patients (aged 28 to 78 years, median 56 years, 11% female). The median (quartiles) of GFAP was 63.8 (47.0, 89.9) pg/mL and of NfL 10.6 (7.2, 14.8) pg/mL at study entry 0–4 days after STEMI. GFAP after STEMI increased in the first 3 months, with a median change of +7.8 (0.4, 19.4) pg/mL (p = 0.007). It remained elevated without further relevant increases after 6 months (+11.7 (0.6, 23.5) pg/mL; p = 0.015), and 12 months (+10.3 (1.5, 22.7) pg/mL; p = 0.010) compared to the baseline. Larger relative infarction size was associated with a higher increase in GFAP (ρ = 0.41; p = 0.009). In contrast, NfL remained unaltered in the course of one year. Our findings support the idea of central nervous system involvement after MI, with GFAP as a potential peripheral biomarker of chronic glial damage as one pathophysiologic pathway. KW - myocardial infarction KW - STEMI KW - glial fibrillary acidic protein KW - GFAP KW - neurofilament light chain KW - NfL KW - glial damage KW - cardiac magnetic resonance imaging KW - MRI KW - infarction size Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-288261 SN - 1422-0067 VL - 23 IS - 18 ER - TY - JOUR A1 - Kraft, Peter A1 - Schuhmann, Michael K. T1 - Cellular and molecular targets in acute ischemic stroke JF - International Journal of Molecular Sciences N2 - No abstract available Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-288294 SN - 1422-0067 VL - 23 IS - 19 ER - TY - JOUR A1 - Tütüncü, Serdar A1 - Olma, Manuel A1 - Kunze, Claudia A1 - Dietzel, Joanna A1 - Schurig, Johannes A1 - Fiessler, Cornelia A1 - Malsch, Carolin A1 - Haas, Tobias Eberhard A1 - Dimitrijeski, Boris A1 - Doehner, Wolfram A1 - Hagemann, Georg A1 - Hamilton, Frank A1 - Honermann, Martin A1 - Jungehulsing, Gerhard Jan A1 - Kauert, Andreas A1 - Koennecke, Hans-Christian A1 - Mackert, Bruno-Marcel A1 - Nabavi, Darius A1 - Nolte, Christian H. A1 - Reis, Joschua Mirko A1 - Schmehl, Ingo A1 - Sparenberg, Paul A1 - Stingele, Robert A1 - Völzke, Enrico A1 - Waldschmidt, Carolin A1 - Zeise-Wehry, Daniel A1 - Heuschmann, Peter U. A1 - Endress, Matthias A1 - Haeusler, Karl Georg T1 - Off-label-dosing of non-vitamin K-dependent oral antagonists in AF patients before and after stroke: results of the prospective multicenter Berlin Atrial Fibrillation Registry JF - Journal of Neurology N2 - 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. KW - NOAC KW - ischemic stroke KW - atrial fibrillation KW - under-dosing Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-266969 SN - 1432-1459 VL - 269 IS - 1 ER - TY - JOUR A1 - Huss, André A1 - Abdelhak, Ahmed A1 - Mayer, Benjamin A1 - Tumani, Hayrettin A1 - Müller, Hans-Peter A1 - Althaus, Katharina A1 - Kassubek, Jan A1 - Otto, Markus A1 - Ludolph, Albert C. A1 - Yilmazer-Hanke, Deniz A1 - Neugebauer, Hermann T1 - Association of serum GFAP with functional and neurocognitive outcome in sporadic small vessel disease JF - Biomedicines N2 - Cerebrospinal fluid (CSF) and serum biomarkers are critical for clinical decision making in neurological diseases. In cerebral small vessel disease (CSVD), white matter hyperintensities (WMH) are an important neuroimaging biomarker, but more blood-based biomarkers capturing different aspects of CSVD pathology are needed. In 42 sporadic CSVD patients, we prospectively analysed WMH on magnetic resonance imaging (MRI) and the biomarkers neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), chitinase3-like protein 1 (CHI3L1), Tau and Aβ1-42 in CSF and NfL and GFAP in serum. GFAP and CHI3L1 expression was studied in post-mortem brain tissue in additional cases. CSVD cases with higher serum NfL and GFAP levels had a higher modified Rankin Scale (mRS) and NIHSS score and lower CSF Aβ1-42 levels, whereas the CSF NfL and CHI3L1 levels were positively correlated with the WMH load. Moreover, the serum GFAP levels significantly correlated with the neurocognitive functions. Pathological analyses in CSVD revealed a high density of GFAP-immunoreactive fibrillary astrocytic processes in the periventricular white matter and clusters of CHI3L1-immunoreactive astrocytes in the basal ganglia and thalamus. Thus, besides NfL, serum GFAP is a highly promising fluid biomarker of sporadic CSVD, because it does not only correlate with the clinical severity but also correlates with the cognitive function in patients. KW - chitinase-3-like protein 1 KW - GFAP KW - neurofilaments KW - white matter hyperintensities KW - biomarker KW - CSVD Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-285973 SN - 2227-9059 VL - 10 IS - 8 ER - TY - JOUR A1 - Kline, Rachel A. A1 - Lößlein, Lena A1 - Kurian, Dominic A1 - Aguilar Martí, Judit A1 - Eaton, Samantha L. A1 - Court, Felipe A. A1 - Gillingwater, Thomas H. A1 - Wishart, Thomas M. T1 - An optimized comparative proteomic approach as a tool in neurodegenerative disease research JF - Cells N2 - Recent advances in proteomic technologies now allow unparalleled assessment of the molecular composition of a wide range of sample types. However, the application of such technologies and techniques should not be undertaken lightly. Here, we describe why the design of a proteomics experiment itself is only the first step in yielding high-quality, translatable results. Indeed, the effectiveness and/or impact of the majority of contemporary proteomics screens are hindered not by commonly considered technical limitations such as low proteome coverage but rather by insufficient analyses. Proteomic experimentation requires a careful methodological selection to account for variables from sample collection, through to database searches for peptide identification to standardised post-mass spectrometry options directed analysis workflow, which should be adjusted for each study, from determining when and how to filter proteomic data to choosing holistic versus trend-wise analyses for biologically relevant patterns. Finally, we highlight and discuss the difficulties inherent in the modelling and study of the majority of progressive neurodegenerative conditions. We provide evidence (in the context of neurodegenerative research) for the benefit of undertaking a comparative approach through the application of the above considerations in the alignment of publicly available pre-existing data sets to identify potential novel regulators of neuronal stability. KW - proteomics KW - systems biology KW - experimental design KW - neurodegeneration KW - pathway analysis KW - data filtering Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-285912 SN - 2073-4409 VL - 11 IS - 17 ER -