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Publication Open Access Anti-pan-neurofascin IgG3 as a marker of fulminant autoimmune neuropathy(Lippincott Williams and Wilkins (LWW), 2019) Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM)Objective: to identify and characterize patients with autoantibodies against different neurofascin (NF) isoforms. Methods: screening of a large cohort of patient sera for anti-NF autoantibodies by ELISA and further characterization by cell-based assays, epitope mapping, and complement binding assays. Results: two different clinical phenotypes became apparent in this study: The well-known clinical picture of subacute-onset severe sensorimotor neuropathy with tremor that is known to be associated with IgG4 autoantibodies against the paranodal isoform NF-155 was found in 2 patients. The second phenotype with a dramatic course of disease with tetraplegia and almost locked-in syndrome was associated with IgG3 autoantibodies against nodal and paranodal isoforms of NF in 3 patients. The epitope against which these autoantibodies were directed in this second phenotype was the common Ig domain found in all 3 NF isoforms. In contrast, anti-NF-155 IgG4 were directed against the NF-155-specific Fn3Fn4 domain. The description of a second phenotype of anti-NF-associated neuropathy is in line with some case reports of similar patients that were published in the last year. Conclusions: our results indicate that anti-pan-NF-associated neuropathy differs from anti-NF-155-associated neuropathy, and epitope and subclass play a major role in the pathogenesis and severity of anti-NF-associated neuropathy and should be determined to correctly classify patients, also in respect to possible differences in therapeutic response.
Item Metadata only Associations between sleep characteristics and glycemic variability in youth with type 1 diabetes(Elsevier, 2023) 0000-0002-2614-0832; 0000-0003-3781-3892; 0000-0001-6312-6004; 0000-0002-8889-6811; 0000-0002-7855-1297; 0000-0003-3919-7763; 0000-0003-1633-9570; Boran, Perran; Baris, Hatice Ezgi; Us, Mahmut Caner; Aygun, Burcu; Haliloglu, BelmaBereket, Abdullah; N/A; N/A; N/A; N/A; Department of Computer Engineering; N/A; N/A; İpar, Necla; Gökçe, Tuğba; Can, Ecem; Eviz, Elif; İnan, Neslihan Gökmen; Mutlu, Rahime Gül Yeşiltepe; Hatun, Şükrü; Doctor; Doctor; Nurse; Researcher; Teaching Faculty; Faculty Member; Faculty Member; N/A; N/A; N/A; School of Medicine; College of Engineering; School of Medicine; School of Medicine; Koç University Hospital; N/A; N/A; N/A; 327618; 285581; 153511; 153504Objective: This study aimed to determine sleep characteristics and their associations with glycemic variability in youth with type 1 diabetes (T1D).Material and methods: This cross-sectional study conducted at two pediatric diabetes centers in Istanbul, Turkey, included 84 children with T1D (mean age 10.5 years). Sleep characteristics and glycemic variability were determined by actigraphy, DSM-5 Level 2-Sleep Disturbance Scale Short Form and continuous glucose monitoring. Circadian preference was evaluated by the Children's Chronotype Questionnaire. Sleep disturbances were assessed by the. The sleep quality was determined by actigraphyderived sleep measures. Results: Eighty-eight percent of participants had insufficient age-appropriate total sleep time (TST) (<9 h for 6-13-year-olds and <8 h for 14-17-year-olds). Chronotype was classified as intermediate in 50%, evening in 45.2%, and morning in 4.8%. A higher chronotype score indicating a stronger eveningness preference was associated with more time spent in hypoglycemia (f3= 0.433, p = 0.002). On nights when participants had lower sleep efficiency and longer sleep onset latency, they had significantly higher overnight glycemic variability (f3 = -0.343, p = 0.016, f3 = 0.129, p = 0.017, respectively). Prolonged nocturnal wake duration was significantly associated with more time spent in daytime hypoglycemia (f3 = 0.037, p = 0.046) and higher overnight glycemic variability (J index, f3 = 0.300, p = 0.015). The associations between TST and glycemic variability indices were not significant.Conclusions: Sleep quality rather than TST was significantly associated with glycemic variability in children with T1D. Eveningness preference might contribute to an increased risk of hypoglycemia. Addressing sleep patterns and chronotypes can be crucial in management plans for youth with T1D.& COPY; 2023 Elsevier B.V. All rights reserved.Item Metadata only Chloride intracellular channel protein-1 (CLIC1) antibody in multiple sclerosis patients with predominant optic nerve and spinal cord involvement(Elsevier Sci Ltd, 2023) 0000-0002-0860-8964; Karaaslan, Zerrin; Sengul-Yediel, Busra; Yuceer-Korkmaz, Hande; Sanlia, Elif; Gezen-Ak, Duygu; Dursun, Erdinc; Timirci-Kahraman, Ozlem; Baykal, Ahmet Tarik; Yilmaz, Vuslat; Turkoglu, Recai; Kurtuncu, Murat; Gunduz, Tuncay; Gursoy-Ozdemir, Yasemin; Tuzun, Erdem; Kucukali, Cem Ismail; N/A; Özdemir, Yasemin Gürsoy; Faculty Member; School of Medicine; 170592Introduction: Antibodies to cell surface proteins of astrocytes have been described in chronic inflammatory demyelinating disorders (CIDD) of the central nervous system including multiple sclerosis (MS) and neuro-myelitis optica spectrum disorder (NMOSD). Our aim was to identify novel anti-astrocyte autoantibodies in relapsing remitting MS (RRMS) patients presenting predominantly with spinal cord and optic nerve attacks (MS-SCON).Methods: Sera of 29 MS-SCON patients and 36 healthy controls were screened with indirect immunofluorescence to identify IgG reacting with human astrocyte cultures. Putative target autoantigens were investigated with immunoprecipitation (IP) and liquid chromatography-mass/mass spectrometry (LC-MS/MS) studies using cultured human astrocytes. Validation of LC-MS/MS results was carried out by IP and ELISA.Results: Antibodies to astrocytic cell surface antigens were detected in 5 MS-SCON patients by immunocyto-chemistry. LC-MS/MS analysis identified chloride intracellular channel protein-1 (CLIC1) as the single common membrane antigen in 2 patients with MS-SCON. IP experiments performed with the commercial CLIC1 antibody confirmed CLIC1-antibody. Home made ELISA using recombinant CLIC1 protein as the target antigen identified CLIC1 antibodies in 9/29 MS-SCON and 3/15 relapsing inflammatory optic neuritis (RION) patients but in none of the 30 NMOSD patients, 36 RRMS patients with only one or no myelitis/optic neuritis attacks and 36 healthy controls. Patients with CLIC1-antibodies showed trends towards exhibiting reduced disability scores.Conclusion: CLIC1-antibody was identified for the first time in MS and RION patients, confirming once again anti-astrocytic autoimmunity in CIDD. CLIC1-antibody may potentially be utilized as a diagnostic biomarker for differentiation of MS from NMOSD.Publication Open Access Cortical spreading depression can be triggered by sensory stimulation in primed wild type mouse brain: a mechanistic insight to migraine aura generation(BioMed Central, 2022) Hanalioğlu, Şahin; Sağ, Aslıhan Taşkıran; Karataş, Hülya; Demir, Buket Dönmez; Özcan, Sinem Yılmaz; Koçak, Emine Eren; Dalkara, Turgay; Özdemir, Yasemin Gürsoy; Faculty Member; Researcher; Faculty Member; School of Medicine; 170592Background: unlike the spontaneously appearing aura in migraineurs, experimentally, cortical spreading depression (CSD), the neurophysiological correlate of aura is induced by non-physiological stimuli. Consequently, neural mechanisms involved in spontaneous CSD generation, which may provide insight into how migraine starts in an otherwise healthy brain, remain largely unclear. We hypothesized that CSD can be physiologically induced by sensory stimulation in primed mouse brain. Methods: cortex was made susceptible to CSD with partial inhibition of Na+/K+-ATPase by epidural application of a low concentration of Na+/K+-ATPase blocker ouabain, allowing longer than 30-min intervals between CSDs or by knocking-down ?2 subunit of Na+/K+-ATPase, which is crucial for K+ and glutamate re-uptake, with shRNA. Stimulation-triggered CSDs and extracellular K+ changes were monitored in vivo electrophysiologically and a K+-sensitive fluoroprobe (IPG-4), respectively. Results: after priming with ouabain, photic stimulation significantly increased the CSD incidence compared with non-stimulated animals (44.0 vs. 4.9%, p < 0.001). Whisker stimulation also significantly increased the CSD incidence, albeit less effectively (14.9 vs. 2.4%, p = 0.02). Knocking-down Na+/K+-ATPase (50% decrease in mRNA) lowered the CSD threshold in all mice tested with KCl but triggered CSDs in 14.3% and 16.7% of mice with photic and whisker stimulation, respectively. Confirming Na+/K+-ATPase hypofunction, extracellular K+ significantly rose during sensory stimulation after ouabain or shRNA treatment unlike controls. In line with the higher CSD susceptibility observed, K+ rise was more prominent after ouabain. To gain insight to preventive mechanisms reducing the probability of stimulus-evoked CSDs, we applied an A1-receptor antagonist (DPCPX) to the occipital cortex, because adenosine formed during stimulation from ATP can reduce CSD susceptibility. DPCPX induced spontaneous CSDs but only small-DC shifts along with suppression of EEG spikes during photic stimulation, suggesting that the inhibition co-activated with sensory stimulation could limit CSD ignition when K+ uptake was not sufficiently suppressed as with ouabain. Conclusions: normal brain is well protected against CSD generation. For CSD to be ignited under physiological conditions, priming and predisposing factors are required as seen in migraine patients. Intense sensory stimulation has potential to trigger CSD when co-existing conditions bring extracellular K+ and glutamate concentrations over CSD-ignition threshold and stimulation-evoked inhibitory mechanisms are overcome.Publication Open Access Identification of circulating MOG-specific B cells in patients with MOG antibodies(Lippincott Williams and Wilkins (LWW), 2019) Winklmeier, Stephan; Schlueter, Miriam; Spadaro, Melania; Thaler, Franziska S.; Gerhards, Ramona; Macrini, Caterina; Mader, Simone A.; Kurne, Asli; Inan, Berin; Karabudak, Rana; Ozbay, Feyza Gul; Esendagli, Gunes; Hohlfeld, Reinhard; Kuempfel, Tania; Meinl, Edgar; Vural, Atay; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); 182369Objective: to identify circulating myelin oligodendrocyte glycoprotein (MOG)-specific B cells in the blood of patients with MOG antibodies (Abs) and to determine whether circulating MOG-specific B cells are linked to levels and epitope specificity of serum anti-MOG-Abs. Methods: we compared peripheral blood from 21 patients with MOG-Abs and 26 controls for the presence of MOG-specific B cells. We differentiated blood-derived B cells in vitro in separate culture wells to Ab-producing cells via engagement of Toll-like receptors 7 and 8. We quantified the anti-MOG reactivity with a live cell-based assay by flow cytometry. We determined the recognition of MOG epitopes with a panel of mutated variants of MOG. Results: MOG-Ab-positive patients had a higher frequency of MOG-specific B cells in blood than controls, but MOG-specific B cells were only detected in about 60% of these patients. MOG-specific B cells in blood showed no correlation with anti-MOG Ab levels in serum, neither in the whole group nor in the untreated patients. Epitope analysis of MOG-Abs secreted from MOG-specific B cells cultured in different wells revealed an intraindividual heterogeneity of the anti-MOG autoimmunity. Conclusions: This study shows that patients with MOG-Abs greatly differ in the abundance of circulating MOG-specific B cells, which are not linked to levels of MOG-Abs in serum suggesting different sources of MOG-Abs. Identification of MOG-specific B cells in blood could be of future relevance for selecting patients with MOG-Abs for B cell-directed therapy.Publication Metadata only Pediatric-onset chronic inflammatory demyelinating polyneuropathy: a multicenter study(Elsevier Science Inc, 2023) Uzan, Gamze Sarikaya; Yuksel, Deniz; Aksoy, Erhan; Oztoprak, Ulkuhan; Canpolat, Mehmet; Ozturk, Selcan; Yildirim, Celebi; Gulec, Ayten; Per, Huseyin; Gumus, Hakan; Okuyaz, Cetin; Direk, Meltem Cobanoullari; Kosmur, Mustafa; Unalp, Aycan; Yilmaz, Unsal; Bektas, Omer; Teber, Serap; Aliyeva, Nargiz; Dundar, Nihal Olgac; Gencpinar, Pinar; Gurkas, Esra; Yilmaz, Sanem Keskin; Kanmaz, Seda; Tekgtil, Hasan; Aksoy, Ayse; Tuncer, Gokcen Oz; Arslan, Elif Acar; Tosun, Ayse; Ayanoglu, Muge; Bodur, Muhittin; Unay, Bulent; Kurul, Semra Hiz; Yis, Uluc; Vural, Atay; Yousefi, Mohammadreza; Kızılırmak, Ali Burak; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; Graduate School of Health SciencesBackground: To evaluate the clinical features, demographic features, and treatment modalities of pediatric-onset chronic inflammatory demyelinating polyneuropathy (CIDP) in Turkey. Methods: The clinical data of patients between January 2010 and December 2021 were reviewed retrospectively. The patients were evaluated according to the Joint Task Force of the European Federation of Neurological Societies and the Peripheral Nerve Society Guideline on the management of CIDP (2021). In addition, patients with typical CIDP were divided into two groups according to the first-line treatment modalities (group 1: IVIg only, group 2: IVIg + steroid). The patients were further divided into two separate groups based on their magnetic resonance imaging (MRI) characteristics. Results: A total of 43 patients, 22 (51.2%) males and 21 (48.8%) females, were included in the study. There was a significant difference between pretreatment and post-treatment modified Rankin scale (mRS) scores (P < 0.05) of all patients. First-line treatments include intravenous immunoglobulin (IVIg) (n = 19, 4 4.2%), IVIg + steroids (n = 20, 46.5%), steroids (n = 1, 2.3%), IVIg + steroids + plasmapheresis (n = 1, 2.3%), and IVIg + plasmapheresis (n = 1, 2.3%). Alternative agent therapy consisted of azathioprine (n = 5), rituximab (n = 1), and azathioprine + mycophenolate mofetil + methotrexate (n = 1). There was no difference between the pretreatment and post-treatment mRS scores of groups 1 and 2 (P > 0.05); however, a significant decrease was found in the mRS scores of both groups with treatment (P < 0.05). The patients with abnormal MRI had significantly higher pretreatment mRS scores compared with the group with normal MRI (P < 0.05). Conclusions: This multicenter study demonstrated that first-line immunotherapy modalities (IVIg vs IVIg + steroids) had equal efficacy for the treatment of patients with CIDP. We also determined that MRI features might be associated with profound clinical features, but did not affect treatment response.Publication Metadata only Reorganization of brain connectivity across the spectrum of clinical cognitive decline(SPRINGER-VERLAG ITALIA SRL, 2024) Dal, Demet Yüksel; Yıldırım, Zerrin; Gurvit, Hakan; Acar, Burak; Department of Physics; Department of Physics; Kabakçıoğlu, Alkan; ; College of Sciences;Clinical cognitive decline, leading to Alzheimer's Disease Dementia (ADD), has long been interpreted as a disconnection syndrome, hindering the information flow capacity of the brain, hence leading to the well-known symptoms of ADD. The structural and functional brain connectome analyses play a central role in studies of brain from this perspective. However, most current research implicitly assumes that the changes accompanying the progression of cognitive decline are monotonous in time, whether measured across the entire brain or in fixed cortical regions. We investigate the structural and functional connectivity-wise reorganization of the brain without such assumptions across the entire spectrum. We utilize nodal assortativity as a local topological measure of connectivity and follow a data-centric approach to identify and verify relevant local regions, as well as to understand the nature of underlying reorganization. The analysis of our preliminary experimental data points to statistically significant, hyper and hypo-assortativity regions that depend on the disease's stage, and differ for structural and functional connectomes. Our results suggest a new perspective into the dynamic, potentially a mix of degenerative and compensatory, topological alterations that occur in the brain as cognitive decline progresses.Publication Metadata only Utility of diffusion tensor imaging and generalized q-sampling imaging for predicting short-term clinical effect of deep brain stimulation in Parkinson's disease(SPRINGER WIEN, 2024) Hasimoglu, Ozan; Balsak, Serdar; Mutlu, Samet; Karagulle, Mehmet; Kose, Fadime; Altinkaya, Ayca; Tugcu, Bekir; Kocak, Burak; Yüzkan, Sabahattin; Koç University HospitalPurpose To assess whether diffusion tensor imaging (DTI) and generalized q-sampling imaging (GQI) metrics could preoperatively predict the clinical outcome of deep brain stimulation (DBS) in patients with Parkinson's disease (PD). Methods In this single-center retrospective study, from September 2021 to March 2023, preoperative DTI and GQI examinations of 44 patients who underwent DBS surgery, were analyzed. To evaluate motor functions, the Unified Parkinson's Disease Rating Scale (UPDRS) during on- and off-medication and Parkinson's Disease Questionnaire-39 (PDQ-39) scales were used before and three months after DBS surgery. The study population was divided into two groups according to the improvement rate of scales: >= 50% and < 50%. Five target regions, reported to be affected in PD, were investigated. The parameters having statistically significant difference were subjected to a receiver operating characteristic (ROC) analysis. Results Quantitative anisotropy (qa) values from globus pallidus externus, globus pallidus internus (qa_Gpi), and substantia nigra exhibited significant distributional difference between groups in terms of the improvement rate of UPDRS-3 scale during on-medication (p = 0.003, p = 0.0003, and p = 0.0008, respectively). In ROC analysis, the best parameter in predicting DBS response included qa_Gpi with a cut-off value of 0.01370 achieved an area under the ROC curve, accuracy, sensitivity, and specificity of 0.810, 73%, 62.5%, and 85%, respectively. Optimal cut-off values of >= 0.01864 and <= 0.01162 yielded a sensitivity and specificity of 100%, respectively. Conclusion The imaging parameters acquired from GQI, particularly qa_Gpi, may have the ability to non-invasively predict the clinical outcome of DBS surgery.