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BACKGROUND: Compared to intensive care unit patients with SARS-CoV-2 negative acute respiratory tract infections, patients with SARS-CoV-2 are supposed to develop more frequently and more severely neurologic sequelae. Delirium and subsequent neurocognitive deficits (NCD) have implications for patients' morbidity and mortality. However, the extent of brain injury during acute COVID-19 and subsequent NCD still remain largely unexplored. Body-fluid biomarkers may offer valuable insights into the quantification of acute delirium, brain injury and may help to predict subsequent NCD following COVID-19. METHODS: In a multicenter, observational case-control study, conducted across four German University Hospitals, hospitalized adult and pediatric patients with an acute COVID-19 and SARS-CoV-2 negative controls presenting with acute respiratory tract infections were included. Study procedures comprised the assessment of pre-existing neurocognitive function, daily screening for delirium, neurological examination and blood sampling. Fourteen biomarkers indicative of neuroaxonal, glial, neurovascular injury and inflammation were analyzed. Neurocognitive functions were re-evaluated after three months. RESULTS: We enrolled 118 participants (90 adults, 28 children). The incidence of delirium [85 out of 90 patients (94.4%) were assessable for delirium) was comparable between patients with COVID-19 [16 out of 61 patients (26.2%)] and SARS-CoV-2 negative controls [8 out of 24 patients (33.3%); p > 0.05] across adults and children. No differences in outcomes as measured by the modified Rankin Scale, the Short-Blessed Test, the Informant Questionnaire on Cognitive Decline in the Elderly, and the pediatrics cerebral performance category scale were observed after three months. Levels of body-fluid biomarkers were generally elevated in both adult and pediatric cohorts, without significant differences between SARS-CoV-2 negative controls and COVID-19. In COVID-19 patients experiencing delirium, levels of GFAP and MMP-9 were significantly higher compared to those without delirium. CONCLUSIONS: Delirium and subsequent NCD are not more frequent in COVID-19 as compared to SARS-CoV-2 negative patients with acute respiratory tract infections. Consistently, biomarker levels of brain injury indicated no differences between COVID-19 cases and SARS-CoV-2 negative controls. Our data suggest that delirium in COVID-19 does not distinctly trigger substantial and persistent subsequent NCD compared to patients with other acute respiratory tract infections. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04359914; date of registration 24-APR 2020.
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Introduction: Advances in spine surgery enable safe interventions in elderly patients, but perioperative neurocognitive disorders (pNCD), such as post-operative delirium (POD) and cognitive dysfunction (POCD), remain a serious concern. Pre-operative cognitive impairment is a major risk factor for pNCD. Comprehensive pre-operative cognitive assessments are not feasible in clinical practice, making effective screening methods desirable. This study investigates whether pre-operative cerebrovascular duplex sonography can assess subcortical (vascular) cognitive impairment and the risk for POD. Methods: This prospective single-center study recruited patients aged ≥60 years scheduled for elective spine surgery at a German university hospital. Patients underwent pre-operative assessments including cognitive abilities (CERAD test battery), structural MRI, and cerebrovascular duplex sonography. POD screening was conducted three times daily for at least 3 days. The primary hypothesis, that the mean pulsatility index (PI) of both internal carotid arteries (ICA) predicts POD risk, was tested using logistic regression. Secondary analyses examined the association between POD risk and ICA flow (time-averaged peak velocities, TAPV) and correlations with cognitive profiles and MRI characteristics. Results: POD occurred in 22% of patients (n = 22/99) within three postoperative days. Patients with POD were significantly older (75.9 ± 5.4 vs. 70.0 ± 6.9 years, p < 0.01) but did not differ by gender (p = 0.51). ICA PI significantly predicted POD risk (OR = 5.46 [95%CI: 1.81-16.49], p = 0.003), which remained significant after adjustment for age and duration of surgery (ORadj = 6.38 [95% CI: 1.77-23.03], p = 0.005). TAPV did not inform the POD risk (p = 0.68). ICA PI Pre-operative cognitive scores were significantly associated with ICA PI (mean CERAD score: r = -0.32, p < 0.001). ICA PI was also significantly associated with total white matter lesion volume (τ = 0.19, p = 0.012) and periventricular white matter lesion volume (τ = 0.21, p = 0.007). Discussion: This is the first study to demonstrate that cerebrovascular duplex sonography can assess the risk for POD in elderly spine surgery patients. Increased ICA PI may indicate subcortical impairment, larger white matter lesion load, and lower white matter volume, predisposing factors for POD. Pre-operative cerebrovascular duplex sonography of the ICA is widely available, easy-to-use, and efficient, offering a promising screening method for POD risk. Increased ICA PI could supplement established predictors like age to adjust surgical and peri-operative procedures to individual risk profiles.
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The MHLC-C is a condition-specific instrument measuring the internal and external loci of control beliefs, adaptable to various health conditions. Translated into Swedish and Chinese, this study aims to translate the MHLC-C into German using the FACID-Method. The English version is validated and reliable; the German version requires these validation steps.
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OBJECTIVE: The role of ipsilateral descending motor pathways in voluntary movement of humans is still a matter of debate, with partly contradictory results. The aim of our study therefore was to examine the excitability of ipsilateral motor evoked potentials (iMEPs) regarding site and the specificity for unilateral and bilateral elbow flexion extension tasks. METHODS: MR-navigated transcranial magnetic stimulation mapping of the dominant hemisphere was performed in twenty healthy participants during tonic unilateral (iBB), bilateral homologous (bBB) or bilateral antagonistic elbow flexion-extension (iBB-cAE), the map center of gravity (CoG) and iMEP area from BB were obtained. RESULTS: The map CoG of the ipsilateral BB was located more anterior-laterally than the hotspot of the contralateral BB within the primary motor cortex, with a significant difference in CoG in iBB and iBB-cAE, but not bBB compared to the hotspot for the contralateral BB (each p < 0.05). However, different tasks had no effect on the size of the iMEPs. CONCLUSION: Our data demonstrated that excitability of ipsilateral and contralateral MEP differ spatially in a task-specific manner suggesting the involvement of different motor networks within the motor cortex.
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Potencial Evocado Motor , Lateralidade Funcional , Córtex Motor , Estimulação Magnética Transcraniana , Humanos , Potencial Evocado Motor/fisiologia , Masculino , Feminino , Adulto , Adulto Jovem , Córtex Motor/fisiologia , Lateralidade Funcional/fisiologia , Eletromiografia , Mapeamento EncefálicoRESUMO
BACKGROUND: New onset or worsening of a headache disorder substantially contributes to the disease burden of post-COVID-19. Its management poses a suitable means to enhance patients' participation in professional, social, and personal activities. Unfortunately, the pathophysiology of post-COVID-19 headaches is poorly understood. This study aims to investigate the role of (neuro-) inflammatory mechanisms in order to guide the development of anti-inflammatory treatment strategies. METHODS: We included patients from the interdisciplinary post-COVID-19 Rehabilitation Study (PoCoRe, n = 184 patients) run at a tertiary care university hospital, comprising patients with PCR-confirmed SARS-CoV-2 infection ≥ 6 weeks prior to their initial consultation. Patients reporting any headache since their infection were considered for this study (n = 93). These were interviewed and classified according to the International Classification of Headache Disorders, Third Edition (ICHD-3) by headache specialists. Patient sera were additionally analysed for levels of VILIP-1, MCP-1 (CCL2), sTREM-2, BDNF, TGF-ß1, VEGF, IL-6, sTREM-1, ß-NGF, IL-18, TNF-alpha, sRAGE, and CX3CL1 (Fractalkine). Markers of inflammation were compared between four groups of patients (none, unchanged, worsened, or new headache disorder). RESULTS: Patients reported experiencing more severe headaches (n = 17), new onset headaches (n = 46), unchanged headaches (n = 18), and surprisingly, some patients denied having any headaches (n = 12) despite self-reports. Serum levels of CX3CL1 were increased in the worsened (2145 [811-4866] pg/ml) and new onset (1668 [0-7357] pg/ml) headache group as compared to patients with no (1129 [0-5379] pg/ml) or unchanged (1478 [346-4332] pg/ml) headaches. Other markers also differed between groups, but most significantly between patients with worsened (TGF-ß1: 60 [0-310] pg/ml, VEGF: 328 [86-842] pg/ml, ß-NGF: 6 [3-38] pg/ml) as compared to unchanged headaches (TGF-ß1: 29 [0-77] pg/ml, VEGF: 183 [72-380] pg/ml, ß-NGF: 3 [2-89] pg/ml). The results did not differ between headache phenotypes. DISCUSSION: This study provides evidence that worsened or new headaches following COVID-19 are associated with pro-(neuro-)inflammatory profiles. This supports the use of anti-inflammatory treatment options in this population, especially in the subacute phase.
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Biomarcadores , COVID-19 , Humanos , COVID-19/complicações , COVID-19/sangue , Feminino , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Biomarcadores/sangue , Adulto , Microglia/metabolismo , Cefaleia/sangue , Cefaleia/etiologia , Idoso , SARS-CoV-2 , Estudos de Coortes , Citocinas/sangueRESUMO
BACKGROUND AND PURPOSE: Fatigue affects patients across a variety of neurological diseases, including chronic pain syndromes such as complex regional pain syndrome (CRPS). In CRPS, fatigue is often underestimated, as the focus lies in the assessment and managing of pain and sensorimotor deficits. This study aimed to investigate the prevalence, characteristics, and influence of fatigue on CRPS severity and quality of life in these patients. Such insights could enhance the clinical management of this challenging condition. METHODS: In this prospective study, 181 CRPS patients and 141 age and gender-matched individuals with injury but without chronic pain were interviewed using the Fatigue Scale for Motor and Cognitive Function to assess fatigue. Depressive symptoms and quality of life (QoL) were also evaluated as additional outcome measures. Statistical analysis was performed to examine differences in fatigue prevalence between the groups, as well as associations with CRPS severity, pain levels, and clinical phenotype. In addition, best subsets regression was used to identify the primary factors influencing QoL. Fatigue was tested in a mediation analysis as a mediator between pain and depression. RESULTS: CRPS patients showed significantly higher fatigue levels compared to controls (CRPS: 75 [IQR: 57-85] vs. controls: 39 [IQR: 25-57]). Based on the FSMC, 44.2% in the control group experienced fatigue, while 85% of patients with CRPS experienced fatigue (p < 0.001), of which 6% were mild, 15% moderate, and 67% severe. In CRPS severe fatigue was associated with higher pain intensities compared to no fatigue (pain at rest: p = 0.003; pain during movement: p = 0.007) or moderate fatigue (pain during movement: p = 0.03). QoL in our cohort was mainly influenced by pain (pain during movement: adj.R2 = 0.38; p < 0.001, pain at rest: Δadj.R2 = 0.02, p = 0.007) and depressive symptoms (Δadj.R2 = 0.12, p < 0.001). Subsequent analyses indicated that pain and depressive symptoms primarily impact QoL in CPRS whereas fatigue may exert an indirect influence by mediating the connection between pain and depression (p < 0.001). CONCLUSIONS: This pioneering study investigates the prevalence of fatigue in CRPS patients and its relation to disease characteristics. Our results indicate a high prevalence of severe fatigue, strongly correlated with pain intensity, and its importance in the interaction between pain and depression in CRPS. These findings underscore the significant role of fatigue as a disease factor in CRPS. Therefore, the evaluation of CRPS-related disability should include a standardized assessment of fatigue for comprehensive clinical management.
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Síndromes da Dor Regional Complexa , Fadiga , Qualidade de Vida , Humanos , Síndromes da Dor Regional Complexa/epidemiologia , Síndromes da Dor Regional Complexa/complicações , Síndromes da Dor Regional Complexa/fisiopatologia , Feminino , Masculino , Fadiga/etiologia , Fadiga/epidemiologia , Pessoa de Meia-Idade , Adulto , Estudos Prospectivos , Depressão/epidemiologia , Depressão/etiologia , Prevalência , Índice de Gravidade de Doença , IdosoRESUMO
BACKGROUND: Eptinezumab is a monoclonal antibody that targets calcitonin gene-related peptide (CGRP mAb) and is used for migraine prophylaxis. Efficacy data are mainly from clinical trials, real-world data are hardly available yet. Reimbursement policy in Germany leads to eptinezumab mainly being used in patients having failed pre-treatment with other CGRP mAb. To date, it is unclear whether eptinezumab is efficacious and well tolerated in this population and how the treatment response differs from patients who are naive to CGRP mAbs. METHODS: We analysed clinical routine data of 79 patients (episodic migraine (EM): n = 19; chronic migraine (CM): n = 60) from four different centres in Germany. All patients were treated with eptinezumab (100mg). Differences in monthly headache (MHD), migraine (MMD) and acute medication days (AMD) after three months were analysed. The correlation of response with the number of CGRP mAb failures was evaluated. Significance level has been corrected (alpha = 0.017). RESULTS: After three months MHD, MMD and AMD were significantly reduced. In EM, the median reduction for MHD was 4.0 days (IQR: -6.5 to -1.0; p = 0.001), for MMD 3.0 days (IQR: -5.5 to -1.5; p < 0.001) and for AMD 2.0 days (IQR: -5.0 to -0.5; p = 0.006). In CM, median reduction of MHD was 4 days (IQR: -8.0 to 0.0; p < 0.001), 3.0 days (IQR: -6.0 to-1.0; p < 0.001) for MMD and 1.0 day (IQR: -5.0 to 0.0; p < 0.001) for AMD. All patients were resistant to conventional preventive therapies and most to CGRP mAbs. Fourteen patients had never received a CGRP mAb and 65 patients had received at least one mAb without sufficient effectiveness and/or intolerability (one: n = 20, two: n = 28, three: n = 17). There was a significant association between the number of prior therapies and the 30% MHD responder rate (none: 78.6%, one: 45.0%, two: 32.1%, three: 23.5%, p = 0.010). Regarding tolerability, 10.4% (8/77) reported mild side effects. CONCLUSIONS: The effectiveness of eptinezumab is significantly reduced in patients who have not previously responded to other CGRP mAbs. However, limitations such as the retrospective nature of the analysis, the small sample size and the short treatment period with only the lower dose of eptinezumab must be considered when interpreting the results.
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Anticorpos Monoclonais Humanizados , Transtornos de Enxaqueca , Humanos , Transtornos de Enxaqueca/tratamento farmacológico , Transtornos de Enxaqueca/prevenção & controle , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Feminino , Masculino , Alemanha , Estudos Retrospectivos , Adulto , Pessoa de Meia-Idade , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/administração & dosagem , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/efeitos adversos , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/uso terapêutico , Resultado do Tratamento , IdosoRESUMO
BACKGROUND: To date, migraine is diagnosed exclusively based on clinical criteria, but fluid biomarkers are desirable to gain insight into pathophysiological processes and inform clinical management. We investigated the state-dependent profile of fluid biomarkers for neuroaxonal damage and microglial activation as two potentially relevant aspects in human migraine pathophysiology. METHODS: This exploratory study included serum and cerebrospinal fluid (CSF) samples of patients with migraine during the headache phase (ictally) (n = 23), between attacks (interictally) (n = 16), and age/sex-matched controls (n = 19). Total Tau (t-Tau) protein, glial fibrillary acidic protein (GFAP), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), and neurofilament light chain (NfL) were measured with the Neurology 4-plex kit on a Single Molecule Array SR-X Analyzer (Simoa® SR-X, Quanterix Corp., Lexington, MA). Markers of microglial activation, C-X3-C motif chemokine ligand 1 (CX3CL1) and soluble triggering receptor expressed on myeloid cells 2 (sTREM2), were assessed using an immunoassay. RESULTS: Concentrations of CX3CL1 but not sTREM2 were significantly increased both ictally and interictally in CSF but not in serum in comparison to the control cohort (p = 0.039). ROC curve analysis provided an AUC of 0.699 (95% CI 0.563 to 0.813, p = 0.007). T-Tau in serum but not in CSF was significantly increased in samples from patients taken during the headache phase, but not interictally (effect size: η2 = 0.121, p = 0.038). ROC analysis of t-Tau protein in serum between ictal and interictal collected samples provided an AUC of 0.729 (95% CI 0.558 to 0.861, p = 0.006). The other determined biomarkers for axonal damage were not significantly different between the cohorts in either serum or CSF. DISCUSSION: CX3CL1 in CSF is a novel potential fluid biomarker of migraine that is unrelated to the headache status. Serum t-Tau is linked to the headache phase but not interictal migraine. These data need to be confirmed in a larger hypothesis-driven prospective study.
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Transtornos de Enxaqueca , Proteínas tau , Humanos , Proteínas tau/líquido cefalorraquidiano , Estudos Prospectivos , Estudos de Casos e Controles , Estudos Transversais , Biomarcadores , Transtornos de Enxaqueca/diagnóstico , Cefaleia , Quimiocina CX3CL1RESUMO
Patients with chronic daily headaches (CDH) are often a diagnostic challenge and frequently undergo neuroimaging. One common underlying cause of CDH is idiopathic intracranial hypertension (IIH). However, certain neuroimaging abnormalities that suggest IIH, such as optic nerve sheath diameters (ONSD), pituitary gland height, and venous sinus diameter, require interpretation due to the absence of established normative values. Notably, intracranial pressure is known to varies with age, sex and weight, further complicating the determination of objectively abnormal findings within a specific patient group. This study aims to assist clinical neuroradiologists in differentiating neuroimaging results in CDH by providing weight-adjusted normative values for imaging characteristics of IIH. In addition to age and BMI we here assessed 1924 population-based T1-weighted MRI datasets of healthy participants for relevant MRI aspects of IIH. Association to BMI was analyzed using linear/logistic regression controlled for age and stratified for sex. ONSD was 4.3 mm [2.8; 5.9]/4.6 mm [3.6; 5.7] and diameter of transverse sinus was 4.67 mm [1.6; 6.5]/4.45 mm [3.0; 7.9]. Height of pituitary gland was 5.1 mm [2.2;8.1]/4.6 mm [1.9;7.1] for female and male respectively. Values generally varied with BMI with regression slopes spanning 0.0001 to 0.05 and were therefor presented as normative values stratified by BMI. Protrusion of ocular papilla, empty sella and transverse sinus occlusion were rare in total. Our data show an association between BMI and commonly used MRI features for diagnosing IIH. We provide categorized normative BMI values for ONSD, pituitary gland height, and transverse sinus diameter. This distinction helps objectively identify potential IIH indicators compared to regular population norms, enhancing diagnostic accuracy for suspected IIH patients. Notably, optic nerve head protrusion, empty sella, and transverse sinus occlusion are rare in healthy individuals, solidifying their importance as imaging markers regardless of BMI.
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Disco Óptico , Pseudotumor Cerebral , Humanos , Masculino , Feminino , Pseudotumor Cerebral/diagnóstico por imagem , Valores de Referência , Imageamento por Ressonância Magnética/métodos , Neuroimagem , Disco Óptico/patologiaRESUMO
BACKGROUND: Neuroinflammation and maladaptive neuroplasticity play pivotal roles in migraine (MIG), trigeminal autonomic cephalalgias (TAC), and complex regional pain syndrome (CRPS). Notably, CRPS shares connections with calcitonin gene-related peptide (CGRP) in its pathophysiology. This study aims to assess if the documented links between CRPS and MIG/TAC in literature align with clinical phenotypes and disease progressions. This assessment may bolster the hypothesis of shared pathophysiological mechanisms. METHODS: Patients with CRPS (n = 184) and an age-/gender-matched control group with trauma but without CRPS (n = 148) participated in this case-control study. Participant answered well-established questionnaires for the definition of CRPS symptoms, any headache complaints, headache entity, and clinical management. RESULTS: Patients with CRPS were significantly more likely to suffer from migraine (OR: 3.23, 95% CI 1.82-5.85), TAC (OR: 8.07, 95% CI 1.33-154.79), or non-classified headaches (OR: 3.68, 95% CI 1.88-7.49) compared to the control group. Patients with MIG/TAC developed CRPS earlier in life (37.2 ± 11.1 vs 46.8 ± 13.5 years), had more often a central CRPS phenotype (60.6% vs. 37.0% overall) and were three times more likely to report allodynia compared to CRPS patients with other types of headaches. Additionally, these patients experienced higher pain levels and more severe CRPS, which intensified with an increasing number of headache days. Patients receiving monoclonal antibody treatment targeting the CGRP pathway for headaches reported positive effects on CRPS symptoms. CONCLUSION: This study identified clinically relevant associations of MIG/TAC and CRPS not explained by chance. Further longitudinal investigations exploring potentially mutual pathomechanisms may improve the clinical management of both CRPS and primary headache disorders. TRIAL REGISTRATION: German Clinical Trials Register (DRKS00022961).
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Síndromes da Dor Regional Complexa , Transtornos de Enxaqueca , Humanos , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Estudos de Casos e Controles , Síndromes da Dor Regional Complexa/terapia , CefaleiaRESUMO
Objective: The study aimed to test the reliability of a semi-structured telephone interview for the classification of headache disorders according to the ICHD-3. Background: Questionnaire-based screening tools are often optimized for single primary headache diagnoses [e.g., migraine (MIG) and tension headache (TTH)] and therefore insufficiently represent the diagnostic precision of the ICHD-3, which limits epidemiological research of rare headache disorders. Brief semi-structured telephone interviews could be an effective alternative to improve classification. Methods: A patient population representative of different primary and secondary headache disorders (n = 60) was recruited from the outpatient clinic (HSA) of a tertiary care headache center. These patients completed an established population-based questionnaire for the classification of MIG, TTH, or trigeminal autonomic cephalalgia (TAC). In addition, they received a semi-structured telephone interview call from three blinded headache specialists individually. The agreement of diagnoses made either using the questionnaires or interviews with the HSA diagnoses was evaluated. Results: Of the 59 patients (n = 1 dropout), 24% had a second-order and 5% had a third-order headache disorder. The main diagnoses were as follows: frequent primary headaches with 61% MIG, 10% TAC, 9% TTH, and 5% rare primary and 16% secondary headaches. Second-order diagnosis was chronic migraine throughout, and third-order diagnoses were medication overuse headache and TTH. Agreement between main headaches from the HSA was significantly better for the telephone interview than for the questionnaire (questionnaire: κ = 0.330; interview: κ = 0.822; p < 0.001). Second-order diagnoses were not adequately captured by questionnaires, while there was a trend for good agreement with the telephone interview (κ = 0.433; p = 0.074). Headache frequency and psychiatric comorbidities were independent predictors of HSA and telephone interview agreement. Male sex, headache frequency, severity, and depressive disorders were independently predictive for agreement between the questionnaire and HSA. The telephone interview showed high sensitivity (≥71%) and specificity (≥92%) for all primary headache disorders, whereas the questionnaire was below 50% in either sensitivity or specificity. Conclusion: The semi-structured telephone interview appears to be a more reliable tool for accurate diagnosis of headache disorders than self-report questionnaires. This offers the potential to improve epidemiological headache research and care even in underserved areas.
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BACKGROUND: Migraine is a disorder associated with neuropeptide release, pain and inflammation. Tau protein has recently been linked to inflammatory diseases and can be influenced by neuropeptides such as CGRP, a key neurotransmitter in migraine. Here, we report serum concentrations of total-tau protein in migraine patients and healthy controls. METHODS: In this cross-sectional study, interictal blood samples from n = 92 patients with episodic migraine (EM), n = 93 patients with chronic migraine (CM), and n = 42 healthy matched controls (HC) were studied. We assessed serum total-tau protein (t-tau) and for comparison neurofilament light chain protein (NfL), glial fibrillary acidic protein (GFAP), and ubiquitin carboxy-terminal hydrolase L (UCH-L1) concentrations using the Neurology 4-plex kit, on a single molecule array HD-X Analyzer (Quanterix Corp Lexington, MA). Matched serum/cerebrospinal fluid (CSF) samples were used for post-hoc evaluations of a central nervous system (CNS) source of relevant findings. We applied non-parametric tests to compare groups and assess correlations. RESULTS: Serum t-tau concentrations were elevated in EM [0.320 (0.204 to 0.466) pg/mL] and CM [0.304 (0.158 to 0.406) pg/mL] patients compared to HC [0.200 (0.114 to 0.288) pg/mL] (p = 0.002 vs. EM; p = 0.025 vs. CM). EM with aura [0.291 (0.184 to 0.486 pg/mL); p = 0.013] and EM without aura [0.332 (0.234 to 0.449) pg/mL; p = 0.008] patients had higher t-tau levels than HC but did not differ between each other. Subgroup analysis of CM with/without preventive treatment revealed elevated t-tau levels compared to HC only in the non-prevention group [0.322 (0.181 to 0.463) pg/mL; p = 0.009]. T-tau was elevated in serum (p = 0.028) but not in cerebrospinal fluid (p = 0.760). In contrast to t-tau, all proteins associated with cell damage (NfL, GFAP, and UCH-L1), did not differ between groups. DISCUSSION: Migraine is associated with t-tau elevation in serum but not in the CSF. Our clinical study identifies t-tau as a new target for migraine research.
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Transtornos de Enxaqueca , Proteínas tau , Humanos , Estudos Transversais , Estudos de Casos e Controles , Sistema Nervoso CentralRESUMO
Advances in spine surgery enable technically safe interventions in older patients with disabling spine disease, yet postoperative delirium (POD) poses a serious risk for postoperative recovery. This study investigates biomarkers of pro-neuroinflammatory states that may help objectively define the pre-operative risk for POD. This study enrolled patients aged ≥60 scheduled for elective spine surgery under general anesthesia. Biomarkers for a pro-neuroinflammatory state included S100 calcium-binding protein ß (S100ß), brain-derived neurotrophic factor (BDNF), Gasdermin D, and the soluble ectodomain of the triggering receptor expressed on myeloid cells 2 (sTREM2). Postoperative changes of Interleukin-6 (IL-6), Interleukin-1ß (IL-1ß), and C-reactive protein (CRP) were assessed as markers of systemic inflammation preoperatively, intraoperatively, and early postoperatively (up to 48 h). Patients with POD (n = 19, 75.7 ± 5.8 years) had higher pre-operative levels of sTREM2 (128.2 ± 69.4 pg/mL vs. 97.2 ± 52.0 pg/mL, p = 0.049) and Gasdermin D (2.9 ± 1.6 pg/mL vs. 2.1 ± 1.4 pg/mL, p = 0.29) than those without POD (n = 25, 75.6 ± 5.1 years). STREM2 was additionally a predictor for POD (OR = 1.01/(pg/mL) [1.00-1.03], p = 0.05), moderated by IL-6 (Wald-χ2 = 4.06, p = 0.04). Patients with POD additionally showed a significant increase in IL-6, IL-1ß, and S100ß levels on the first postoperative day. This study identified higher levels of sTREM2 and Gasdermin D as potential markers of a pro-neuroinflammatory state that predisposes to the development of POD. Future studies should confirm these results in a larger cohort and determine their potential as an objective biomarker to inform delirium prevention strategies.
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Delírio , Delírio do Despertar , Humanos , Idoso , Interleucina-6/metabolismo , Delírio/diagnóstico , Delírio/etiologia , Gasderminas , Complicações Pós-Operatórias/etiologia , Estudos Prospectivos , Biomarcadores/metabolismoRESUMO
STUDY DESIGN: Prospective quasi-experimental observational study. OBJECTIVE: The objective of this study was to evaluate whether duration of surgery is a modifiable risk factor for postoperative delirium (POD) after spine surgery and explore further modifiable risk factors. In addition, we sought to investigate the association between POD and postoperative cognitive dysfunction and persistent neurocognitive disorders. SUMMARY OF BACKGROUND DATA: Advances in spine surgery enable technically safe interventions in elderly patients with disabling spine disease. The occurrence of POD and delayed neurocognitive complications ( e.g. postoperative cognitive dysfunction/persistent neurocognitive disorder) remain a concern since these contribute to inferior functional outcomes and long-term care dependency after spine surgery. MATERIALS AND METHODS: This prospective single-center study recruited patients aged 60 years or above and scheduled for elective spine surgery between February 2018 and March 2020. Functional (Barthel Index, BI) and cognitive outcomes [Consortium to Establish a Registry for Alzheimer's Disease (CERAD) test battery; telephone Montréal Cognitive Assessment] were assessed at baseline, three (V3), and 12 months postoperatively. The primary hypothesis was that the duration of surgery predicts POD. Multivariable predictive models of POD included surgical and anesthesiological parameters. RESULTS: Twenty-two percent of patients developed POD (n=22/99). In a multivariable model, duration of surgery [OR adj =1.61/h (95% CI, 1.20-2.30)], age [OR adj =1.22/yr (95% CI, 1.10-1.36)], and baseline deviations of intraoperative systolic blood pressure [25th percentile: OR adj =0.94/mm Hg (95% CI, 0.89-0.99); 90th percentile: OR adj =1.07/mm Hg (95% CI, 1.01-1.14)] were significantly associated with POD. Postoperative cognitive scores generally improved (V3, ΔCERAD total z -score: 0.22±0.63). However, this positive group effect was counteracted by POD [beta: -0.87 (95% CI, -1.31 to 0.42)], older age [beta: -0.03/yr (95% CI, -0.05 to 0.01)], and lack of functional improvement [ΔBI; beta: -0.04/point (95% CI, -0.06 to 0.02)]. Cognitive scores at twelve months remained inferior in the POD group, adjusted for baseline cognition/age. CONCLUSIONS: This study identified distinct neurocognitive effects after spine surgery, which are influenced by perioperative risk factors. Potential cognitive benefits are counteracted by POD, rendering its prevention critical in an aging population.
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Delírio , Complicações Cognitivas Pós-Operatórias , Idoso , Humanos , Delírio/etiologia , Estudos Prospectivos , Pressão Sanguínea , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Fatores de Risco , Transtornos Neurocognitivos/complicaçõesRESUMO
(1) Background: COVID-19 is often associated with significant long-term symptoms and disability, i.e., the long/post-COVID syndrome (PCS). Even after presumably mild COVID-19 infections, an increasing number of patients seek medical help for these long-term sequelae, which can affect various organ systems. The pathogenesis of PCS is not yet understood. Therapy has so far been limited to symptomatic treatment. The Greifswald Post COVID Rehabilitation Study (PoCoRe) aims to follow and deeply phenotype outpatients with PCS in the long term, taking a holistic and comprehensive approach to the analysis of their symptoms, signs and biomarkers. (2) Methods: Post-COVID outpatients are screened for symptoms in different organ systems with a standardized medical history, clinical examination, various questionnaires as well as physical and cardiopulmonary function tests. In addition, biomaterials are collected for the analysis of immunomodulators, cytokines, chemokines, proteome patterns as well as specific (auto)antibodies. Patients are treated according to their individual needs, adhering to the current standard of care. PoCoRe's overall aim is to optimize diagnostics and therapy in PCS patients.
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BACKGROUND: Post-stroke delirium (PSD) is a modifiable predictor for worse outcome in stroke. Knowledge of its risk factors would facilitate clinical management of affected patients, but recently updated national guidelines consider available evidence insufficient. AIMS: The study aimed to establish risk factors for PSD incidence and duration using high-frequency screening. METHODS: We prospectively investigated patients with ischemic stroke admitted within 24 h. Patients were screened twice daily for the presence of PSD throughout the treatment period. Sociodemographic, treatment-related, and neuroimaging characteristics were evaluated as predictors of either PSD incidence (odds ratios (OR)) or duration (PSD days/unit of the predictor, b), using logistic and linear regression models, respectively. RESULTS: PSD occurred in 55/141 patients (age = 73.8 ± 10.4 years, 61 female, National Institutes of Health Stroke Scale (NIHSS) = 6.4 ± 6.5). Age (odds ratio (OR) = 1.06 (95% confidence interval (CI): 1.02-1.10), b = 0.08 (95% CI = 0.04-0.13)), and male gender (b = 0.99 (95% CI = 0.05-1.93)) were significant non-modifiable risk factors. In a multivariable model adjusted for age and gender, presence of pain (OR < sub > mvar = 1.75 (95% CI = 1.12-2.74)), urinary catheter (OR < sub > mvar = 3.16 (95% CI = 1.10-9.14)) and post-stroke infection (PSI; OR < sub > mvar = 4.43 (95% CI = 1.09-18.01)) were predictors of PSD incidence. PSD duration was impacted by presence of pain (b < sub > mvar = 0.49 (95% CI = 0.19-0.81)), urinary catheter (b < sub > mvar = 1.03 (95% CI = 0.01-2.07)), intravenous line (b < sub > mvar = 0.36 (95% CI = 0.16-0.57)), and PSI (b < sub > mvar = 1.60 (95% CI = 0.42-2.78)). PSD (OR = 3.53 (95% CI = 1.48-5.57)) and PSI (OR = 5.29 (95% CI = 2.92-7.66)) independently predicted inferior NIHSS at discharge. Insular and basal ganglia lesions increased the PSD risk about four- to eight-fold. DISCUSSION/CONCLUSION: This study identified modifiable risk factors, the management of which might reduce the negative impact PSD has on outcome.
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Delírio , Acidente Vascular Cerebral , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/diagnóstico , Incidência , Fatores de Risco , Delírio/diagnóstico , Delírio/epidemiologia , Delírio/etiologia , Dor , Depressão/diagnósticoRESUMO
Neuroinflammatory mechanisms and maladaptive neuroplasticity underlie the progression of complex regional pain syndrome (CRPS), which is prototypical of central neuropathic pain conditions. While cortical maladaptive alterations are well described, little is known about the contribution of the brainstem to the pathophysiology. This study investigates the role of pain-modulatory brainstem pathways in CRPS using the nociceptive blink reflex (nBR), which not only provides a direct read-out of brainstem excitability and habituation to painful stimuli but may also be suitable for use as a diagnostic biomarker for CRPS. Thirteen patients with CRPS and thirteen healthy controls (HCs) participated in this prospective case-control study investigating the polysynaptic trigemino-cervical (R2) nBR response. The R2 area and its habituation were assessed following repeated supraorbital electrical stimulation. Between-group comparisons included evaluations of diagnostic characteristics as a potential biomarker for the disease. Patients with CRPS showed a substantial decrease in habituation on the stimulated (Cohen's d: 1.3; p = 0.012) and the non-stimulated side (Cohen's d: 1.1; p = 0.04). This is the first study to reveal altered nBR habituation as a pathophysiological mechanism and potential diagnostic biomarker in CRPS. We confirmed previous findings of altered nBR excitability, but the diagnostic accuracy was inferior. Future studies should investigate the nBR as a marker of progression to central mechanisms in CRPS and as a biomarker to predict treatment response or prognosis.
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Síndromes da Dor Regional Complexa , Dor , Humanos , Estudos de Casos e Controles , Tronco Encefálico , PiscadelaRESUMO
Vascular risk factors may predispose to post-stroke delirium (PSD). A systematic review and meta-analysis were performed by searching PubMed, Web of Science, and Scopus. The primary outcome was the prevalence of vascular risk factors in PSD vs. non-PSD patients. Odds ratios (ORs) with 95% confidence intervals (CIs) and mean differences (MDs) with 95% CIs were calculated for categorical and continuous variables, respectively. Fixed effects or random effects models were used in case of low- or high-statistical heterogeneity, respectively. We found an increased prevalence of atrial fibrillation (OR = 1.74, p = 0.0004), prior stroke (OR = 1.48, p < 0.00001), coronary artery disease (OR = 1.48, p < 0.00001), heart failure (OR = 2.01, p < 0.0001), and peripheral vascular disease (OR = 2.03, p < 0.00001) in patients with vs. without PSD. PSD patients were older (MD = 5.27 y, p < 0.00001) compared with their non-PSD counterparts. Advanced age, atrial fibrillation, prior stroke, coronary artery disease, heart failure, and peripheral vascular disease appeared to be significantly associated with PSD.
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BACKGROUND: Understanding how SARS-CoV-2 affects respiratory centres in the brainstem may help to preclude assisted ventilation for patients in intensive care setting. Viral invasion appears unlikely, although autoimmunity has been implicated, the responsible antigens remain unknown. We previously predicted the involvement of three epitopes within distinct brainstem proteins: disabled homolog 1 (DAB1), apoptosis-inducing-factor-1 (AIFM1), and surfeit-locus-protein-1 (SURF1). METHODS: Here, we used microarrays to screen serum from COVID-19 patients admitted to intensive care and compared those with controls who experienced mild course of the disease. FINDINGS: The results confirm the occurrence of IgG and IgM antibodies against the hypothesised epitopes in COVID-19 patients. Importantly, while IgM levels were similar in both groups, IgG levels were significantly elevated in severely ill patients compared to controls, suggesting a pathogenic role of IgG. INTERPRETATION: The newly discovered anti-neuronal antibodies might be promising markers of severe disease and the targeted peptide epitopes might be used for targeted immunomodulation. Further work is needed to determine whether these antibodies may play a role in long-COVID. FUNDING: AF, CF and PR received support from the German Research Foundation (grants FL 379/22-1, 327654276-SFB 1315, FR 4479/1-1, PR 1274/8-1). SH, DR, and DB received support from the Ministry of Economy, State of Mecklenburg Western Pomerania, Germany (grant COVIDPROTECT: "Optimisation of diagnostic and therapeutic pathways for COVID-19 patients in MV"). SH received support from the Research Group Molecular Medicine University of Greifswald (FVMM, seed funding FOVB-2021-01). AV received support from the Else Kröner Fresenius Foundation and the Alzheimer Research Initiative.
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COVID-19 , Anticorpos Antivirais , Tronco Encefálico , COVID-19/complicações , Epitopos , Humanos , Imunoglobulina G , Imunoglobulina M , SARS-CoV-2 , Síndrome de COVID-19 Pós-AgudaRESUMO
INTRODUCTION: A substantial number of patients diagnosed with COVID-19 experience long-term persistent symptoms. First evidence suggests that long-term symptoms develop largely independently of disease severity and include, among others, cognitive impairment. For these symptoms, there are currently no validated therapeutic approaches available. Cognitive training interventions are a promising approach to counteract cognitive impairment. Combining training with concurrent transcranial direct current stimulation (tDCS) may further increase and sustain behavioural training effects. Here, we aim to examine the effects of cognitive training alone or in combination with tDCS on cognitive performance, quality of life and mental health in patients with post-COVID-19 subjective or objective cognitive impairments. METHODS AND ANALYSIS: This study protocol describes a prospective randomised open endpoint-blinded trial. Patients with post-COVID-19 cognitive impairment will either participate in a 3-week cognitive training or in a defined muscle relaxation training (open-label interventions). Irrespective of their primary intervention, half of the cognitive training group will additionally receive anodal tDCS, all other patients will receive sham tDCS (double-blinded, secondary intervention). The primary outcome will be improvement of working memory performance, operationalised by an n-back task, at the postintervention assessment. Secondary outcomes will include performance on trained and untrained tasks and measures of health-related quality of life at postassessment and follow-up assessments (1 month after the end of the trainings). ETHICS AND DISSEMINATION: Ethical approval was granted by the Ethics Committee of the University Medicine Greifswald (number: BB 066/21). Results will be available through publications in peer-reviewed journals and presentations at national and international conferences. TRIAL REGISTRATION NUMBER: NCT04944147.